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3-(1-arylpiperidin-4-yl)-2-arylthiazolin-4-one compounds, their preparation method and use

A compound, thiazoline technology, applied in the field of medicine and chemical industry, can solve problems such as poor pharmacokinetic properties

Inactive Publication Date: 2016-09-21
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 still have deficiencies in biological activity and channel selectivity; Therefore, there is still a demand for the development of new small molecule N-type calcium ion channel blockers.

Method used

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  • 3-(1-arylpiperidin-4-yl)-2-arylthiazolin-4-one compounds, their preparation method and use
  • 3-(1-arylpiperidin-4-yl)-2-arylthiazolin-4-one compounds, their preparation method and use
  • 3-(1-arylpiperidin-4-yl)-2-arylthiazolin-4-one compounds, their preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0126] Example 1: (±) 3-(1-benzylpiperidin-4-yl)-2-(4-fluorophenyl)-thiazolin-4-one

[0127] Under the protection of nitrogen, dissolve 3.72g (0.03mol) of 4-fluorobenzaldehyde and 5.71g (0.03mol) of 4-amino-1-benzylpiperidine in 50ml of benzene, and the reaction bottle is equipped with a water separator, and the reaction is carried out under reflux for 2 hours , no water came out, lowered to room temperature, added 5.53g (0.06mol) of mercaptoacetic acid, then heated up and refluxed for 2 hours, and anhydrous was generated. Stop the reaction, pour the reaction solution into 30ml of saturated aqueous sodium carbonate solution after being cooled to room temperature, extract with dichloromethane, wash the organic layer with saturated aqueous sodium chloride solution, wash with water, dry over anhydrous sodium sulfate, filter out sodium sulfate, reclaim the dichloromethane, A light yellow oil was obtained, which was recrystallized from absolute ethanol to obtain 10.37 g of a white...

Embodiment 2

[0128] Example 2: (±) 3-(1-benzylpiperidin-4-yl)-2-(2-fluorophenyl)-thiazolin-4-one

[0129] Weigh 2.48g (0.02mol) 2-fluorobenzaldehyde and 3.81g (0.02mol) 4-amino-1-benzylpiperidine, and 3.68g (0.04mol) mercaptoacetic acid, synthesized according to the synthetic method of Example 1, 5.52 g of white solid was obtained, m.p.159-161°C, yield 74.5%. 1 H-NMR (DMSO-d 6 , ppm) δ: 7.05-7.33 (m, 9H), 5.92 (s, 1H), 3.97-4.03 (m, 1H), 3.87-3.91 (dd, 1H, J 1 =1.40Hz,J 2 =15.40Hz), 3.54-3.58(d, 1H, J=15.40Hz), 3.43(s, 2H), 2.72-2.95(m, 2H), 1.91-2.05(m, 3H), 1.45-1.74(m, 3H). MS[M+H] + : 371.2.

Embodiment 3

[0130] Example 3: (±) 3-(1-benzylpiperidin-4-yl)-2-(2-chloro-6-fluorophenyl)-thiazolin-4-one

[0131] Take by weighing 4.77g (0.03mol) 2-chloro-6-fluorobenzaldehyde and 5.71g (0.03mol) 4-amino-1-benzylpiperidine, and 5.53g (0.06mol) mercaptoacetic acid, according to Example 1 Synthetic method Synthesized to obtain 9.12g of white solid, m.p.148-150℃, yield 75%. 1 H-NMR (DMSO-d 6 , ppm) δ: 7.22-7.27 (m, 8H), 6.30 (s, 1H), 3.93-4.02 (m, 2H), 3.58-3.63 (dd, 1H, J 1 =3.92Hz,J 2 =15.40Hz), 3.44(s, 2H), 2.70-2.95(m, 2H), 1.87-2.09(m, 3H), 1.12-1.73(m, 3H). MS[M+H] + : 405.2.

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Abstract

The invention belongs to the field of pharmaceutical chemicals, and relates to a 3-(1-aryl-piperidin-4-yl)-2-aryl-thiazole-4-ketone compound, medicinal salt thereof, a preparation method thereof and use thereof, in particular to a compound shown in the formula I or medicinal salt thereof. The 3-(1-aryl-piperidin-4-yl)-2-aryl-thiazole-4-ketone compound or the medicinal salt thereof has obvious N-type calcium channel blocking-up activity and good pharmacokinetics properties, can prevent and cure or relieve pain effectively, and has potential used as novel medicine for preventing and / or treating pain, apoplexy and cerebral ischemia, alcohol addiction and intoxication, acute and chronic renal failure, or renal insufficiency.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to 3-(1-arylpiperidin-4-yl)-2-arylthiazolin-4-one compounds, pharmaceutically acceptable salts thereof, preparation methods and applications thereof. Background technique [0002] The N-type calcium ion channel belongs to a subtype of the voltage-gated calcium channel (VDCC), which is composed of α1β subunits and has the characteristics of high voltage activation and relatively rapid inactivation. It is mainly distributed in nerve tissue and can be detected by w-conotoxin GVIA (wCgTx) block. N-type calcium ion channel has been confirmed as a new drug target with clinical relevance. Studies have shown that N-type calcium ion channel blockers are effective in the treatment of stroke and cerebral ischemia, analgesia, especially neurogenic pain, and in reducing Alcohol addiction and treatment of alcoholism, renal protection and other aspects have good application prospects (...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/04C07D417/14A61K31/454A61K31/4545A61P9/10A61P13/12A61P25/04A61P25/06A61P25/32A61P29/02A61P39/02
Inventor 恽榴红董国兴张树卓张城吴宁王好山庞冲陈瑛王勃刘莹刘晓燕苏瑞斌杨日芳郑建全李锦
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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