Compounds for the treatment of neuromuscular disorders

A technology of compounds, solvates, in the field of compounds for the treatment of neuromuscular disorders

Pending Publication Date: 2022-02-01
NMD PHARMA AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite the serious side effects of AChE inhibitors, these drugs are still...

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

[0825] Example 1: Synthesis of (2S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]propionic acid

[0826]

[0827] Step 1: Synthesis of (S)-methyl 2-(2-acetyl-4-bromophenoxy)propionate 2

[0828] Under stirring, to (R)-methyl 2-hydroxypropionate 1 (3.07g, 29.44mmol), 1-(5-bromo-2-hydroxyphenyl)ethanone (6.33g, 29.44 mmol) and TPP (9.28 g, 35.38 mmol) in 150 mL of DCM was slowly added DIAD (6.96 mL). The ice bath was then removed, and the mixture was stirred at room temperature overnight, then concentrated under reduced pressure. After removing the solvent, the residue was passed through a short silica gel column (Hexane-EtOAc, 25:1, 10:1) to give the desired product 2 (7.9 g, 89%) as a pale yellow oil.

[0829] 1 H NMR (300MHz, CDCl 3 )δ7.83(d,1H); 7.48(dd,1H); 6.67(d,1H); 4.87(q,1H); 3.75(s,3H); 2.67(s,3H); 1.68(d,3H ).

[0830] Step 2: Synthesis of (S)-methyl 2-(4-bromo-2-(1,1-difluoroethyl)phenoxy)propionate 3

[0831] To (S)-methyl 2-(2-acetyl-4-bromophenoxy)propio...

Embodiment 2

[0838] Example 2: Synthesis of (S)-2-(4-bromo-2-(1,1-difluoropropyl)phenoxy)propionic acid

[0839] This compound was prepared as described in Example 1.

[0840] (S)-Methyl 2-(4-bromo-2-propionylphenoxy)propionate

[0841] 1H NMR (300MHz, CDCl3) δ7.84(d,1H),7.52(dd,1H),6.72(d,1H),4.91(q,1H),3.82(s,3H),3.16–3.07(m, 2H), 1.73(d,3H), 1.23(t,3H).

[0842] (S)-Methyl 2-(4-bromo-2-(1,1-difluoropropyl)phenoxy)propionate

[0843] 1H NMR (300MHz, CDCl3) δ7.48(dd,1H),7.27(dd,1H),6.50(d,1H),4.63(q,1H),3.59(s,3H),3.34–3.14(m, 2H), 1.48(d, 3H), 0.79(t, 3H). 19 F NMR (300 MHz, CDCl3) δ -93.5 and -99 ppm.

[0844] (S)-2-(4-Bromo-2-(1,1-difluoropropyl)phenoxy)propionic acid

[0845] 1H NMR (300MHz, CDCl3) δ9.69(br s,1H),7.45(dd,1H),7.27(dd,1H),6.52(d,1H),4.63(q,1H),2.9–2.05(m ,2H), 1.50(d,3H), 0.74(t,3H). 19 F NMR (300MHz, CDCl3) δ-94 and -98ppm.

[0846] MS(ES-): m / z 321.2(M-H) - . HPLC retention time: 13.56min

[0847] Chiral SCF method 1: 1.09 min (>97.2% e.e.). (R)-ena...

Embodiment 3

[0848] Example 3: Synthesis of (R)-2-(4-bromo-2-(1,1-difluoropropyl)phenoxy)-3-fluoropropionic acid

[0849]

[0850] Synthesis of (S)-1-(benzyloxy)-3-fluoropropan-2-ol

[0851] (R)-benzyl glycidyl ether (200g, 1.22mol, 1.0eq.), CsF (191g, 1.26mol, 1.0eq.) and KHF 2 (99g, 1.27mol, 1.0eq.) at RT and N 2 Add to the flask. Add 1M TBAF in THF (3.91 L, 3.2 eq.) [no exotherm], and react at RT and N 2 Stir down. The reaction was heated to 65 °C over 1 h 30 min and stirred at 65 °C for 21 h at which time LC showed 76% product. Cool the reaction to 25 °C and add KHF 2 (9.9 g, 0.13 mol, 0.1 eq) and CsF (19.1 g, 0.13 mol, 0.1 eq). The reaction was heated to 65°C for 18 hours at which time LC showed 77% product. The reaction was cooled to room temperature and H was added over 5 min 2 O (3.90 L) [mildly exothermic]. The aqueous phase was extracted with toluene (3x1.00L). The combined organic extracts were washed with 20% K 2 CO 3 (aq)(1.90L) and H 2 O (2 x 1.90 L) washes ...

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Abstract

The present disclosure 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 can inhibit the ClC-1 ion channel.

Description

technical field [0001] The present disclosure relates to compounds for treating, ameliorating and / or preventing neuromuscular disorders, including reversing drug-induced neuromuscular blockade, and their usefulness in treating, ameliorating, and / or preventing neuromuscular disorders, including reversing drug-induced neuromuscular blockade use in . Compounds as defined herein inhibit the ClC-1 ion channel. The present disclosure further relates to methods of treating, preventing and / or ameliorating neuromuscular disorders by administering said compositions 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 potential, which t...

Claims

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Application Information

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IPC IPC(8): C07C59/68C07C51/09C07C67/31C07C67/307C07C69/712C07C51/295C07C51/41C07C41/26C07C43/23C07C67/14C07C67/287C07C67/28C07C69/63C07C45/64C07C49/84A61K31/19A61P21/04A61P21/00A61P3/10A61P25/00
CPCC07C59/68C07C51/09C07C67/31C07C67/307C07C51/295C07C51/412C07C41/26C07C67/14C07C67/287C07C67/28C07C45/64A61P21/04A61P21/00A61P3/10A61P25/00C07B2200/07C07C69/712C07C49/84C07C69/63C07C43/23C07C2601/02C07C69/708C07C255/57C07C205/42C07D277/22A61K31/192A61K31/12A61K31/426C07C2601/04C07C59/70C07C59/72C07C255/54C07D277/24
Inventor L·J.S.克努森N·凯利M·B·斯高夫A·里萨格N·萨瓦斯瓦迪
Owner NMD PHARMA AS
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