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O-desmethylvenlafaxine phenyl ether compound and preparation method and application thereof

A technology for desmethylvenlafaxine and a compound is applied in the field of O-desmethylvenlafaxine derivatives, which can solve the problems of less research on pain uses, pain and distress of patients and the like

Active Publication Date: 2019-05-17
YANTAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Long-term use of O-desmethylvenlafaxine can cause a series of adverse reactions, especially adverse reactions of sedation and drowsiness. These adverse reactions have become an important factor limiting the use of the drug, bringing pain and distress to patients
[0004] In addition, the current research on O-desmethylvenlafaxine is mostly focused on depression, and there are fewer studies on the use of pain

Method used

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  • O-desmethylvenlafaxine phenyl ether compound and preparation method and application thereof
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  • O-desmethylvenlafaxine phenyl ether compound and preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031]

[0032] step 1:

[0033] Add 115g of O-desvenlafaxine, 200g of 30% potassium methoxide solution, 100ml of methanol into a 2L single-necked bottle, and put it in a water bath at 85°. After reflux for 60min, remove the solvent under reduced pressure to obtain an off-white solid powder.

[0034] Step 2:

[0035] To the white solid powder obtained in step 1, add 82g of iodobenzene, 30g of cuprous iodide and 1200ml of DMF, heat the oil bath at an external temperature of 152°C under the protection of nitrogen to react for 72h, distill off most of the solvent DMF under reduced pressure, and dichloro After extraction with methane and DCM, it was washed with 2% hydrochloric acid, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 190 g of dark brown viscous oil.

[0036] Step 3:

[0037] Purification was carried out by column chromatography, using ethyl acetate-dichloromethane-n-heptane (1:1:1) as the elu...

Embodiment 2

[0039] Embodiment 2: in vitro experiment

[0040] Test 1: Radioligand Binding Experiment

[0041] 1.1 Experimental cells: CHO cells

[0042] 1.2 Experimental drugs: compound of formula I, nisoxetine, BTCP, imipramine, desipramine

[0043] 1.3 Experimental design:

[0044] To determine the binding of LPM580098 to serotonin transporter (SERT), norepinephrine transporter (NET) or dopamine transporter (DAT), respectively, radioligand binding experiments were performed.

[0045] 1.4 Experimental steps:

[0046] CHO cell membrane homogenate was mixed with [3H] Nisoxetine or [3H] BTCP was incubated at 4°C for 120 min, or with [3H]Imipramine was incubated at 22°C for 60 min. In this experiment, only 10 μM of LPM580098 was tested, and the non-specific binding of the compound was determined in the presence of 1 μM desipramine, 10 μM BTCP and 10 μM imipramine, respectively. Reactions were performed by rapid filtration under vacuum using glass fiber filters pre-soaked with 0.3% po...

Embodiment 3

[0056] Embodiment 3: experiment in vivo

[0057] Test 1: Mouse formalin pain model

[0058] 1.1 Experimental animal: KM mouse, 18-22g

[0059] 1.2 Experimental drugs and reagents: compound of formula I, pregabalin, CMC-Na solution, formaldehyde solution

[0060] 1.3 Experimental Design: The experiment is divided into 6 groups:

[0061] 1, normal group; 2, model group; 3, pregabalin group (60mg / kg); 4, formula I compound (16mg / kg); 5, formula I compound (32mg / kg); 6, formula I compound ( 64mg / kg).

[0062] 1.4 Experimental steps:

[0063] 1.4.1 Mice were administered orally for 1 hour in advance;

[0064] 1.4.2 Put the mouse to be tested into a transparent mouse cage, and start modeling after 5 minutes of adaptation: insert a 25ul micro-syringe into the middle toe of the mouse's right hind foot, and inject 20 μL of 2.5% formalin when the needle reaches the center of the foot Lin solution (the normal group was injected with 20 μL of normal saline in the same way), and the ...

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PUM

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Abstract

The invention relates to an O-desmethylvenlafaxine derivative, in particular to an O-demethylvenlafaxine phenyl ether compound (a compound of formula I), and further discloses a preparation process ofthe compound and application of the compound for treating pain, as well as pharmaceutical compositions containing the compound. (Please see the specification for the formula).

Description

technical field [0001] The present invention relates to an O-desmethylvenlafaxine derivative, in particular to an O-desmethylvenlafaxine phenyl ether compound, its preparation method and its application in the preparation of pain medicine. Background technique [0002] O-desmethylvenlafaxine is the active metabolite of antidepressant venlafaxine, and it is a second-generation antidepressant that has no or much lower affinity with neuroreceptors than the first generation, thereby reducing side effects and toxicity. At present, Wyeth of the United States has completed the relevant clinical trials, and obtained the FDA's production approval in March 2007. With the same mechanism of action as venlafaxine, O-desmethylvenlafaxine is also a serotonin-norepinephrine reuptake inhibitor (SNRIs), which inhibits both serotonin (5-HT) and The reuptake of norepinephrine (NE) plays a pharmacological role, and is widely used in the treatment of depression and other diseases. For various d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/06C07C217/74A61P29/00A61K31/137
Inventor 田京伟李春梅钟彦徐钱钱杨米娜
Owner YANTAI UNIV
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