CN103012381B - Benzofuran compound, preparation method thereof and application of benzofuran compound in preparation of antiarrhythmic drugs - Google Patents

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

Phenyl furan compound, its preparation method and its application in the preparation of antiarrhythmic drugs

technical field

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. the

Background technique

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 focus has shifted to antiarrhythmic drugs acting on other targets. Among them, class III antiarrhythmic drugs are a class of drugs with rapid development, and they are also the main direction of research on antiarrhythmic drugs at present. the

The main target of the traditional class III antiarrhythmic drugs is the outward rapid activation delayed finishing potassium current (I _Kr ), but long-term clinical practice has found that the antiarrhythmic effect of this class of drugs is inversely frequency-dependent: in slow heart When the rate or β-adrenaline level is low, it can excessively prolong APD (Action Potential Duration), and at the same time, the excessive prolongation of APD will increase the Ca ^{2+ influx} in the plateau phase of the second phase of the action potential, leading to early afterdepolarization, and in some cases Can produce severe fatal torsades de pointes arrhythmia; the antiarrhythmic effect is weakened when the heart rate is fast or the level of β-adrenaline is high, which is mainly due to the strong upregulation of _IKs . In particular, the results of two large clinical trials SWORD (SurvivalWith ORal D-sotalol) and DIAMOND (Danish Investigation of Arrhythmia and Mortality ON Dofetilide) showed that the selective I _Kr blocker made the mortality rate of the test group higher than that of the placebo group, which made people less enthusiastic about finding selective I _Kr blockers as antiarrhythmic drugs, and began to search for new antiarrhythmic drugs without negative frequency dependence.

At present, the research direction of antiarrhythmic drugs is mainly compound antiarrhythmic drugs - (1) drugs that simultaneously block the fast-activating potassium channel current (I _Kr ) and the slow-activating potassium channel current (I _Ks ); (2) Drugs that also block rapidly activating potassium channel currents (I _Kr ) and other ion channels. Azimilide (SDUL-012-065) discovered by Procter&Gamble Company is the first reported compound that can block I _Kr and I _Ks at the same time. It has a structural skeleton different from traditional antiarrhythmics, that is, a phenylfuran structural fragment. It is particularly important that the drug can still maintain pharmacological activity when the heart rate is fast. At present, the drug has completed Phase III clinical trials and is being applied for the treatment of atrial flutter and atrial fibrillation.

This patent uses computer-aided drug design technology to comprehensively analyze the structure of the lead compound Azimilide, and utilizes the previously constructed homology models of hERG (the main regulatory subunit of I _Kr ) and KCNQ1 (the main regulatory subunit of I _Ks ) and their blockade The agent pharmacophore model was used to rationally optimize the structure of phenylfuran compounds from the perspectives of receptor-based and ligand-based,

Synthesis and activity evaluation to obtain safer and more effective antiarrhythmic drug molecules with novel backbone structures. the

Contents of the invention

The purpose of the present invention is to overcome the above-mentioned deficiencies in the prior art and provide a phenylfuran compound, its preparation method and its application in the preparation of antiarrhythmic drugs. the

To achieve the above object, the present invention adopts the following technical solutions:

Phenylfuran compounds, which are compounds of the following structural formula and pharmaceutically acceptable salts thereof:

In the formula, R1 is _an electron-withdrawing, electron-donating or neutral group substituted at the 4-position or 2,4-position simultaneously; R2 is a nitrogen _- containing six-membered heterocycle or an N-substituted piperazine ring.

Preferably, wherein R ₁ is 2,4-dichloro, 4-methoxy, 4-methyl, 4-halogen, 4-nitro, R ₂ is piperidinyl, morpholinyl, methylpiperazinyl , piperazine, 1-(2-methoxyphenyl)piperazine, 4-phenylpiperazine.

The pharmaceutically acceptable salt of the compound refers to the hydrochloride of the compound. the

Phenylfuran compounds of the present invention are preferably following compounds:

N-[[5-(4-chlorophenyl)furan-2-yl]methyl]-2-(4-morpholinylmethyl-1H-1,2,3-triazol-1-yl) Acetamide (L1, SDUL-009-098);

N-[[5-(4-chlorophenyl)furan-2-yl]methyl]-2-[4-[(4-methylpiperazin-1-yl)methyl]-1H-1,2 ,3-triazol-1-yl]acetamide (L2, SDUL-012-042);

N-[5-(4-chlorophenyl)furan-2-yl]methyl]-2-[4-[[4-(2-methoxyphenyl)piperazin-1-yl]methyl] -1H-1,2,3-triazol-1-yl]acetamide (L3, SDUL-009-099);

N-[5-(4-chlorophenyl)furan-2-yl]methyl]-2-[4-[(4-phenylpiperazin-1-yl)methyl]-1H-1,2, 3-triazol-1-yl]acetamide (L4, SDUL-009-111);

N-[[5-(4-chlorophenyl)furan-2-yl]methyl]-2-[4-(piperidin-1-ylmethyl)-1H-1,2,3-triazole -1-ylacetamide] (L6, SDUL-012-038);

N-[[5-(4-bromophenyl)furan-2-yl]methyl]-2-[4-[(4-methylpiperazin-1-yl)methyl]-1H-1,2 ,3-triazol-1-yl]acetamide (L7, SDUL-009-075);

N-[[5-(4-bromophenyl)furan-2-yl]methyl]-2-(4-morpholinylmethyl-1H-1,2,3-triazol-1-yl) Acetamide (L8, SDUL-009-101);

N-[[5-(4-bromophenyl)furan-2-yl]methyl]-2-[4-[[4-(2-methoxyphenyl)piperazin-1-yl]methyl ]-1H-1,2,3-triazol-1-yl]acetamide (L9, SDUL-009-102);

N-[5-(4-bromophenyl)furan-2-yl]methyl]-2-[4-[(4-phenylpiperazin-1-yl)methyl]-1H-1,2, 3-triazol-1-yl]acetamide (L10, SDUL-009-116);

N-[[5-(4-bromophenyl)furan-2-yl]methyl]-2-[4-(piperazin-1-ylmethyl)-1H-1,2,3-triazole -1-yl]acetamide (L11, SDUL-012-020);

N-[[5-(4-bromophenyl)furan-2-yl]methyl]-2-[4-(piperidin-1-ylmethyl)-1H-1,2,3-triazole -1-ylacetamide] (L12, SDUL-012-039);

N-[[5-(4-nitrophenyl)furan-2-yl]methyl]-2-[4-[(4-methylpiperazin-1-yl)methyl]-1H-1, 2,3-Triazol-1-yl]acetamide (L13, SDUL-012-043);

N-[[5-(4-nitrophenyl)furan-2-yl]methyl]-2-(4-morpholinylmethyl-1H-1,2,3-triazol-1-yl ) Acetamide (L14, SDUL-009-106);

N-[[5-(4-nitrophenyl)furan-2-yl]methyl]-2-[4-[[4-(2-methoxyphenyl)piperazin-1-yl]methyl Base]-1H-1,2,3-triazol-1-yl]acetamide (L15, SDUL-009-107);

N-[[5-(2,4-dichlorophenyl)furan-2-yl]methyl]-2-[4-[4-methylpiperazin-1-yl)methyl]-1H-1 , 2,3-triazol-1-yl]acetamide (L16, SDUL-009-054);

N-[[5-(2,4-dichlorophenyl)furan-2-yl]methyl]-2-(4-morpholinylmethyl-1H-1,2,3-triazole-1 -yl) acetamide (L17, SDUL-009-077);

N-[[5-(2,4-dichlorophenyl)furan-2-yl]methyl]-2-[4-[4-(2-methoxyphenyl)piperazin-1-yl] Methyl]-1H-1,2,3-triazol-1-yl]acetamide (L18, SDUL-009-091);

N-[[5-(2,4-Dichlorophenyl)furan-2-yl]methyl]-2-[4-[(4-phenylpiperazin-1-yl)methyl]-1H- 1,2,3-Triazol-1-yl]acetamide (L19, SDUL-009-110);

N-[[5-(2,4-dichlorophenyl)furan-2-yl]methyl]-2-[4-(piperazin-1-ylmethyl)-1H-1,2,3- Triazol-1-yl]acetamide (L20, SDUL-012-017);

N-[[5-(4-methoxyphenyl)furan-2-yl]methyl]-2-[4-[(4-methylpiperazin-1-yl)methyl]-1H-1 , 2,3-triazol-1-yl]acetamide (L21, SDUL-012-022);

N-[[5-(4-methoxyphenyl)furan-2-yl]methyl]-2-(4-morpholinylmethyl-1H-1,2,3-triazole-1- base) acetamide (L22, SDUL-012-025);

N-[5-(4-methoxyphenyl)furan-2-yl]methyl]-2-[4-[(4-phenylpiperazin-1-yl)methyl]-1H-1, 2,3-Triazol-1-yl]acetamide (L23, SDUL-012-027);

N-[[5-(4-methoxyphenyl)furan-2-yl]methyl]-2-[4-(piperazin-1-ylmethyl)-1H-1,2,3-tri Azol-1-yl]acetamide (L24, SDUL-012-052);

N-[[5-(4-methoxyphenyl)furan-2-yl]methyl]-2-[4-(piperidin-1-ylmethyl)-1H-1,2,3-tri Azol-1-ylacetamide] (L25, SDUL-012-028);

N-[[5-(p-methylphenyl)furan-2-yl]methyl]-2-[4-[(4-methylpiperazin-1-yl)methyl]-1H-1,2, 3-triazol-1-yl]acetamide (L26, SDUL-012-035);

N-[[5-(p-tolyl)furan-2-yl]methyl]-2-(4-morpholinylmethyl-1H-1,2,3-triazol-1-yl)ethyl Amide (L27, SDUL-012-034)

N-[5-(p-tolyl)furan-2-yl]methyl]-2-[4-[(4-phenylpiperazin-1-yl)methyl]-1H-1,2,3 - Triazol-1-yl]acetamide (L28, SDUL-012-031);

N-[[5-(p-tolyl)furan-2-yl]methyl]-2-[4-(piperazin-1-ylmethyl)-1H-1,2,3-triazole- 1-yl]acetamide (L29, SDUL-012-051);

N-[[5-(p-tolyl)furan-2-yl]methyl]-2-[4-(piperidin-1-ylmethyl)-1H-1,2,3-triazole- 1-ylacetamide] (L30, SDUL-012-030). the

The preparation method of above-mentioned phenylfuran compound, comprises the following steps:

( ₁ ) Use the aniline substituted by R1 as the starting material, add acid to dissolve it, then slowly add sodium nitrite solution dropwise under ice bath, after the dropwise addition, continue the reaction for 20-30min, the reaction generates diazonium salt, and then Add copper chloride or titanium trichloride as a catalyst, add furfurylamine, stir at room temperature for 12-36 hours, a coupling reaction occurs, and the product is separated and purified to obtain the intermediate 5-substituted phenyl-2-aminomethylfuran;

(2) Add K ₂ CO ₃ and CH ₂ Cl ₂ to 5-substituted-2-aminomethylfuran, then slowly add chloroacetyl chloride CH ₂ Cl ₂ solution dropwise under ice bath, after the drop is complete, stir the reaction at room temperature until TLC detects no raw material intermediate, separates and purifies to obtain intermediate 2-chloro-N-[[5-substituted phenyl-2-furyl]methyl]-acetamide;

(3) React 2-chloro-N-[[5-substituted phenyl-2-furyl]methyl]-acetamide with sodium azide in acetonitrile for 10-18 hours under reflux and stirring to obtain the intermediate 2-azide Nitro-N-[[5-substituted phenyl-2-furyl]methyl]-acetamide;

(4) Put 2-azido-N-[[5-substituted phenyl-2-furyl]methyl]-acetamide and the compound of formula VII in a mixed solvent of methanol and water, add sodium ascorbate and CuSO _4. Catalyze, avoid light and stir at room temperature for 12-24h, a cyclization reaction occurs to obtain phenylfuran compounds; react phenylfuran compounds with hydrochloric acid ethanol solution to obtain the hydrochloride of the phenylfuran compounds

Wherein X is O, CH ₂ , NH; R ₃ is methyl, phenyl, N-(2-methoxyphenyl).

In the above preparation method, the reaction molar ratio of the aniline substituted by R1 in step ( ₁ ) and sodium nitrite, acid, catalyst, furfurylamine is 1:1:5-10:0.02-3:1-5, the sodium nitrite solution The concentration is 2mol/L.

The reaction molar ratio of 5-substituted-2-aminomethylfuran, K ₂ CO ₃ and chloroacetyl chloride in the above step (2) is 1:1-4:1-2.

In step (3), the reaction molar ratio of 2-chloro-N-[[5-substituted phenyl-2-furyl]methyl]-acetamide to sodium azide is 1:3-5. the

In step (4), 2-azido-N-[[5-substituted phenyl-2-furyl] methyl]-acetamide and the compound of structural formula VII, sodium ascorbate and CuSO _The reaction molar ratio is 1 :1:0.5-1:0.05-1, the mixed solvent is methanol and water mixed in a volume ratio of 1-5:1.

The synthetic route of phenylfuran compound is as follows:

1, the preparation of compound described in general formula III

Add distilled water and concentrated hydrochloric acid to the substituted aniline II, heat to dissolve completely, cool in an ice-salt bath to below 0°C, slowly add sodium nitrite solution dropwise, and continue the reaction for 20-30 minutes, add furfurylamine and copper chloride or three Titanium chloride, stirred at room temperature for 12-36h, precipitated a brown solid, suction filtered to obtain a reddish-brown solid, the filter cake was washed with a small amount of water and ethyl acetate in turn to obtain a light brown solid, the solid was decolorized and recrystallized with methanol/ethanol activated carbon, vacuum Dry to obtain solid intermediate III. the

2, the preparation of the compound described in general formula IV

Redistilled CH ₂ Cl ₂ and anhydrous K ₂ CO ₃ were added to Intermediate III, resulting in a white turbid liquid. Dissolve chloroacetyl chloride in CH ₂ Cl ₂ and slowly add it dropwise to the reaction liquid under ice-cooling. After dropping, react at room temperature until TLC detects that there is no intermediate III. The solvent was evaporated to dryness under reduced pressure, distilled water was added, extracted with dichloromethane, the organic layers were combined, dried overnight over anhydrous MgSO ₄ , filtered with suction, the filtrate was evaporated to dryness under reduced pressure to obtain a brown solid, which was recrystallized with ethanol and decolorized with activated carbon to obtain a solid intermediate Body IV.

3, the preparation of the compound described in general formula V

DMF/acetonitrile was added to intermediate IV, the solid was completely dissolved, then NaN ₃ was added, the reaction solution was turbid, stirred at reflux for 10-18h, the reaction solution was orange yellow, part of the solvent was evaporated under reduced pressure, extracted with dichloromethane, and the organic layers were combined, Wash with saturated NaCl solution and dry over anhydrous Na ₂ SO ₄ . After suction filtration, the filtrate was evaporated to dryness under reduced pressure to obtain an oily intermediate V, which was directly used for the next reaction.

4, the preparation of the compound described in general formula VII

Add anhydrous potassium carbonate (1.5eq) and acetone to nitrogen-containing six-membered heterocycle or N-substituted piperazine ring compound VI (1.5eq), slowly add bromopropyne (1eq) under nitrogen protection, and stir at room temperature for 16- 24h. Suction filtration, the solid was washed with a small amount of acetone, the filtrates were combined, and the solvent was evaporated under reduced pressure. Distilled water was added to the residue, extracted with CH ₂ Cl ₂ , the organic layers were combined, washed with saturated brine, and dried over anhydrous Na ₂ SO ₄ . Suction filtration and spin-drying of the solvent gave a colorless oily substance. Then, a saturated ethanol solution of hydrogen chloride was added dropwise to the above oil until a large amount of white solid was produced, and filtered by suction to obtain intermediate VII as a white powder solid.

5, the preparation of the compound described in general formula I

Add methanol to intermediate V, then sequentially add intermediate VII, sodium ascorbate, CuSO ₄ solution, keep away from light and stir at room temperature, monitor the reaction by TLC until the raw material (intermediate V) is completely reacted, stop the reaction, evaporate part of the solvent under reduced pressure, add Distilled water, extracted with dichloromethane, the organic layer was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After suction filtration, the solvent was evaporated to dryness under reduced pressure to obtain a brown solid, which was subjected to column chromatography to obtain the target compound I. Or continue to dissolve the target compound in methanol, and add dropwise a saturated ethanol solution of hydrogen chloride to obtain the hydrochloride of the target compound.

Application of the above-mentioned phenylfuran compounds and salts thereof in the preparation of antiarrhythmic drugs. the

An antiarrhythmic pharmaceutical composition, comprising the above-mentioned phenylfuran compound, and one or more pharmaceutically acceptable carriers or excipients. the

It may be a pharmaceutical composition suitable for oral administration to mammals, including the above-mentioned phenylfuran compound, and one or more pharmaceutically acceptable carriers or excipients. the

It can also be a pharmaceutical composition suitable for parenteral administration to mammals, including the above-mentioned phenylfuran compound, and one or more pharmaceutically acceptable carriers or excipients. the

The phenylfuran compound provided by the invention has strong antiarrhythmia activity, is a hERG potassium ion channel inhibitor with novel structure, and can be used as a lead compound of an antiarrhythmia drug. The phenylfuran compound provided by the present invention is based on the first reported, safer and more effective I _Kr and I _Ks dual blocker Azimilide (Azimilide), which is currently in Phase III clinical research, as the lead compound for further research It is entirely possible to discover new antiarrhythmic drugs with independent intellectual property rights. The preparation method provided by the invention has mild reaction conditions, cheap and easy-to-obtain raw materials, and simple operation and post-treatment.

detailed description

The following examples can enable those skilled in the art to understand the present invention more comprehensively, but do not limit the present invention in any way. the

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

(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-aminomethylfuran, the yield is 18%. ¹ H-NMR (600MHz, DMSO-d6): δ=8.58(s,3H),7.77(m,2H),7.53(t,J=7.8Hz,2H),7.02(d,J=3.6Hz,1H ), 6.66 (d, J = 3.0 Hz, 1H), 4.14 (d, J = 4.2 Hz, 2H); ESI-MS: [M-NH ₂ ] ⁺ : 191.3, 193.3.

(2) Add redistilled CH ₂ Cl ₂ 35mL and dry K ₂ CO ₃ powder (2.00g, 14.4mmol) to the intermediate 5-(4-chlorophenyl)-2-aminomethylfuran (1.17g, 4.79mmol) ), appearing as a white cloudy liquid. Chloroacetyl chloride (0.81 g, 7.19 mmol) was dissolved in 5 mL CH ₂ Cl ₂ , and slowly added dropwise to the reaction liquid under ice-cooling. After dropping, react at room temperature until TLC detects that there is no raw material intermediate 5-(4-chlorophenyl)-2-aminomethylfuran. The solvent was evaporated to dryness under reduced pressure, 40 mL of distilled water was added, extracted with dichloromethane (40 mL × 3), and the organic layers were combined and dried overnight with anhydrous MgSO ₄ . MgSO ₄ was filtered off, and the filtrate was evaporated to dryness under reduced pressure to obtain a brown solid, which was recrystallized from ethanol and decolorized with activated carbon to obtain a white solid intermediate 2-chloro-N-[[5-(4-chlorophenyl)-2-furyl] Methyl]-acetamide 0.8g, yield is 58.8%. mp: 124-126°C, ¹ H-NMR (600MHz, DMSO-d6): δ=8.76(d, 1H), 7.68(d, J=8.4Hz, 2H), 7.47(d, J=8.4Hz, 2H), 6.94(d, J3Hz, 1H), 6.40(d, J=3Hz, 1H), 4.36(d, J=6Hz, 2H), 4.12(s, 2H); ESI-MS: [M+H] ⁺ :283.8;[M+NH ₄ ] ⁺ :300.8,302.9.

(3) Add DMF10mL and acetonitrile 10mL to the intermediate 2-chloro-N-[[5-(4-chlorophenyl)-2-furyl]methyl]-acetamide (0.49g, 1.5mmol), the solid is completely After dissolving, NaN ₃ (0.49g, 7.5mmol) was added, and the reaction solution became turbid. After stirring for 12 h, the reaction solution was orange-yellow. Part of the solvent was evaporated under reduced pressure, extracted with dichloromethane (30 mL×3), the organic layers were combined, washed with saturated NaCl solution (40 mL×2), and dried over anhydrous Na ₂ SO ₄ . After suction filtration, the filtrate was evaporated to dryness under reduced pressure to obtain an orange-yellow oily intermediate 2-azido-N-[[5-(4-chlorophenyl)-2-furyl]methyl]-acetamide.

(4) Add anhydrous potassium carbonate (4.18g, 30mmol) and 40mL of acetone to 1-methylpiperazine (3.00g, 30mmol), slowly add propyne bromide (3.38g, 20mmol) under nitrogen protection, and stir at room temperature for 16h . Suction filtration, the solid was washed with a small amount of acetone, the filtrates were combined, and the solvent was evaporated under reduced pressure. Add 40 mL of distilled water to the residue, extract with CH ₂ Cl ₂ (40 mL×3), combine the organic layers, wash with saturated brine, and dry over anhydrous Na ₂ SO ₄ . After suction filtration, the solvent was spin-dried to obtain the intermediate 1-methyl-4-propynylpiperazine as a colorless oil. Add hydrogen chloride saturated ethanol solution dropwise to the above oil until a large amount of white solids are produced, and filter with suction to obtain 2.8 g of hydrochloride of 1-methyl-4-propynylpiperazine, the yield is 68%, mp: 210 °C, ¹ H-NMR (600MHz, D ₂ O): δ=3.96(s,2H),3.69(s,4H),3.35(s,4H),2.98(d,J=2.4Hz,1H), 2.85(s,3H); ESI-MS: [M+H] ⁺ : 139.1.

(5) 2-Azido-N-[[5-(4-chlorophenyl)-2-furyl]methyl]-acetamide (from the reaction in step (3), 1.5 mmol) was dissolved in 14 mL of methanol Clarify, then add intermediate 1-methyl-4-propynylpiperazine hydrochloride (0.32 g, 1.5 mmol, dissolved in 2 mL of methanol), sodium ascorbate (0.15 g, 0.75 mmol, dissolved in 2 mL of distilled water) in sequence , 0.5N CuSO ₄ (0.15mL, 0.075mmol), stirred at room temperature, TLC monitored the reaction to the starting material 2-azido-N-[[5-(4-chlorophenyl)-2-furyl]methyl]- The acetamide reaction was complete, and the reaction was stopped. Part of the solvent was evaporated under reduced pressure, 25 mL of distilled water was added, and extracted with dichloromethane (40 mL×3). The dichloromethane layer was washed with saturated sodium chloride solution, and dried overnight over anhydrous sodium sulfate. Suction filtration, evaporation of the solvent under reduced pressure gave a brown solid, column chromatography (CH ₂ Cl ₂ :MeOH=30:1), gave a white solid 0.19g, yield 29.6%, mp: 160-161°C, ¹ H-NMR (300MHz, CDCl ₃ ): δ=7.62(s,1H),7.51(d,J=8.4Hz,2H),7.32(d,J=8.4Hz,1H),6.53(m,2H), 6.27(d,J2.7Hz,1H),5.06(s,2H),4.47(d,J=5.7Hz,2H),3.68(d,J=2.1Hz,2H),2.56-2.45(br.d, 8H), 2.28(s,3H); ESI-HRMS: m/z calcd for C ₂₁ H ₂₆ ClN ₆ O ₂ [(M+H) ⁺ ], 429.1806; found, 429.1800.

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

(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, yield 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.

(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 yellow solid 2-chloro-N-[[5-(4-bromophenyl)-2-furyl]methyl]-acetamide 0.65g, yield 58%, mp: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.

(3) Prepared according to the method of step (3) in Example 1, except that 2-chloro-N-[[5-(4-bromophenyl)-2-furyl]methyl]-acetamide (0.49 g, 1.5mmol) reacted with NaN ₃ to obtain oily 2-azido-N-[[5-(4-bromophenyl)-2-furyl]methyl]-acetamide, which was directly used for the next reaction.

(4) Prepared according to the method of step (4) in Example 1, except that morpholine (2.61g, 30mmol) was used instead of 1-methylpiperazine to react to obtain white solid N-propynylmorpholine hydrochloride 1.15 g, the yield is 46%, mp: 161-163°C, ¹ H-NMR (600MHz, D ₂ O): δ=3.95-3.90(m,4H),3.77(s,2H),3.43(s, 2H), 3.13(s, 2H), 2.95(t, J=2.4Hz, 1H); ESI-MS: [M+H] ⁺ : 126.0.

(5) Prepared according to the method of step (5) in Example 1, except that 2-azido-N-[[5-(4-bromophenyl)-2-furyl]methyl]-acetamide (1.5mmol) reacted with N-propynylmorpholine hydrochloride (0.24g, 1.5mmol) to obtain 0.24g of a light yellow solid, which was dissolved in methanol and dropped into a saturated ethanol solution of HCl to form a salt to obtain a light yellow crystalline solid , the yield is 36.2%. ¹ H-NMR(300MHz,DMSO-d6):δ=11.40(br.s,1H),8.98(t,J=5.4Hz,1H),7.62(m,4H),6.95(d,J=3.3Hz ,1H),6.43(d,J3.3Hz,1H),5.26(s,2H),4.46(s,2H),4.38(d,J=5.4Hz,2H),3.98-3.93(m,2H), 3.78-3.70(m,2H),3.32-3.28(m,2H),3.10(s,2H);ESI-HRMS:m/z calcd for C ₂₀ H ₂₃ BrN ₅ O ₂ [(M+H) ⁺ ], 460.0984; found, 460.1052.

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

(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. the

(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) to obtain a yellow solid 1.56g, yield 63%, mp: 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.

(3) Prepared according to the method of step (3) in Example 1, except that 2-chloro-N-[[5-(4-nitrophenyl)-2-furyl]methyl]-acetamide ( 0.44g, 1.5mmol) was reacted with NaN ₃ to obtain the oily substance 2-azido-N-[[5-(4-nitrophenyl)-2-furyl]methyl]-acetamide, which was directly injected into the next step reaction.

(4) Prepared according to the method of step (4) in Example 1, except that 1-(2-methoxyphenyl)piperazine (2.88g, 15mmol) and propyne bromide (1.19g, 10mmol) were reacted , column chromatography gave white solid 1-(2-methoxyphenyl)-4-propynyl-piperazine 1.69g, the yield was 73.5%, mp: 75-77°C, ¹ H-NMR (600MHz , CDCl ₃ ): δ=7.01(m, 1H), 6.96(d, J=1.2Hz, 1H), 6.92(t, J=7.2Hz, 1H), 6.86(d, J=7.8Hz, 1H), 3.87 (s, 3H), 3.36 (d, J=1.8Hz, 4H), 2.79 (s, 4H), 2.27 (s, 1H); ESI-MS: [M+H] ⁺ : 231.2.

(5) According to the method of step (5) in Example 1, the difference is that 2-azido-N-[[5-(4-nitrophenyl)-2-furyl]methyl]- Acetamide (1.5mmol) and 1-(2-methoxyphenyl)-4-propynyl-piperazine (0.35g, 1.5mmol) were reacted to obtain 0.28g of a yellow solid, which was dissolved in methanol and dropped into HCl ethanol The saturated solution was salted to obtain a yellow solid with a yield of 32.9%, ¹ H-NMR (300MHz, DMSO-d6): δ=11.19(br.s, 1H), 9.06(t, J=5.4Hz, 1H), 8.39(s,1H),8.39-8.27(m,2H),7.94-7.91(m,2H),7.26(d,J=3.3Hz,1H),7.04-6.86(m,4H),6.54(d, J=3.3Hz,1H),5.30(s,2H),4.53(s,2H),4.44(d,J=5.4Hz,2H),3.78(s,3H),3.52-3.44(br.m,4H ),3.19(br.m,2H),3.05-3.01(br.m,2H);ESI-HRMS:m/z calcd for C ₂₇ H ₃₀ N ₇ O ₅ [(M+H) ⁺ ],532.2308; found, 532.2295.

Example 4: N-[[5-(2,4-dichlorophenyl)furan-2-yl]methyl]-2-[4-[(4-phenylpiperazin-1-yl)methyl ]-1H-1,2,3-triazol-1-yl]acetamide

(1) Prepared according to the method of step (1) in Example 1, except that 2,4-dichloroaniline (3.24g, 20mmol) and furfurylamine (2.91g, 30mmol) were reacted to obtain a white solid 5-(2, 1.92 g of 4-dichlorophenyl)-2-aminomethylfuran, the yield was 34.5%. ¹ H-NMR(600MHz,DMSO-d6):δ=8.39(s,3H),7.96(d,J=8.4Hz,1H),7.76(d,J=1.8Hz,1H),7.59(dd,J ₁ =2.4,8.4Hz,1H),6.71(d,J=3.6Hz,1H),6.17(d,J=3.6Hz,1H),4.17(s,2H);ESI-MS:[M+H] ⁺ :225.3.

(2) Prepared according to the method of step (2) in Example 1, except that 5-(2,4-dichlorophenyl)-2-aminomethylfuran (0.47g, 1.87mmol) and chloroacetyl chloride ( 0.31g, 2.72mmol) reacted to obtain 0.25g of white solid 2-chloro-N-[[5-(2,4-dichlorophenyl)-2-furyl]methyl]-acetamide with a yield of 46% , mp: 127-129°C, ¹ H-NMR (600MHz, DMSO-d6): δ=8.81(s, 1H) 7.81(d, J=9Hz, 1H), 7.73(s, 1H), 7.55(dd ,J ₁ =8.4Hz,1.2Hz,1H),7.10(d,J=3Hz,1H),6.47(d,J=3Hz,1H),4.39(d,J=5.4Hz,2H),4.13(s ,2H); ESI-MS: [M+H] ⁺ : 317.8; [M+NH ₄ ] ⁺ : 334.8, 336.8.

(3) Prepared according to the method of step (3) in Example 1, except that 2-chloro-N-[[5-(2,4-dichlorophenyl)-2-furyl]methyl]-B Amide (0.48g, 1.5mmol) was reacted with NaN3 to give oily substance 2-azido-N-[[5-(4-nitrophenyl)-2-furyl]methyl]-acetamide, which was dropped directly One step reaction. the

(4) Prepared according to the method of step (4) in Example 1, except that 4-phenylpiperazine (1.95g, 12mmol) and propyne bromide (1.19g, 10mmol) were reacted to obtain a white solid 1-phenyl- 4-propynylpiperazine 1.64g, yield 82%, mp: 46-48°C, ¹ H-NMR (600MHz, DMSO-d6): δ=7.19(dd,J ₁ =9.0,7.8Hz, 2H),6.92(d,J=7.8Hz,2H),6.76(t,J=7.2Hz,1H),3.36(s,2H),3.22(s,1H),3.15(s,4H),2.62( s, 4H); ESI-MS: [M+H] ⁺ : 201.4.

(5) Prepared according to the method of step (5) in Example 1, except that 2-azido-N-[[5-(4-nitrophenyl)-2-furyl]methyl]-B Amide (1.5mmol) and 1-phenyl-4-propynylpiperazine (0.3g, 1.5mmol) were reacted to obtain 0.3g of a white solid, which was dissolved in methanol and dropped into a saturated ethanol solution of HCl to form a salt to obtain a white solid. The yield is 38.1%, ¹ H-NMR (300MHz, DMSO-d6): δ=11.07(br.s,1H),9.03(s,1H),8.34(s,1H),7.81(d,J=8.7 Hz,1H),7.72(m,1H),7.56-7.53(dd,J=8.7Hz,2.1Hz,1H),7.23(m,2H),7.10(d,J=3.3Hz,1H),6.96( d,J=8.4Hz,2H),6.88-6.83(t,J=7.2Hz,1H),6.50(d,J=3.3Hz,1H),5.28(s,2H),4.54(s,2H), 4.41(d,J=5.1Hz,2H),3.85-3.81(m,2H),3.50-3.39(br.m,2H),3.17-3.06(br.m,4H);ESI-HRMS:m/z calcd for C ₂₆ H ₂₇ Cl ₂ N ₆ O ₂ [(M+H) ⁺ ], 525.1573; found, .525.1571.

Example 5: N-[[5-(4-methoxyphenyl)furan-2-yl]methyl]-2-[4-(piperidin-1-ylmethyl)-1H-1,2 ,3-triazol-1-ylacetamide] 

(1) Preparation of diazonium salt: Add 10mL of distilled water and 5mL of concentrated hydrochloric acid to p-methoxyaniline (1.23g, 10mmol), it turns reddish brown and clear at night, cool in an ice-salt bath, slowly add sodium nitrite (0.69g dissolved in 6mL distilled water), after dropping, continue to react for 20min, and filter out the insoluble matter. the

Under the protection of nitrogen, slowly add the diazonium salt solution dropwise to the titanium trichloride solution (30ml, about 30mmol) and furfurylamine (4.86g, 50mmol) solution, after the dropping, react at room temperature for 1h, adjust the reaction with anhydrous sodium carbonate powder solution pH to alkaline (pH=9), the reaction solution was dark blue, and solids were precipitated, the solids were filtered off, the filtrate was washed with ethyl acetate and extracted with ethyl acetate (30mL×3), the organic layers were combined, and anhydrous Dry over magnesium sulfate, filter off anhydrous magnesium sulfate, add HCl saturated ethanol solution after concentrating the filtrate to form a salt, refrigerate and crystallize to obtain 0.47g of brown solid 5-(4-methoxyphenyl)-2-aminomethylfuran, yield 19.6%, ¹ H-NMR (600MHz, DMSO-d6): δ=8.42(s,3H),7.67(d,J=8.4Hz,2H),7.01(d,J=8.4Hz,2H),6.80 (d, J=3.0Hz, 1H), 6.60(d, J=3.6Hz, 1H), 4.13(s, 2H), 3.79(d, J=8.4Hz, 3H); ESI-MS: [M-NH ₂ ] ⁺ : 187.4.

(2) Prepared according to the method of step (2) in Example 1, except that 5-(4-methoxyphenyl)-2-aminomethylfuran (0.91g, 3.73mmol) and chloroacetyl chloride (0.84 g, 7.46mmol) reacted to obtain 0.8g of white needle-like solid 2-methoxyl-N-[[5-(2,4-dichlorophenyl)-2-furyl]methyl]-acetamide, mp: 120-122°C, the yield is 74.5%. ¹ H-NMR(600MHz,DMSO-d6):δ=8.73(t,1H),7.60-7.58(m,2H),6.97-6.99(m,2H),6.70(d,J=3Hz,1H), 6.34(d,J=3Hz,1H),4.35(d,J=5.4Hz,2H),4.11(s,2H),3.78(s,3H);ESI-MS:[M+H] ⁺ :280.3, 282.5; [M+Na] ⁺ : 302.5, 304.4.

(3) Prepared according to the method of step (3) in Example 1, except that 2-methoxy-N-[[5-(2,4-dichlorophenyl)-2-furyl]methyl] -Acetamide (0.28g, 1mmol) was reacted with NaN3 to give oil 2-azido-N-[[5-(4-methoxyphenyl)-2-furyl]methyl]-acetamide, Directly cast the next reaction. the

(4) Prepared according to the method of step (4) in Example 1, except that piperidine (1.92g, 22.5mmol) and propyne bromide (1.78g, 15mmol) were reacted to obtain white solid N-propynylpiperidinium salt Salt 1.12g, yield 46.9%, mp: 178-180°C, ¹ H-NMR (600MHz, D ₂ O-d6): δ=3.79(s,2H), 3.45-3.43(m,2H) ,2.90-2.83(m,3H),1.80-1.78(m,2H),1.65-1.63(m,1H),1.57-1.50(m,2H),1.29-1.26(m,1H);ESI-MS: [M+H] ⁺ :124.3.

(5) Prepared according to the method of step (5) in Example 1, except that 2-azido-N-[[5-(4-methoxyphenyl)-2-furyl]methyl]- Acetamide (1.5mmol) and N-propynylpiperidine hydrochloride (0.16g, 1mmol) were reacted to give a white solid 0.08g, the yield was 19.5%, mp: 147-148°C, ¹ H-NMR (300MHz , CDCl ₃ ):δ=7.62(s,1H),7.50(d,J=8.7Hz,2H),1.39(br.m,2H),6.88(d,J=8.7Hz,2H),6.53(br .s,1H),6.39(d,J=3.3Hz,1H),6.23(d,J=3.3Hz,1H),5.05(s,2H),4.45(d,J=5.7Hz,2H),3.82 (s,2H),3.64(s,2H),2.42(br.s,4H),1.51(br.s,4H);ESI-HRMS:m/z calcd for C ₂₂ H ₂₈ N ₅ O ₃ [( M+H) ⁺ ], 410.2192; found, 410.2199.

Example 6: N-[[5-(p-tolyl)furan-2-yl]methyl]-2-[4-(piperazin-1-ylmethyl)-1H-1,2,3- Triazol-1-yl]acetamide

(1) Prepared according to the method of step (1) in Example 5, the difference is that p-methylaniline (0.54g, 5mmol) is used instead of p-methoxyaniline, and the amount of furfurylamine is (2.48g, 25mmol), and the reaction yields brown Solid 5-(4-methylphenyl)-2-aminomethylfuran 0.76g, yield 34.1%, ¹ H-NMR (600MHz, DMSO-d6): δ=8.43(s, 3H), 7.67( d,J=8.4Hz,2H),7.26(d,J=8.4Hz,2H),6.88(d,J=3.0Hz,1H),6.62(d,J=3.6Hz,1H),4.13(s, 2H), 2.32 (d, 3H, J=8.4H); ESI-MS: [M- _NH2 ] ⁺ : 171.4.

(2) According to the method of step (2) in Example 1, the difference is that the intermediate is 5-(4-methylphenyl)-2-aminomethylfuran (0.96g, 4.25mmol), and chloroacetyl chloride is (0.96g, 8.5mmol), the reaction gave 0.85g of white needle-like solid 2-methyl-N-[[5-(2,4-dichlorophenyl)-2-furyl]methyl]-acetamide, mp: 117-119°C, the yield is 71.2%. ¹ H-NMR (300MHz, DMSO-d6): δ=8.72(t,1H),7.55(d,J=8.1Hz,2H),7.21(d,J=8.1Hz,2H),6.70(d,J =3.3Hz, 1H), 6.34(d, J=3.3Hz, 1H), 4.35(d, J=5.7Hz, 2H), 4.11(s, 2H), 2.31(s, 3H); ESI-MS: [ M+H] ⁺ :264.3,266.3; [M+NH ₄ ] ⁺ :281.4,283.5;[M+Na] ⁺ :286.3,288.3.

(3) According to the method of step (3) in Example 1, the difference is that 2-methyl-N-[[5-(2,4-dichlorophenyl)-2-furyl]methyl]- Acetamide (0.26g, 1mmol) was reacted with NaN3 to give oily substance 2-azido-N-[[5-(4-methylphenyl)-2-furyl]methyl]-acetamide, which was dropped directly One step reaction. the

(4) Dissolve anhydrous piperazine (1.72g, 20mol) in 20mL of absolute ethanol, stir and dissolve until colorless and clear, slowly add 4.05mL of 40% HBr solution (20mol) dropwise, a large amount of white solid precipitates, wash with 4mL of distilled water Add hydrobromic acid dropwise to a constant-pressure dropping funnel, and continue stirring at room temperature for 5 min. Dissolve propyne bromide in 5 mL of ethanol, then slowly add dropwise to the reaction solution of piperazine and hydrobromic acid, after the addition is complete, heat and reflux in an oil bath at 76°C for 5 hours to obtain a colorless and clear reaction solution, refrigerate and precipitate white solid, filtered with suction, the filtrate was spun to remove the solvent, added 20mL of distilled water, extracted with ethyl acetate (40mL×4), the organic layer was dried with anhydrous sodium sulfate, filtered out, and spin-dried to obtain a light yellow oil, which was added dropwise with HCl Saturated ethanol solution, refrigerated, suction filtered, and dried to obtain 0.26 g of white solid 4-propynylpiperazine hydrochloride, with a yield of 13.3%, mp: 199°C (dec), ¹ H-NMR (600MHz, D ₂₀ -d6): δ = 3.88 (d, J = 2.4Hz, 2H), 3.41 (s, 8H), 2.94 (s, 1H); ESI-MS: [M+H] ⁺ : 125.1.

(5) Prepared according to the method of step (5) in Example 1, with 2-azido-N-[[5-(4-methylphenyl)-2-furyl]methyl]-acetamide and 4 - Proynylpiperazine hydrochloride (0.20g, 1mmol) was reacted to give 0.05g of white solid, the yield was 12.7%, ¹ H-NMR (300MHz, CDCl ₃ ): δ=7.61(s, 1H), 7.50- 7.47(d, J=8.1Hz, 2H), 7.18-7.15(d, J=8.1Hz, 2H), 6.52-6.47(br.m, 2H), 6.25(d, J=3Hz, 1H), 5.05( s,2H),4.46(d,J=5.7Hz,2H),3.66(s,2H), 2.85(t,J=4.5Hz,4H),2.46(br.s,4H),2.35(s,3H ); ESI-HRMS: m/z calcd for C ₂₁ H ₂₇ N ₆ O ₂ [(M+H) ⁺ ], 395.2195; found, 395.2179.

Bioactivity assay:

The activity test adopts the radioligand binding experiment to measure its inhibitory activity on the hERG potassium ion channel, and calculate the IC ₅₀ .

Table 1: Inhibitory activity of phenylfuran compounds on hERG potassium ion channel

Note: IC ₅₀ is the concentration that binds 50% of hERG potassium channel.

The above 30 compounds were screened for activity, and their inhibitory activity on hERG potassium ion channel is listed in Table 1. the

It can be seen from Table 1 that L8, L9, L10, L22, L2, L12, L6, L16, and L11 have good inhibitory activity, among which L8 has the best activity with an IC ₅₀ of 518nM, and compounds L7, L20, and L30 have moderate activity. It can be seen that, when the substituent of benzene ring R1 is bromine, the activity is better _than other substituents, the halogen substituent is better than other types of substituents, and the smaller volume of R substituent is conducive to activity, when the piperazine ring ₄ When the position is substituted by a large benzene ring, the methoxy substituent on the benzene ring is beneficial to the activity.

Activity research shows that the above-mentioned phenylfuran compound has the activity of inhibiting hERG potassium ion channel, is a hERG potassium ion channel inhibitor with novel structure, and can be used as a lead compound of antiarrhythmic drugs. the

The application of the phenylfuran compound of the present invention as an antiarrhythmia inhibitor, specifically, as a drug for treating arrhythmia. the

An antiarrhythmic pharmaceutical composition, comprising the phenylfuran compound of the present invention. the

Preparation, pharmaceutical composition, dosage and administration:

The phenylfuran derivatives of the present invention may exist in a free form or in a salt form. Pharmaceutically acceptable salts of many compound types and methods for their preparation are known to those skilled in the art. Pharmaceutically acceptable salts include conventional non-toxic salts, including quaternary salts of bases of such compounds with inorganic or organic acids. the

The compounds of the present invention may form hydrates or solvates. Methods are known to those skilled in the art to form hydrates of the compounds when lyophilized with water or to form solvates when they are concentrated in solution with a suitable organic solvent. the

The present invention comprises a pharmaceutical composition comprising a therapeutic amount of the compound of the present invention, and one or more pharmaceutically acceptable carriers and/or excipients. Carriers include, for example, saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof, discussed in more detail below. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. The composition may be a liquid, suspension, emulsion, tablet, pill, capsule, sustained release formulation or powder. The composition can be formulated as a suppository, with traditional ingredients and carriers such as triglycerides. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Formulations can be designed to mix, granulate and compress or dissolve ingredients, depending on the formulation required. In another approach, the composition can be formulated as nanoparticles. the

The pharmaceutical carrier used can be, for example, solid or liquid. the

Typical solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. A solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; Can be encapsulation material. In powders, the carrier is a finely divided solid, which is in admixture with the finely divided active ingredient. In tablets the active ingredient is mixed with the carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Powders and tablets preferably contain up to 99% active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone Ketones, low melting waxes and ion exchange resins. the

Typical liquid carriers include syrup, peanut oil, olive oil, water, and the like. Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, tinctures and sealed compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators agent. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, such as cellulose derivatives, preferably carboxymethylcellulose sodium salt solution), alcohols (including monohydric and polyhydric alcohols , such as glycols) and their derivatives, and oils (such as fractionated coconut and peanut oils). For parenteral administration the carrier can also be an oil or fat such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant. Sterile solutions or suspensions. Liquid pharmaceutical compositions can be administered, for example, for intravenous, intramuscular, intraperitoneal or subcutaneous injection. When injecting, it can be pushed in once or gradually injected into the meridian infusion for 30 minutes. The compound can also be administered orally in the form of liquid or solid compositions. the

Carriers or excipients may include time delay materials known in the art such as glyceryl monostearate or glyceryl distearate, and may also include waxes, ethylcellulose, hydroxypropylmethylcellulose, isobutylene methyl ester, etc. When the preparation is used for oral administration, it is recognized that 0.01% Tween 80 in PHOSALPG-50 is used for the preparation of acceptable oral preparations of other compounds, which can be adapted to the preparation of various compounds of the present invention. A wide variety of pharmaceutical forms can be used in administering the compounds of the present invention. If a solid carrier is used, the preparation can be in tablet, powder or pellet form placed into a hard capsule or in the form of a troche or lozenge. The amount of solid carrier will vary widely, but preferably will be from about 25 mg to about 1.0 g. If a liquid carrier is used, the preparation can be a syrup, emulsion, soft capsule, sterile injectable solution or suspension in ampoules or vials or non-aqueous liquid suspension. the

To obtain stable water-soluble dosage forms, the compound or a pharmaceutically acceptable salt thereof can be dissolved in an aqueous solution of organic or inorganic acid, 0.3M succinic acid or citric acid solution. Alternatively, the acidic derivatives can be dissolved in a suitable basic solution. If a soluble form is not available, the compound can be dissolved in a suitable co-solvent or combination thereof. Examples of such suitable co-solvents include, but are not limited to, ethanol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerol, polyoxyethylene fatty acid esters, Fatty alcohols or glycerin light fatty acid esters, etc. the

Various delivery systems are known and can be used to administer the compound or other formulations including tablets, capsules, injectable solutions, capsules in liposomes, microparticles, microcapsules, and the like. Methods of introduction include, but are not limited to, cutaneous, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, pulmonary, epidural, ocular and (usually preferred) oral routes . The compounds may be administered by any convenient or other appropriate route, such as by injection or bolus injection, absorption via epithelial or mucosal lines (e.g., oral mucosa, rectal and intestinal mucosa, etc.) or via drug-loaded stents and It can be administered together with other bioactive agents. Administration can be systemic or local. For the treatment or prevention of nasal, bronchial or pulmonary diseases, the preferred route of administration is oral, nasal or bronchial aerosol or nebulizer. the

Claims (9)

1. benzofurane compounds, it is the following compound of structural formula and pharmaceutical salts thereof:

In formula,

R ₁be 2,4-dichloro, 4-methoxyl group, 4-methyl, 4-halogen, 4-nitro, R ₂for piperidyl, morpholinyl, methylpiperazine base, piperazine, 1-(2-p-methoxy-phenyl) piperazine, 4-phenylpiperazine.

2. benzofurane compounds according to claim 1, is characterized in that, compound is:

N-[[5-(4-chloro-phenyl-) furans-2-base] methyl]-2-(4-morpholinyl methyl-1H-1,2,3-triazole-1-base) ethanamide;

N-[[5-(4-chloro-phenyl-) furans-2-base] methyl]-2-[4-[(4-methylpiperazine-1-yl) methyl]-1H-1,2,3-triazole-1-base] ethanamide;

N-[5-(4-chloro-phenyl-) furans-2-base] methyl]-2-[4-[[4-(2-p-methoxy-phenyl) piperazine-1-base] methyl]-1H-1,2,3-triazole-1-base] ethanamide;

N-[5-(4-chloro-phenyl-) furans-2-base] methyl]-2-[4-[(4-phenylpiperazine-1-base) methyl]-1H-1,2,3-triazole-1-base] ethanamide;

N-[[5-(4-chloro-phenyl-) furans-2-base] methyl]-2-[4-(piperidin-1-yl methyl)-1H-1,2,3-triazole-1-yl acetamide];

N-[[5-(4-bromophenyl) furans-2-base] methyl]-2-[4-[(4-methylpiperazine-1-yl) methyl]-1H-1,2,3-triazole-1-base] ethanamide;

N-[[5-(4-bromophenyl) furans-2-base] methyl]-2-(4-morpholinyl methyl-1H-1,2,3-triazole-1-base) ethanamide;

N-[[5-(4-bromophenyl) furans-2-base] methyl]-2-[4-[[4-(2-p-methoxy-phenyl) piperazine-1-base] methyl]-1H-1,2,3-triazole-1-base] ethanamide;

N-[5-(4-bromophenyl) furans-2-base] methyl]-2-[4-[(4-phenylpiperazine-1-base) methyl]-1H-1,2,3-triazole-1-base] ethanamide;

N-[[5-(4-bromophenyl) furans-2-base] methyl]-2-[4-(piperazine-1-ylmethyl)-1H-1,2,3-triazole-1-base] ethanamide;

N-[[5-(4-bromophenyl) furans-2-base] methyl]-2-[4-(piperidin-1-yl methyl)-1H-1,2,3-triazole-1-yl acetamide];

N-[[5-(4-nitrophenyl) furans-2-base] methyl]-2-[4-[(4-methylpiperazine-1-yl) methyl]-1H-1,2,3-triazole-1-base] ethanamide;

N-[[5-(4-nitrophenyl) furans-2-base] methyl]-2-(4-morpholinyl methyl-1H-1,2,3-triazole-1-base) ethanamide;

N-[[5-(4-nitrophenyl) furans-2-base] methyl]-2-[4-[[4-(2-p-methoxy-phenyl) piperazine-1-base] methyl]-1H-1,2,3-triazole-1-base] ethanamide;

N-[[5-(2,4 dichloro benzene base) furans-2-base] methyl]-2-[4-[4-methylpiperazine-1-yl) methyl]-1H-1,2,3-triazole-1-base] ethanamide;

N-[[5-(2,4 dichloro benzene base) furans-2-base] methyl]-2-(4-morpholinyl methyl-1H-1,2,3-triazole-1-base) ethanamide;

N-[[5-(2,4 dichloro benzene base) furans-2-base] methyl]-2-[4-[4-(2-p-methoxy-phenyl) piperazine-1-base] methyl]-1H-1,2,3-triazole-1-base] ethanamide;

N-[[5-(2,4 dichloro benzene base) furans-2-base] methyl]-2-[4-[(4-phenylpiperazine-1-base) methyl]-1H-1,2,3-triazole-1-base] ethanamide;

N-[[5-(2,4 dichloro benzene base) furans-2-base] methyl]-2-[4-(piperazine-1-ylmethyl)-1H-1,2,3-triazole-1-base] ethanamide;

N-[[5-(4-p-methoxy-phenyl) furans-2-base] methyl]-2-[4-[(4-methylpiperazine-1-yl) methyl]-1H-1,2,3-triazole-1-base] ethanamide;

N-[[5-(4-p-methoxy-phenyl) furans-2-base] methyl]-2-(4-morpholinyl methyl-1H-1,2,3-triazole-1-base) ethanamide;

N-[5-(4-p-methoxy-phenyl) furans-2-base] methyl]-2-[4-[(4-phenylpiperazine-1-base) methyl]-1H-1,2,3-triazole-1-base] ethanamide;

N-[[5-(4-p-methoxy-phenyl) furans-2-base] methyl]-2-[4-(piperazine-1-ylmethyl)-1H-1,2,3-triazole-1-base] ethanamide;

N-[[5-(4-p-methoxy-phenyl) furans-2-base] methyl]-2-[4-(piperidin-1-yl methyl)-1H-1,2,3-triazole-1-yl acetamide];

N-[[5-(p-tolyl) furans-2-base] methyl]-2-[4-[(4-methylpiperazine-1-yl) methyl]-1H-1,2,3-triazole-1-base] ethanamide;

N-[[5-(p-tolyl) furans-2-base] methyl]-2-(4-morpholinyl methyl-1H-1,2,3-triazole-1-base) ethanamide;

N-[5-(p-tolyl) furans-2-base] methyl]-2-[4-[(4-phenylpiperazine-1-base) methyl]-1H-1,2,3-triazole-1-base] ethanamide;

N-[[5-(p-tolyl) furans-2-base] methyl]-2-[4-(piperazine-1-ylmethyl)-1H-1,2,3-triazole-1-base] ethanamide;

N-[[5-(p-tolyl) furans-2-base] methyl]-2-[4-(piperidin-1-yl methyl)-1H-1,2,3-triazole-1-yl acetamide].

3. the preparation method of benzofurane compounds according to claim 1, is characterized in that, comprise the following steps:

(1) with R ₁the aniline replaced is starting raw material, acid dissolve is added to it, then under ice bath, slowly drip sodium nitrite solution, dropwise, continue reaction 20-30min, reaction generates diazonium salt, then add cupric chloride or titanous chloride makes catalyzer, add chaff amine, stirring at room temperature 12-36h, linked reaction occurs, and product separation is purified to obtain intermediate 5-substituted-phenyl-2-aminomethyl-furan;

(2) in 5-replacement-2-aminomethyl-furan, K is added ₂cO ₃and CH ₂cl ₂, then under ice bath, slowly drip chloroacetyl chloride CH ₂cl ₂solution, drips and finishes, and stirring at room temperature reaction detects without raw material midbody to TLC, and separating-purifying obtains the chloro-N-of intermediate 2-[[5-substituted-phenyl-2-furyl] methyl]-ethanamide;

(3) chloro-for 2-N-[[5-substituted-phenyl-2-furyl] methyl]-ethanamide and sodiumazide return stirring in acetonitrile are reacted 10-18h, obtain intermediate 2-azido--N-[[5-substituted-phenyl-2-furyl] methyl]-ethanamide;

(4) by 2-azido--N-[[5-substituted-phenyl-2-furyl] methyl]-ethanamide and structural formula if the compound of VII is in methyl alcohol, water mixed solvent, add sodium ascorbate and CuSO ₄catalysis, there is ring-closure reaction, obtain benzofurane compounds in lucifuge stirring at room temperature 12-24h; Benzofurane compounds and ethanol solution hydrochloride react, must the hydrochloride of this benzofurane compounds

Wherein X is O, CH ₂, NH; R ₃for methyl, phenyl, N-(2-p-methoxy-phenyl).

4. the preparation method of benzofurane compounds according to claim 3, is characterized in that, step (1) R ₁replace aniline and Sodium Nitrite, acid, catalyzer, chaff amine reaction mol ratio be 1:1:5-10:0.02-3:1-5, the concentration of sodium nitrite solution is 2mol/L; In step (2), 5-replaces-2-aminomethyl-furan and K ₂cO ₃and the equivalence ratio of chloroacetyl chloride is 1:1-4:1-2.

5. the preparation method of benzofurane compounds according to claim 3, is characterized in that, in step (3), the equivalence ratio of the chloro-N-of 2-[[5-substituted-phenyl-2-furyl] methyl]-ethanamide and sodiumazide is 1:3-5.

6. the preparation method of benzofurane compounds according to claim 3, it is characterized in that, 2-azido--N-[[5-substituted-phenyl-2-furyl] methyl]-ethanamide and structural formula are as the compound of VII, sodium ascorbate and CuSO in step (4) ₄equivalence ratio be 1:1:0.5-1-0.05-1, mixed solvent be first alcohol and water by volume 1-5:1 mixing.

7. benzofurane compounds according to claim 1 is preparing the application in antiarrhythmic drug.

8. an antiarrhythmic pharmaceutical composition, comprises benzofurane compounds according to claim 1, one or more pharmaceutically acceptable carriers or vehicle.

9. the antiarrhythmic pharmaceutical composition of one according to claim 8, is characterized in that, acceptable carrier comprises solid or liquid vehicle, and solid carrier is selected from starch, lactose, sucrose, dextrin, Magnesium Stearate; Liquid vehicle is selected from syrup, peanut oil, sweet oil, water.