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N,N'-disubstituted piperazine derivative, and its preparation method and medicinal composition and uses

A di-substituted and derivative technology, applied in the direction of drug combination, pharmaceutical formulation, medical preparation containing active ingredients, etc., can solve the problems of Shaker channel selectivity loss, ion selectivity influence, channel loss selectivity, etc. Abundant, low toxicity, mild reaction conditions

Inactive Publication Date: 2007-08-01
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

After removing G or Y, it has a great impact on ion selectivity, such as the selectivity of Shaker channel will be completely lost
Heginbotham et al. 2 mutated the residues in the Shaker channel pore region one by one, and found that 4 residues are very critical, they are TVGG, which are located at positions 1, 5, 6 and 8 of the characteristic sequence, and the mutation of these residues will lead to channel loss of selectivity

Method used

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  • N,N'-disubstituted piperazine derivative, and its preparation method and medicinal composition and uses
  • N,N'-disubstituted piperazine derivative, and its preparation method and medicinal composition and uses
  • N,N'-disubstituted piperazine derivative, and its preparation method and medicinal composition and uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Computer Virtual Screening :

[0063] In April 1998, Doyle published the crystal structure of the first ion-selective channel in Science, which was derived from the potassium ion channel of the bacterium Streptomyces lividans. Using the crystal structure of the potassium channel, as well as the information on the action sites of quaternary ammonium ion (QA), 4-aminoquinoline, and toxins such as scorpion venom, snake venom, and honeybee venom on the potassium channel, two active sites of the potassium channel were selected, and the molecular The docking program DOCK4.0 carried out a three-dimensional database search on them to find possible blockers. The small molecule three-dimensional structure database searched is the ACD-3D small molecule database, which has about 250,000 compounds.

[0064] experimental method:

[0065] (1) Structure processing of small molecule compounds

[0066] Before the three-dimensional structure of small molecules can be used for molecu...

Embodiment 2

[0088] Preparation of 1-benzyl-4-[2-(4-chloro-benzenesulfonyl)-ethyl]-piperazine (Ia)

[0089]

[0090] At normal temperature, feed freshly prepared dry HCl gas into a 200ml three-necked flask containing 8.6g (0.1mol) anhydrous piperazine dissolved in 50ml THF. Under vigorous stirring, react for 6h, remove HCl gas, add 8.6g (0.1mol) of anhydrous piperazine, react at room temperature for 2h, then reflux for 6h under vigorous stirring. Cool, filter and wash the filter cake with cold THF. After drying, 22.4 g of white crystals of piperazine monohydrochloride were obtained (92.3% yield).

[0091] Put 4.86g (0.02mol) of piperazine monohydrochloride and 20ml of THF into a 100ml eggplant-shaped bottle. At 0-5°C, 2.28 g (0.018 mol) benzyl chloride dissolved in 20 ml THF was added dropwise, and the drop was completed after 1 h. Reacted overnight at room temperature, refluxed for 2 hours, and evaporated the solvent. Then, add 30ml of water, adjust the pH=8-9 with saturated potass...

Embodiment 3

[0098] Preparation of 1-(4-fluorophenyl)-4-[2-(4-chloro-benzenesulfonyl)-ethyl]-piperazine (Ib)

[0099] Replace 1-benzylpiperazine with 1-(4-fluorophenyl)-piperazine, operate as described in Example 2, all the other required raw materials, reagents and preparation methods are the same as Example 2, to obtain target compound 1-( 4-fluorophenyl)-4-[2-(4-chloro-phenylsulfonyl)-ethyl]-piperazine.

[0100] IR (KBr): 1625cm -1 . 1 HNMR (CDCl 3 )ppm: 2.55(t, 4H,); 2.85(t, 2H); 2.98(t, 4H); 3.35(t, 2H); 6.82(m, 2H); 6.94(m, 2H); 2H); 7.87 (m, 2H). HRMS(SCI)m / z calcd for M + , 382.0918; found, 382.0922.

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Abstract

The invention relates to field of medical design, medical chemistry and pharmaceutics. The invention intends to find out molecule that can activate or prevent potassium ion channel activity by employing computer on the basis of crystal three-dimensional structure of potassium ion channel, then derivatives sifted compound and provides N, N'- disubstituted piperazine derivatives and its salt accepted by pharmacy. The construction formula of said derivatives is expressed in following graph. The invention also relates to the method for preparing said derivatives and its salt and their application. Said compound can be used as activating agent or preventing agent for potassium ion channel, and the potassium ion can be selectively shifted in or out cell by activating or preventing the activity of potassium ion channel. The compound mentioned in this invention can be used to treat and / or prevent cranial vascular disease relevant to physiological pathological and pharmacologia of cardiovascular system effectively.

Description

technical field [0001] The present invention relates to the fields of drug design, medicinal chemistry and pharmacology. More specifically, the present invention uses computer virtual screening based on the three-dimensional structure of potassium ion channel crystals to seek molecules that can stimulate or inhibit the activity of potassium ion channels, and the screened Derivatized compound molecules, thereby providing novel N, N'-disubstituted piperazine derivatives with potassium ion channel inhibitory activity, the present invention also relates to the preparation method of N, N'-disubstituted piperazine derivatives And its pharmaceutical composition and application. Background technique [0002] Potassium ion channel is a special membrane protein that exists in all cells and has high selectivity and high permeability to potassium ions. Potassium ion channels are involved in many important cellular functions, such as controlling the current excitability of cells and exc...

Claims

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Application Information

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IPC IPC(8): C07D295/00C07D295/04A61K31/495A61P9/00
Inventor 蒋华良柳红胡国渊罗小民姚志艺高召兵周宇郑苏欣沈建华朱维良于坤千李扬谭小健陈凯先
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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