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Phenoxy acids for the treatment of neuromuscular disorders

A technology selected from compounds, applied in the field of treatment, prevention and/or improvement of neuromuscular disorders, improvement and/or prevention of neuromuscular disorders, capable of solving problems such as harmful long-term consequences

Pending Publication Date: 2020-08-04
NMD PHARMA AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Unfortunately, all currently used drug regimens for the treatment of myasthenia gravis are associated with deleterious long-term consequences despite studies identifying new treatments (Gilhus, N.E. New England Journal of Medicine, 2016, 375, 2570-2581) (Howard, J.F.Jr. Adverse drug effects on neuromuscular transmission. Semin Neurol. 1990, 10, 89-102)

Method used

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  • Phenoxy acids for the treatment of neuromuscular disorders
  • Phenoxy acids for the treatment of neuromuscular disorders
  • Phenoxy acids for the treatment of neuromuscular disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1065] Example 1: Synthesis of (S)-2-(4-bromo-2-ethynylphenoxy)propionic acid; synthetic strategy following General Method A

[1066]

[1067] (S)-Methyl 2-(4-bromo-2-iodophenoxy)propionate (1.2)

[1068] To (R)-methyl 2-hydroxypropionate (1.1) (1 mmol), 4-bromo-2-iodophenol (1 mmol) and triphenylphosphine (1.2 mmol) in THF (15 mL) at 0 °C over 20 minutes ) solution was added DIAD (1.2 mmol) dropwise. The solution was stirred for an additional 15 minutes at 0°C. The bright yellow solution was warmed to room temperature and stirred overnight. The volatiles were removed in vacuo to give a dark orange oil. The crude product was purified by silica gel chromatography (0-10% EtOAc / hexanes) to afford (S)-methyl 2-(4-bromo-2-iodophenoxy)propanoate (1.2 ) (75% yield). 1 H NMR (300MHz, CDCl 3 )δ7.91(d,1H); 7.37(dd,1H); 6.58(d,1H); 4.73(q,1H); 3.77(s,3H); 1.70(d,3H); ES-MS:386 [M+1].

[1069] (S)-Methyl 2-(4-bromo-2-ethynylphenoxy)propionate (1.3)

[1070] 1) Methyl (S)-2...

Embodiment 2

[1075] Example 2: Synthesis of (2S)-2-(4-bromo-2-vinylphenoxy)propionic acid; synthetic strategy following General Method A

[1076]

[1077] 4-Bromo-2-vinylphenol (2.2)

[1078] To a solution of sodium hydride (6 mmol) in THF (15 mL) at 0 °C was added methyl-triphenylphosphonium bromide (2 mmol), and the mixture was stirred for 1 h, then 5 in THF was introduced dropwise over 20 min. -Bromo-2-hydroxybenzaldehyde (2.1) (1 mmol). The solution was stirred for an additional 15 minutes at 0°C. The bright yellow solution was warmed to room temperature and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride, and the aqueous solution was extracted with EtOAc (2 x 100 mL). The combined organics were subjected to MgSO 4 Dried and adsorbed onto silica. The crude product was purified by silica gel chromatography (0-10% EtOAc / hexanes) to afford 4-bromo-2-vinylphenol (2.2) (65% yield) as a colorless liquid. 1 H NMR (300MHz, CDCl 3 )δ7.58(d,1H);7...

Embodiment 3

[1084] Example 3: Synthesis of (2S)-2-(4-bromo-2-cyclobutylphenoxy)propionic acid and its sodium salt, following the synthesis strategy of General Method A

[1085]

[1086] 2-(1-Hydroxycyclobutyl)phenol (3.2)

[1087] 2-Bromophenol (3.1) (8.04 mL, 69.4 mmol) was dissolved in dry diethyl ether (144 mL) and cooled to -78°C under nitrogen. N-Butyllithium (2.5M in hexane) (61.0 mL, 153 mmol) was added dropwise, keeping the reaction temperature below -70°C. Once the addition was complete, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stirred for 2.5 hours. The reaction mixture was cooled to -78°C, then cyclobutanone (5.18ml, 69.4mmol) was added dropwise while keeping the reaction temperature below -70°C. Once the addition was complete, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched into ice-cold ammonium chloride soluti...

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PUM

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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 and their use for the treatment, amelioration and / or prevention of neuromuscular disorders, including reversal of drug-induced neuromuscular blockade. 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 is essentially at rest, and contractile activity occurs only in response to commands from the central nervous system (CNS). This neuronal command takes the form of an action potential, which is transmitted from the brain to the muscle fiber in several steps. The neuromuscular junction (NMJ) is a highly specializ...

Claims

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Application Information

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IPC IPC(8): A61K31/192A61K31/216A61P21/00A61P21/04
CPCA61K31/192A61K31/216A61P21/04A61P21/00Y02A50/30C07C2601/02C07C59/72C07C2601/04C07C59/68C07C2601/10C07C59/90C07B2200/05C07C69/736C07C69/738C07C255/37C07B2200/07
Inventor L·J.S.克努森N·凯利T·霍尔姆彼得森C·埃尔斯伯格奥勒森M·拉贝尔P·B·利特尔M·伊库珀N·萨瓦斯瓦迪D·杜德库拉R·艾塔杰
Owner NMD PHARMA AS
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