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Water-soluble cucurbit [8] urea sulfonate derivative as well as preparation method and application thereof

A technology of ureasulfonate and urea derivatives, which is applied in the field of new antagonist water-soluble cucurbit [8] ureasulfonate derivatives and its preparation, which can solve neuromuscular blockade, irreversibility, lack of specific antagonistic drugs, etc. problem, to achieve strong binding ability and low animal acute toxicity

Active Publication Date: 2021-10-29
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Sugammadex sodium can specifically bind rocuronium bromide and vecuronium bromide in the aqueous phase through the desolvation effect in the field of supramolecular chemistry, effectively reversing the corresponding neuromuscular blockade, so it is widely used in the world The sales market share has risen rapidly, but it cannot reverse the neuromuscular blockade induced by cis-atracurium, pancuronium bromide, etc. clinically
[0007] Regrettably, at present, for the neuromuscular blockade caused by cisbesylate atracurium and long-acting neuromuscular blocker pancuronium bromide, which account for the highest share of the global neuromuscular blocker market, Xinsi’s drug is still used. Traditional antagonists such as the Ming Dynasty have been reversed, and there is a lack of corresponding specific antagonistic drugs

Method used

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  • Water-soluble cucurbit [8] urea sulfonate derivative as well as preparation method and application thereof
  • Water-soluble cucurbit [8] urea sulfonate derivative as well as preparation method and application thereof
  • Water-soluble cucurbit [8] urea sulfonate derivative as well as preparation method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0049] Example 1: Preparation of water-soluble cucurbit [8] urea sulfonate derivatives. Its reaction route is as follows figure 1 shown.

[0050] Schematic diagram of the structure of water-soluble cucurbit [8] urea sulfonate derivatives (see figure 1 ), among them, with CB[8]-(Y 3 )-2 molecule as an example to illustrate the preparation process of water-soluble cucurbit [8] urea derivatives. Refer to literature reports ( J. Am. Chem. Soc. 2003, 125 , 10186-10187), oxidized cucurbit [8] urea with 2 times the equivalent of potassium persulfate to obtain the corresponding hydroxylated cucurbit [8] urea CB [8]-(OH)-2, which undergoes a proton exchange reaction with a strong base, The corresponding oxygen anion cucurbit[8]uril was obtained, and then the side chain modified cucurbit[8]uril was obtained through nucleophilic substitution reaction. The specific operation is: weigh CB[8]-(OH)-2 (1.362 g, 1 mmol) and sodium tert-butoxide (1.922 g, 20 mmol) respectively and unifor...

Embodiment 2

[0052] Example 2: NMR titration experiment of water-soluble cucurbit [8] urea sulfonate derivatives and neuromuscular blocking agents.

[0053] With CB[8]-(Y 3 )-2 molecules and cis-atracurium in heavy water NMR titration experiment as an example to illustrate the water-soluble cucurbit [8] urea sulfonate derivatives of the present invention and neuromuscular blocking agent in aqueous NMR titration experiment procedure. The specific operation is: prepare cis-besylate atracurium (1 mM) and CB[8]-(Y 3 )-2 (5 mM) heavy aqueous solution, gradually drop CB[8]-(Y 3 )-2 solution, and measure the proton nuclear magnetic resonance spectrum (see image 3 ). This study shows that after the water-soluble cucurbit [8] urea sulfonate derivatives of the present invention are combined with neuromuscular blocking agents, the chemical shifts of the latter's characteristic NMR peaks change and the resolution decreases (see Figure 3~Figure 6 ), which shows that the water-soluble cucurbit [8...

Embodiment 3

[0054] Example 3: Determination of the binding constant of water-soluble cucurbit [8] urea sulfonate derivatives and neuromuscular blocking agents.

[0055] With CB[8]-(Y 3The determination of the binding constant of )-2 molecule and cis-atracurium besylate is taken as an example to illustrate the experimental process of the determination of the binding constant of water-soluble cucurbit [8] urea sulfonate derivatives and neuromuscular blocking agents. We tested it by UV-Vis absorption spectroscopic titration using the competition method in which all solutions were 2 PO 4 Buffer (10 mM, pH=7.4) was carried out as solvent, and the titration was completed in two steps. The specific operation is as follows: in the first step, we choose proflavin hemisulfate as the competition object, and prepare 10 μM proflavin hemisulfate solution A, 500 μMCB[8]-(Y 3 )-2 and 10 μM protoflavin hemisulfate mixed solution B, add 2 mL of the above solution A to a quartz cuvette and gradually drop...

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Abstract

The invention belongs to the technical field of biological medicine, and relates to a water-soluble cucurbit [8] urea sulfonate derivative serving as a neuromuscular blocker antagonist as well as a preparation method and application thereof. The water-soluble cucurbit [8] urea sulfonate derivative is obtained by taking cucurbit [8] urea as a raw material and introducing a water-soluble side chain group through a chemical reaction; a hydrophobic cavity of the water-soluble cucurbit [8] urea sulfonate derivative can be combined with neuromuscular blockers including cis-asatracurium besylate, rocuronium bromide, vecuronium bromide and pantocuronium bromide in a water phase through interaction of hydrophobic agents, so that antagonism is achieved. Experiments show that the water-soluble cucurbit [8] uril derivative can efficiently antagonize various neuromuscular blockers in a living body, is high in universality and low in biotoxicity, and is an ideal neuromuscular blocker antagonist.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and specifically relates to a water-soluble cucurbit [8] urea sulfonate derivative of a novel antagonist capable of antagonizing various neuromuscular blocking agents in vivo and a preparation method thereof. Background technique [0002] Neuromuscular blocking agents: Every year, more than 400 million patients receive neuromuscular blocking agents (NMBAs) or muscle relaxants during anesthesia in operating rooms and intensive care units. Neuromuscular blocking agents are divided into two types: depolarizing and nondepolarizing. Depolarizing neuromuscular blocking agents bind to N2 choline receptors on the motor nerve endplate membrane, reducing or eliminating the response of muscle cells to acetylcholine; non-depolarizing neuromuscular blocking agents can compete with acetylcholine for bone N2 choline receptors on the motor endplate membrane, leading to skeletal muscle relaxation. Clinicall...

Claims

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Application Information

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IPC IPC(8): C07D487/22A61P21/00A61K31/4188
CPCC07D487/22A61P21/00Y02P20/55
Inventor 黎占亭张丹维刘鸿琨王辉周伟马达
Owner FUDAN UNIV
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