Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

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
View PDF1 Cites 0 Cited by
  • 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 the treatment of choice for many conditions involving neuromuscular damage today

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • 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 ...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
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
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com