Benzofuran compound, preparation method thereof and application of benzofuran compound in preparation of antiarrhythmic drugs

A technology of phenylfuran and compounds, applied in the field of drug synthesis, can solve the problem of weakened antiarrhythmic effect

Active Publication Date: 2015-01-07
SHANDONG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] The main target of traditional class III antiarrhythmic drugs is the outward rapid activation of delayed finishing potassium currents (I Kr ), but long-term clinical practice has found that the antiarrhythmic effect of this type of drug is reverse frequency-dependent: when the heart rate is slow or the level of β-adrenaline is low, it can excessively prolong the APD (Action Potential Duration), and at the same time the APD Excessive prolongation causes action potential phase 2 plateau Ca 2+ Increased inflow leads to early and afterdepolarizations, which in some cases can produce severe and fatal torsades de pointes; the antiarrhythmic effect is weakened at faster heart rates or higher levels of beta-adrenaline, which is mainly is due to I Ks due to the strong upregulation of

Method used

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  • Benzofuran compound, preparation method thereof and application of benzofuran compound in preparation of antiarrhythmic drugs
  • Benzofuran compound, preparation method thereof and application of benzofuran compound in preparation of antiarrhythmic drugs
  • Benzofuran compound, preparation method thereof and application of benzofuran compound in preparation of antiarrhythmic drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Example 1: N-[[5-(4-chlorophenyl)furan-2-yl]methyl]-2-[4-[(4-methylpiperazin-1-yl)methyl]-1H -1,2,3-Triazol-1-yl]acetamide

[0074](1) Add 20mL of distilled water and 14mL of concentrated hydrochloric acid to p-chloroaniline (2.55g, 20mmol), it turns white and turbid, heat to 60°C until completely dissolved, cool to 0°C in an ice-salt bath, slowly add sodium nitrite solution dropwise (1.38g dissolved in 10mL distilled water), after dropping, continue to react for 20min, add furfurylamine (2.19g, 30mmol) and copper chloride (0.54g, 4mmol), the reaction solution is green, stir overnight, a brown solid is precipitated, and suction filtered , to obtain a reddish-brown solid, the filter cake was washed successively with a small amount of water and ethyl acetate to obtain an off-white solid, the solid was decolorized and recrystallized with methanol / ethanol activated carbon, and dried in vacuo to obtain a white solid intermediate 5-(4-chlorophenyl) - 0.88g of 2-aminomethylfu...

Embodiment 2

[0079] Example 2: N-[[5-(4-bromophenyl)furan-2-yl]methyl]-2-(4-morpholinomethyl-1H-1,2,3-triazole- 1-yl)acetamide

[0080] (1) Prepared according to the method of step (1) in Example 1, except that p-bromoaniline (3.44g, 20mmol) and furfurylamine (2.91g, 30mmol) were reacted to obtain a white solid 5-(4-bromophenyl) -2-Aminomethylfuran 1.18g, the yield is 20.4%, 1 H-NMR(600MHz,DMSO-d6):δ=8.61(s,3H),7.66(m,4H),7.03(d,J=3.6Hz,1H),6.66(d,J=3.6Hz,1H) ,4.13(d,J=3.6Hz,2H);ESI-MS:[M-NH 2 ] + : 235.1, 237.1.

[0081] (2) Prepared according to the method of step (2) in Example 1, except that 5-(4-bromophenyl)-2-aminomethylfuran (2.16g, 8.5mmol) and chloroacetyl chloride (1.44g, 12.75mmol) to obtain 0.65g of yellow solid 2-chloro-N-[[5-(4-bromophenyl)-2-furyl]methyl]-acetamide, the yield is 58%, m.p:131-133 °C, 1 H-NMR (600MHz, DMSO-d6): δ=8.77(t,1H),7.62(m,4H),6.95(d,J=3Hz,1H),6.40(d,J=3Hz,1H),4.36 (d,J=5.4Hz,2H),4.12(s,2H);ESI-MS:[M+H] + :327.7;[M+NH 4 ] + :344.7, 346.8.

...

Embodiment 3

[0085] Example 3: N-[[5-(4-nitrophenyl)furan-2-yl]methyl]-2-[4-[[4-(2-methoxyphenyl)piperazine-1 -yl]methyl]-1H-1,2,3-triazol-1-yl]acetamide

[0086] (1) Prepared according to the method of step (1) in Example 1, except that p-nitroaniline (2.76g, 20mmol) and furfurylamine (2.91g, 30mmol) were reacted to obtain a yellow solid 5-(4-nitrobenzene Base)-2-aminomethylfuran 1.10g, yield is 21.6%. 1H-NMR(600MHz,DMSO-d6):δ=8.65(s,3H),8.31(m,2H),8.00(m,2H),7.32(d,J=3Hz1H),6.76(d,J=3Hz ,1H), 4.19(s,2H); ESI-MS: [M-NH2]+: 202.3.

[0087] (2) Prepared according to the method of step (2) in Example 1, except that 5-(4-nitrophenyl)-2-aminomethylfuran (0.98g, 3.4mmol) and chloroacetyl chloride (0.77g , 6.8mmol) reacted to obtain a yellow solid 1.56g, the yield was 63%, m.p:144-146°C, 1 H-NMR (600MHz, CDCl 3 ):δ=8.24(d,J=9Hz,2H),7.76(d,J=8.4Hz,2H),6.96(s,1H),6.82(d,J3.6Hz,1H),6.43(d,J =3.6Hz,1H),4.58(d,J=5.4Hz,2H),4.12(s,2H);ESI-MS:[M+H] + :295.4,[M+Na] + :317.3.

[0088] (3) Prepared ...

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Abstract

The invention relates to a benzofuran compound, a preparation method thereof and an application of the benzofuran compound in preparation of antiarrhythmic drugs. The structural formula of the compound and substituent groups of the compound are described in the specification; and the preparation method comprises the following steps of: reacting R1-substituted phenylamine with sodium nitrite under an acidic condition firstly to generate diazonium salt, then carrying out coupled reaction with furfuryl amine in presence of copper chloride or titanium trichloride to generate an intermediate III, stirring the intermediate III and chloroacetyl chloride in K2CO3 and CH2Cl2 at room temperature and reacting to obtain an intermediate IV, carrying out refluxing of the intermediate IV and sodium azide in acetonitrile and stirring and reacting to obtain an intermediate V; and carrying out cycloaddition reaction on the intermediate V and a compound VII under the catalysis of sodium ascorbate and CuSO4 to obtain the target compound. The compound provided by the invention has the activity of inhibiting an hERG potassium ion channel and can be utilized as a leading compound of the antiarrhythmic drugs.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a phenylfuran compound, and also relates to a preparation method of the compound and its application in pharmacy. Background technique [0002] Arrhythmia is a common but fatal concomitant disease of cardiovascular system diseases. According to the classic Vaughan Williams and Singh's classification, the current antiarrhythmic drugs can be divided into the following four categories - class I sodium ion channel blockers, class II β-adrenoceptor blockers, class III potassium ion channel blockers, class IV calcium antagonists. Among them, class I sodium ion channel blockers were the earliest discovered antiarrhythmic drugs, but two large-scale clinical trials in 1989 and 1992 showed that these drugs not only had strong antiarrhythmic effects, but also had Serious arrhythmogenic side effects, increased mortality in the test group compared with the placebo group. Since then, the research...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/12A61K31/5377A61K31/496A61K31/454A61P9/06
Inventor 杜吕佩李敏勇刘真真王荣李静
Owner SHANDONG UNIV
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