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Analgesic active compounds and their medicinal uses

A compound and toxicity technology, applied in the direction of active ingredients of heterocyclic compounds, antipyretics, organic chemistry, etc., can solve problems such as side effects

Active Publication Date: 2017-12-01
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In the previous research work, we found the compound ZBH-ZP-21 with significantly stronger analgesic activity than Ralfinamide, but further evaluation found that ZBH-ZP-21 and Ralfinamide have certain side effects related to pharmacological activity
For example, the acute toxicity of ZBH-ZP-21 and the side effects on the nervous system affecting the free movement of mice are greater than that of Ralfinamide; in addition, similar to Ralfinamide, ZBH-ZP-21 has a certain inhibitory effect on the heart Herg channel, showing a certain degree of cardiac side effect;

Method used

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  • Analgesic active compounds and their medicinal uses
  • Analgesic active compounds and their medicinal uses
  • Analgesic active compounds and their medicinal uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Synthesis of Example 1 (S)-2-(4-(benzo[1,3]dioxacyclo-5-oxymethyl)benzyl)amino-propionamide (1)

[0049]

[0050] 1.1 Synthesis of 4-hydroxymethylbenzaldehyde (17)

[0051] Take 5.0g p-phthalaldehyde (37.5mM) in a round bottom bottle, add 60ml ethanol and 90ml tetrahydrofuran to dissolve, add NaBH under ice-cooling 4 0.43g (9.3mM), reacted for 6h, and monitored the reaction by TLC. Stop the reaction, add 2M hydrochloric acid solution to quench, reduce the pH to about 5, rotary evaporate the solution, add water and ethyl acetate to dissolve the residue, separate the liquid, extract the aqueous phase with ethyl acetate 2 to 3 times, combine the organic phase, and saturate Wash with brine and dry over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography, the eluent was petroleum ether: ethyl acetate = 3:1, and the required components were collec...

Embodiment 2

[0056] Synthesis of Example 2 (S)-2-(4-(benzo[1,3]dioxacyclo-5-oxomethyl)benzyl)amino-acetamide (2)

[0057]

[0058] Dissolve 1.2g (11.0mM) glycinamide hydrochloride, 0.5g (8.0mM) sodium cyanoborohydride, 1.0g3A molecular sieve and 1ml triethylamine in 40ml methanol, stir at room temperature for 15min, and quickly add 2.56g compound 19 (10.0mM), heated to 40°C and stirred for 3h. After stopping the reaction, filter, distill off the solvent, add water and ethyl acetate to dissolve, separate the layers, wash with saturated brine and dry for 8 hours. The desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography. The eluent was dichloromethane: anhydrous methanol: ammonia water = 80:1:0.1, and the required components were collected to obtain compound 2 0.8 g of white solid, yield 25.7%. MS (ESI) m / z: 315.6 (M+H + ); Proton NMR spectrum: 1H-NMR (400MHz, DMSO-d4): 1H-NMR (400MHz, DMSO-d4...

Embodiment 3

[0059] Synthesis of Example 3 (S)-2-(4-(benzo[1,3]dioxacyclo-4-oxymethyl)benzyl)amino-acetamide (3)

[0060]

[0061] 3.1 Synthesis of 4-(benzo[1,3]-dioxacyclo-4-oxomethyl)benzaldehyde (20)

[0062] Dissolve 3.1g o-hydroxypiperone (22.7mM, 1.0eq), 3.4g compound 13 (25.0mM, 1.1eq, compound), 6.5g triphenylphosphine (25.0mM, 1.1eq) in 100ml tetrahydrofuran, ice bath Slowly add DEAD3.9ml (25.0mM) dropwise under stirring, react at room temperature for 10h, then add DEAD1.3ml (8.3mM), react at room temperature for 10h, then stop the reaction. After filtration, the filtrate was rotated to evaporate, washed with 0.5N NaOH solution, washed with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography, the eluent was petroleum ether: ethyl acetate = 7:1, and the required components were collected to obtain compound 20 as a pale yel...

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Abstract

The present invention provides compounds of general formula I, isomers thereof, non-toxic pharmaceutically acceptable salts or solvates thereof. The compounds have remarkably strengthened analgesic activity, reduce the acute toxicity obviously, have no inhibition to heart Herg channel, and reduce side effects on coordination movement of mice remarkably. The present invention realizes the separation of activity and side effects, and has a good application prospect.

Description

technical field [0001] The present invention relates to novel amide derivatives or their pharmaceutically acceptable salts with strong analgesic activity and low toxic and side effects, pharmaceutical compositions containing these compounds as active ingredients, and said derivatives or their pharmaceutically acceptable salts The use of salts for the preparation of analgesics. Background technique [0002] Neuropathic pain is a major disease that threatens human health. It has a high incidence rate, a long course of disease (>6 months), recurrent attacks, prolonged healing, and progressive development of the disease. Studies have shown that patients with a history of neuropathic pain account for 25%-30% of the population, while elderly patients with neuropathic pain account for 50%-75% of the adult population, which brings a heavy burden to families and society. [0003] Due to the complexity of the etiology and mechanism of neuropathic pain, traditional opioid receptor ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D317/64A61K31/36A61P29/00
CPCC07D317/64A61K31/36A61P29/00
Inventor 仲伯华张凭史卫国贾红新樊士勇姚宜山付仁芳
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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