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Diaryl methyl piperazine compounds containing saturated nitrogen heterocyclic amide and application thereof

A compound, dimethyl technology, applied in the field of diarylmethylpiperazine compounds, can solve the problems of poor metabolic stability, limited clinical application value, and inability to take oral administration

Inactive Publication Date: 2013-12-25
KUNMING UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, most of the existing δ receptor agonists contain easily metabolized N-diethylamide or N-dimethylamide structural fragments, which limit the clinical Value
For example, SNC80 [18], animal experiments show that its metabolic stability is poor, resulting in low bioavailability and cannot be administered orally

Method used

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  • Diaryl methyl piperazine compounds containing saturated nitrogen heterocyclic amide and application thereof
  • Diaryl methyl piperazine compounds containing saturated nitrogen heterocyclic amide and application thereof
  • Diaryl methyl piperazine compounds containing saturated nitrogen heterocyclic amide and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Example 1: 4-((α-R)-α-((2S,5R)-4-(3-fluorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzene Preparation of formyl-1-piperidine

[0088]

[0089] The specific synthesis method is as follows:

[0090] Step 1, the preparation of (4-formyl)benzoyl-1-piperidine: take 4-formylbenzoic acid (50.0 g, 333.3 mmol), dissolve in dichloromethane (500 ml), and cool to At about 0°C, slowly add thionyl chloride (78.6 g, 666.6 mmol) dropwise, stir, remove the ice bath after the dropwise addition, and heat to reflux until the reaction is complete; cool down to room temperature, and concentrate the reaction solution to obtain 4-formylbenzene Formyl chloride, and then under ice-bath conditions, piperidine (28.26 g, 333.3 mmol) dissolved in dichloromethane (250 ml) was transferred to 4-formylbenzoyl chloride, stirred for 1 h, added water (500 ml), separate the organic phase, dry the organic phase with anhydrous sodium sulfate, and concentrate to obtain 50.0 g of oily matter,...

Embodiment 2

[0100] Example 2: 4-((α-R)-α-((2S,5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoyl-1- Preparation of piperidine

[0101]

[0102] Synthetic method is the same as embodiment 1, and difference is that step two, five:

[0103] Step 2. Preparation of (2R,5S)-1-benzyl-2,5-dimethylpiperazine: 1-benzyl-2, 5-Dimethylpiperazine racemate, yield 93%; and then obtained (2R,5S)-1-benzyl-2,5-dimethylpiperazine through chiral tartaric acid salt crystallization resolution, yield 37% %;

[0104] 1 H NMR (400 MHz, CDCl 3 ) δ 7.22-7.32 (m, 5H), 4.10 (d, J = 13.5 Hz, 1H), 3.09 (d, J = 13.5 Hz, 1H), 2.91 (dd, J = 12.1, 3.1 Hz, 1H), 2.83-2.74 (m, 1H), 2.70-2.60 (m, 2H), 2.28-2.17 (m, 1H), 1.63 (dd, J = 11.0, 10.3 Hz, 1H), 1.49 (br, 1H), 1.14 (d, J = 6.0 Hz, 3H), 0.94 (d, J = 6.2 Hz, 3H);

[0105] Step 5, 4-((α-R)-α-((2S,5R)-4-benzyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoyl - Preparation of 1-piperidine: Using (2R,5S)-1-benzyl-2,5-dimethylpiperazine as...

Embodiment 3

[0107] Example 3: 4-((α-R)-α-((2S,5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzene Preparation of formyl-1-piperidine

[0108]

[0109] Synthetic method is the same as embodiment 1, and difference is that step two, five:

[0110] Step 2. Preparation of (2R,5S)-1-(3-chlorobenzyl)-2,5-dimethylpiperazine: using 3-chlorobenzyl chloride as raw material, using the method described in step 2 of Example 1 1-(3-Chlorobenzyl)-2,5-dimethylpiperazine racemate was obtained with a yield of 92%; then, (2R,5S)-1-(3- Chlorobenzyl)-2,5-dimethylpiperazine, yield 35%;

[0111] 1 H NMR (400 MHz, CDCl 3 ) δ 7.26-7.22 (m,2H), 7.06-7.04 (m, 2H), 4.07 (d, J = 13.7 Hz, 1H), 3.06 (d, J = 13.7 Hz, 1H), 2.91 (dd, J = 12.1, 3.0 Hz, 1H), 2.80-2.78 (m, 1H), 2.65-2.59 (m, 2H), 2.24-2.23 (m, 1H), 1.76 (br, 1H), 1.65 (t, J = 10.7 Hz, 1H), 1.10 (d, J = 6.1 Hz, 3H), 0.94 (d, J = 6.4 Hz, 3H).

[0112] Step five, 4-((α-R)-α-((2S,5R)-4-(3-chlorobenzyl)-2,5-dimethyl-1-p...

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Abstract

The invention discloses substituted diaryl methyl piperazine compounds containing saturated nitrogen heterocyclic amide, or pharmaceutically acceptable esters, or pharmaceutically acceptable salts thereof. The compounds provided by the invention are delta opiate receptor agonists which can be used for treating Parkinsonism; compared with the existing diaryl methyl piperazine delta receptor agonists, such as BW373U86 and SNC80, the original N-diethyl amide is substituted by saturated nitrogen heterocyclic amide structural fragments with better metabolic stability in the compounds provided by the invention; the metabolic stability can be increased expectedly; the treatment effect of the compounds is well played.

Description

technical field [0001] The invention relates to a class of diarylmethylpiperazine compounds, in particular to diarylmethylpiperazine compounds substituted with saturated nitrogen-heterocyclic amides, and their application in the preparation of medicines for treating Parkinson's disease. Background technique [0002] Parkinson's disease (Parkinson's disease) is a common neurodegenerative disease, mainly in the elderly, the pathological manifestations are mainly the degeneration and death of dopaminergic neurons, resulting in a significant decrease in striatal dopamine [1] . The treatment of Parkinson's disease is currently mainly aimed at the lack of dopamine, and drugs such as levodopa are used for treatment [2] . However, after three to five years of treatment, the curative effect of the patient weakened, and side effects such as "switching" phenomenon and abnormal involuntary movement appeared, and gradually aggravated, seriously affecting the quality of life of the pati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/04C07D403/10A61K31/55A61K31/496A61P25/16
Inventor 沈悦海崔本强伊首璞刘许歌杨帆张宽仁
Owner KUNMING UNIV OF SCI & TECH
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