4-amino piperidine compounds and their pharmaceutical use

A technology of aminopiperidine and compounds, applied in the field of 4-aminopiperidine compounds, which can solve problems such as addiction and poor pharmacokinetic properties

Active Publication Date: 2006-12-27
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

On the one hand, these compounds are structurally too similar to opioid analgesics such as fentanyl, which may be potentially addictive; on the other hand, these compounds have poor pharmacokinetic properties and require extracereb

Method used

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  • 4-amino piperidine compounds and their pharmaceutical use
  • 4-amino piperidine compounds and their pharmaceutical use
  • 4-amino piperidine compounds and their pharmaceutical use

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0168] Example 1: N-(3-methyl-2-butene-1-yl)-N-benzyl-1-(4-dimethylaminobenzyl)-piperidin-4-amine trihydrochloride synthesis

[0169] 1.1 Dissolve 1.07g (10mmol) benzylamine in 25ml dichloromethane, and add 1.99g (10mmol) 1-tert-butoxycarbonyl-4-piperidone under stirring. Stir at room temperature for 30 min. Cool to 0°C, add 3.18g (15mmol) NaBH(OAc) in portions 3 After the addition, the reaction solution was raised to room temperature, and the stirring reaction was continued for 18h. Spot the plate to monitor the reaction, developer: ethyl acetate-petroleum ether=1:1. Add 25ml of dichloromethane, wash with 2×50ml of saturated sodium bicarbonate solution, and once with 50ml of saturated sodium chloride solution. An appropriate amount of anhydrous sodium sulfate was added to the dichloromethane layer to dry overnight. After filtering, the solvent was distilled off to obtain a yellow-brown oily viscous substance. Silica gel column separation, eluent: dichloromethane-methano...

Embodiment 2

[0173] Example 2: N-(3-methyl-1-butyl)-N-(4-benzyloxybenzyl)-1-(4-dimethylaminobenzyl)-piperidin-4-amine trisalt salt synthesis

[0174] 2.1 Dissolve 1.99g (10mmol) of 1-tert-butoxycarbonyl-4-piperidone in 40ml of dichloromethane, add 0.87g (10mmol) of 3-methyl-butylamine (R 2 NH 2 ), stirred at room temperature for 2h. Add 3.18g (15mmol) NaBH(OAc) in portions under ice-cooling 3 After the addition, the reaction solution was raised to room temperature, and the stirring reaction was continued for 18h. Spot the plate to monitor the reaction, developer: dichloromethane-methanol = 15:1. Add 40ml of dichloromethane, wash with saturated sodium bicarbonate solution 80ml×2, saturated sodium chloride solution 80ml×1 time. An appropriate amount of anhydrous sodium sulfate was added to the dichloromethane layer to dry overnight. After filtering, the solvent was distilled off to obtain a yellow-brown oily viscous substance. Silica gel column separation, eluent: dichloromethane-meth...

Embodiment 3

[0178] Example 3: Synthesis of N-(3-methyl-2-buten-1-yl)-1-(4-dimethylaminobenzyl)-piperidin-4-amine trihydrochloride

[0179] 3.1 Add 27.2g (0.147mol) phthalimide potassium salt and 270ml DMF into a 250ml two-necked flask, and add 18.5g (0.124mol) 4-bromo-2-methyl-2- butene. Keep the internal temperature at 120°C and stir the reaction for 4h. After cooling to room temperature, 400ml of water and 400ml of dichloromethane were added. The aqueous phase was extracted with 400ml of dichloromethane x 2 times, the extract was washed with 250ml of 0.2mol / L NaOH aqueous solution x 4 times, and washed with 400ml of saturated sodium chloride x 1 time. The dichloromethane layer was separated, and an appropriate amount of anhydrous sodium sulfate was added to dry it overnight. Filtrate, evaporate the solvent under reduced pressure, precipitate a solid, and recrystallize with petroleum ether at 60-90°C to obtain 22.2 g of white crystals, which are N-(3-methyl-2-ene-butyl)-phthaloyl Ami...

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Abstract

The invention relates to 4- amino piperidines compound showed in general formula 1, its optic antimer, racemic material, or its medicinal salt, and medical compound containing them. The invention also relates to the application in preparing drug preventing or treating pain after operation, cephalagra, visceralgia, neuralgia and addiction and survivability caused by analgesic such as opium drug.

Description

technical field [0001] The present invention relates to 4-aminopiperidine compounds, their optical enantiomers, racemates, and pharmaceutically acceptable salts thereof, their preparation methods, pharmaceutical compositions containing them, and the use of such compounds for the preparation of preventive and / or The use of medicines to treat pain and conditions such as addiction and tolerance caused by analgesic drugs such as opioids. Background technique [0002] Pain is a common symptom of many diseases. The current research results show that N-type calcium ion channels are an important link in the process of pain generation and pain transmission, because the blockers for N-type calcium ion channels directly act on N-type calcium ion channels. channels, do not involve second messengers or G proteins, and are therefore less prone to addiction. Highly selective N-type calcium ion channel blocker ω-conotoxin MVIIA (Piralt _ ) was approved by the U.S. FDA to enter the market ...

Claims

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Application Information

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IPC IPC(8): C07D211/58A61K31/445A61P25/04A61P25/06
Inventor 恽榴红张城李伟章杨日芳王好山孟革吴宁苏瑞斌李锦盖晓丹翁谢川郑建全
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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