Isoquinoline compound or salt thereof, medicinal composition, preparation method and application thereof

A technology of tetrahydroisoquinoline hydrochloride and compound, applied in the field of isoquinoline compound or its salt, can solve the problems of poor oral absorption, irregularity and the like

Inactive Publication Date: 2010-01-06
SHANGHAI INST OF PHARMA IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, berberine exhibits class III antiarrhythmic activity. It is clinically used to treat refractory ventricular tachycardia and premature ventricular, with a total effective rate of more than 60%. However, it is a quaternary ammonium salt, and its oral absorption is poor and irregular.

Method used

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  • Isoquinoline compound or salt thereof, medicinal composition, preparation method and application thereof
  • Isoquinoline compound or salt thereof, medicinal composition, preparation method and application thereof
  • Isoquinoline compound or salt thereof, medicinal composition, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Example 1 1-p-methoxybenzyl-2-[1-(p-aminophenoxy)-2-hydroxy-propyl]-6,7-dimethoxy-1,2,3,4- Tetrahydroisoquinoline hydrochloride (I-5)

[0060] (1) 1-(p-methoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride 0.1mol 3,4-dimethoxybenzene Mix ethylamine with 0.1mol p-methoxyphenylacetic acid, heat at 170-180°C for 4 hours, cool, dissolve in chloroform, wash with 2M HCl, 2M NaOH and water successively, dry over anhydrous magnesium sulfate, evaporate under reduced pressure solvent, the remainder was treated with EtOH-H 2 O was recrystallized to obtain N-(3,4-dimethoxyphenethyl)-4-oxyphenylacetamide.

[0061] Dissolve 0.05 mol of the above amide in dry chloroform, add 26 ml of phosphorus oxychloride, reflux for 4 hours, evaporate the solvent and excess phosphorus oxychloride under reduced pressure, wash the residue with petroleum ether to obtain a solid, and recrystallize from ethanol to obtain 1-(p-methoxybenzyl)-6.7-dimethoxy-3,4-dihydroisoquinoline hyd...

Embodiment 2

[0067] Example 2 1-p-methoxybenzyl-2-[1-(p-aminophenoxy)-2-hydroxy-propyl]-6,7-dimethoxy-1,2,3,4- tetrahydroisoquinoline tartrate salt

[0068] The 1-p-methoxybenzyl-2-[1-(p-aminophenoxy)-2-hydroxy-propyl]-6,7-dimethoxy-1,2 prepared in Example 1, Dissolve 3,4-tetrahydroisoquinoline in ethyl acetate, add saturated 8wt% tartaric acid ethyl acetate solution dropwise to about pH=1.5, stir to precipitate crystals, filter, wash the filter cake with ethyl acetate, and dry , to get 1-p-methoxybenzyl-2-[1-(p-aminophenoxy)-2-hydroxy-propyl]-6,7-dimethoxy-1,2,3,4-tetra Hydroisoquinoline tartrate.

Embodiment 3

[0069] Example 3 1-p-methoxybenzyl-2-[1-(p-aminophenoxy)-2-hydroxy-propyl]-6,7-methylenedioxy-1,2,3,4 -Tetrahydroisoquinoline hydrochloride (I-11)

[0070] (1) 1-(p-methoxybenzyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline hydrochloride

[0071] According to the method of step (1) in Example 1, 3,4-dimethoxyphenethylamine is replaced by piperonyl ethylamine to obtain 1-(p-methoxybenzyl)-6,7-methylenedi Oxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. The melting point is 113-116°C.

[0072] (2) 1-(p-methoxybenzyl)-2-[1-(p-nitrophenoxy)-2-hydroxy-propyl]-6,7-methylenedioxy-1,2, 3,4-tetrahydroisoquinoline hydrochloride (I-10)

[0073] 3.65g (8.57mmol) of 1-(p-methoxybenzyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, compound (Formula III) 4g (17.14mmol), KOH1.63g (29.14mmol), 100ml volume ratio 91% methanol and NaI 0.26g (1.71mmol) mixed, heated to reflux, thin-layer chromatography detected that the reactant was consumed and stopped the reactio...

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Abstract

The invention discloses an isoquinoline compound or salt thereof shown as a formula I, wherein R1 and R2 are H, -OCH3 and -OCH2Ph or -NHSO2CH3 independently or R1 and R2 are connected into -OCH2O-; R3 is -NO2, -NH2 or -NHSO2CH3; and R4, R5, R6 and R7 are independently H, -OCH3, -NO2, -NH2 or -NHSO2CH3. The invention also discloses a preparation method of the compound, the medicinal composition containing the compound, and application of the compound in preparing medicaments for treating anti-arrhythmia. The isoquinoline compound or salt thereof has the effect of potassium ion channel blocker, and shows effective activity of prolonging effective refractory period and better heart selectivity, so the isoquinoline compound or salt thereof has better anti-arrhythmia activity.

Description

technical field [0001] The present invention relates to a class of novel compounds, as well as pharmaceutical compositions containing them, their preparation methods and applications, in particular to a class of isoquinoline compounds or their salts, and their pharmaceutical compositions, their preparation methods and applications. Background technique [0002] Sudden cardiac death (SCD) is one of the leading causes of cardiovascular death. The occurrence of SCD is due to the loss of regular heart rhythm due to the instability of myocardial electrophysiology, and the most serious ones are sustained ventricular tachycardia (VT, vetricular tachycardia) and ventricular fibrillation (VF, vetricar fibrillation). [0003] Antiarrhythmic drugs can be divided into four categories: Class I is a sodium channel blocker represented by quinidine, which mainly treats supraventricular tachycardia, while Class IC flecainide, locainide, etc. Premature beats are also effective, but they all ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/04A61K31/472A61P9/06
CPCY02P20/55
Inventor 谢美华冉崇昭闵旸
Owner SHANGHAI INST OF PHARMA IND CO LTD
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