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Dopamine D4 receptor ligand and preparation method thereof

A dopamine and receptor technology, applied in the field of dopamine D4 receptor ligands, can solve problems such as unsatisfactory selectivity, affinity or pharmacological properties, and achieve high affinity, simple process and product yield and high purity

Inactive Publication Date: 2016-07-13
HUNAN INSTITUTE OF ENGINEERING
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to existing D 4 The selectivity, affinity or pharmacological properties of receptor ligands are not satisfactory, therefore, people are exploring new D 4 receptor ligand

Method used

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  • Dopamine D4 receptor ligand and preparation method thereof
  • Dopamine D4 receptor ligand and preparation method thereof
  • Dopamine D4 receptor ligand and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Example 1: Synthesis of 2-(3-(4-(4-fluorobenzyl)piperazin-1-yl)propyl)benzothiazole

[0017] (1) 2-(3-(4-piperazine formaldehyde-1-yl)propyl)benzothiazole

[0018] Add 0.50g (2.36mmol) of 2-(3-chloropropyl)benzothiazole and 0.50g (3.80mmol) of N-formylpiperazine to 10mL of anhydrous dichloromethane, add 1.00ml of sodium triacetoxyborohydride g (4.72mmol), stirred and reacted at room temperature for 24h, then added 20mL of ice water, extracted with dichloromethane (3×10mL), and the organic layer was dried over anhydrous sodium sulfate and purified by column chromatography to obtain 2-(3-( 4-piperazinecarbaldehyde-1-yl)propyl)benzothiazole 0.42 g, yield: 61.7%. 1 HNMR (CDCl 3 ,500MHz) δ: 7.91(d,J=8.0Hz,1H),7.83(s,1H),7.50(d,J=8.0Hz,1H),7.40(t,J=8.0Hz,1H),7.32( t,J=8.0Hz,1H),3.60(t,J=9.4Hz,2H),3.36(m,J=6.8Hz,2H),3.16-3.20(m,4H),2.70-2.75(m4H), 2.26-2.32(m,2H); ESIMSm / z(%)290.4(M+1 + , 100); elemental analysis, measured value (calculated value), %: C62.11 (62.26), H6.6...

Embodiment 2

[0023] Example 2: Synthesis of 2-(3-(4-(4-hydroxybenzyl)piperazin-1-yl)propyl)benzothiazole

[0024] Dissolve 2-(3-(4-piperazin-1-yl)propyl)benzothiazole (0.10 g, 0.38 mmol) in methanol (10 mL), add p-hydroxybenzaldehyde 70 μL (0.65 mmol), acetic acid ( 80μL), sodium cyanoborohydride (0.050g, 0.80mmol), stirred at room temperature for 5 hours, extracted the mixture with dichloromethane and water, dried the organic layer over anhydrous sodium sulfate, concentrated under reduced pressure, and passed the crude product through a Flash column After chromatographic separation, 0.12 g of 2-(3-(4-(4-hydroxybenzyl)piperazin-1-yl)propyl)benzothiazole was obtained with a yield of 85.4%. 1 HNMR (CDCl 3 ,500MHz) δ: 9.32(s,1H),7.92(d,J=7.5Hz,1H),7.50(d,J=9.3Hz,1H),7.43(t,J=6.2Hz,1H),7.40( q, J=5.0Hz, 2H), 7.32(t, J=6.5Hz, 1H), 7.20(t, J=8.0Hz, 2H), 3.65(t, J=9.4Hz, 2H), 3.35(s, 2H),3.26(s,2H),3.12-3.19(m,4H),2.72-2.77(m4H),2.25-2.30(m,2H);ESIMSm / z(%)368.5(M+1 + , 100); elemental analysi...

Embodiment 3

[0025] Example 3: Synthesis of 2-(3-(4-(4-methylbenzyl)piperazin-1-yl)propyl)benzothiazole

[0026] Dissolve 2-(3-(4-piperazin-1-yl)propyl)benzothiazole (0.10g, 0.38mmol) in methanol (10mL), add p-tolualdehyde 70μL (0.59mmol), acetic acid (80μL), sodium cyanoborohydride (0.050g, 0.80mmol), stirred at room temperature for 5 hours, extracted the mixture with dichloromethane and water, dried the organic layer over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was flash After separation by column chromatography, 0.09 g of 2-(3-(4-(4-methylbenzyl)piperazin-1-yl)propyl)benzothiazole was obtained with a yield of 64.3%. 1 HNMR (CDCl 3 ,500MHz) δ: 7.93(d,J=8.0Hz,1H),7.49(d,J=8.0Hz,1H),7.45(t,J=8.5Hz,1H),7.42(q,J=5.5Hz, 2H), 7.30(t, J=8.2Hz, 1H), 7.18(t, J=8.6Hz, 2H), 3.66(t, J=8.0Hz, 2H), 3.32(s, 2H), 3.25(m, J=6.0Hz, 2H), 3.15-3.20(m, 4H), 2.72-2.75(m4H), 2.32(s, 3H), 2.20-2.24(m, 2H); ESIMSm / z(%)366.5(M+ 1 + , 100); Elemental analysis, meas...

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Abstract

The invention discloses a dopamine D4 receptor ligand and a preparation method thereof.The dopamine D4 receptor ligand is a 2-(3-(4-(4- substituted-benzyl) piperazine-1-base) propyl group) benzothiazole type compound, and the structural formula is as shown in formula (I).The preparation method includes the steps that 2-(3-three methyl chlorine) benzothiazole and N-piperazinecarboxaldehyde are dissolved in anhydrous solvent, a reducing agent is added, stirring is conducted at the room temperature, ice water is added, extraction is conducted with organic solvent, separation and purification are conducted, and the 2-(3-(4-(4- substituted-benzyl) piperazine-1-base) propyl group) benzothiazole is obtained; the 2-(3-(4-(4- substituted-benzyl) piperazine-1-base) propyl group) benzothiazole reacts with H2SO4 and is then cooled to the room temperature, alkali is added for neutralization, an alkalinity mixture is obtained, extraction is conducted with organic solvent, separation and purification are conducted, and the 2-(3-(4-(4- substituted-benzyl) piperazine-1-base) propyl group) benzothiazole is obtained; the 2-(3-(4-(4- substituted-benzyl) piperazine-1-base) propyl group) benzothiazole is dissolved in organic alcohol solvent, 4-substituted benzaldehyde, acetic acid and the reducing agent are added, stirring is conducted at the room temperature, the mixture is extracted with organic solvent and water, an organic layer is subjected to drying, pressure reduction and concentration, and a product is obtained after a coarse product is separated.

Description

technical field [0001] The present invention belongs to a class of dopamine D 4 Receptor ligands, specifically a dopamine D 4 Receptor ligand 2-(3-(4-(4-substituted benzyl) piperazin-1-yl) propyl) benzothiazole compound and its preparation method. Background technique [0002] Dopamine plays an important role in many physiological processes. Although there are relatively few dopamine neurons in the brain, it is important for many diseases such as memory, learning, cognition, motor behavior and drug addiction, schizophrenia, Parkinson's disease, etc. The importance of regulating brain physiology and disease is widely recognized. Therefore, there are many drugs that target dopamine receptors. Based on pharmacological characteristics, structural characteristics and different effects on cAMP, dopamine receptors can be divided into D 1 -like and D 2 There are two types of -like receptors. D. 1 -like receptors including D 1 receptor, D 5 Receptor; D 2 -like receptors can...

Claims

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Application Information

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IPC IPC(8): C07D277/64
CPCC07D277/64
Inventor 李谷才易兵张儒
Owner HUNAN INSTITUTE OF ENGINEERING
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