Benzofuran derivatives and their preparation methods and applications

Abstract

The application discloses a benzofuran derivative and a preparation method thereof. The application further discloses application of the compound or a composition with the compound as a main active ingredient in preparation of a medicine for resisting arrhythmia.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a novel atrial-selective benzofuran derivative and a preparation method and application thereof. Background Art

[0002] Atrial fibrillation (AF) is one of the most common sustained cardiac arrhythmias, with an overall prevalence of approximately 2%. Its prevalence increases with age, reaching 10% in people over 75 years old. The primary cause of AF is atrial electrical remodeling, characterized by a shortening of the atrial action potential duration (APD) and atrial effective refractory period (ERP). Clinically, AF is categorized as paroxysmal, persistent, and permanent. Currently, the mechanisms of action of clinically used medications for the treatment of AF are sodium channel blockers, beta-adrenergic receptor blockers, calcium channel blockers, and potassium channel blockers.

[0003] Potassium channels, comprising over 80 genes in the human genome, form one of the largest and most structurally diverse ion channel families. Potassium channels are the primary current in the repolarization phase of the action potential in cardiomyocytes, in addition to phase 0 depolarization. Inhibition of potassium channels can reduce membrane excitability, prolong the cardiac action potential and effective refractory period, and reduce susceptibility to arrhythmias. The acetylcholine (ACh)-activated potassium channel (KACh) is a member of the inwardly rectifier potassium channel family and is a heterotetramer composed of Kir3.1 and Kir3.4 proteins in a 2:2 ratio. Channel activity is regulated by G proteins activated by ACh and other ligands, extracellular Na+, and intracellular pH. The ACh-activated potassium current (IKACh) plays a crucial role in maintaining the cell membrane resting potential and phase 3 repolarization. This channel is abundantly expressed in the conduction system and atrial myocyte membranes, expressed in small amounts in ventricular tissue, and distributed along the T-tubules of myocardial cells. Theoretically, inhibiting the KAch channel can prolong the action potential duration and effective refractory period to treat atrial fibrillation without the risk of causing arrhythmia.

[0004] With the development of the economy and society, the problem of population aging has become increasingly prominent, and the prevalence and incidence of atrial fibrillation have continued to increase. However, the commonly used drugs in clinical practice, such as amiodarone, propafenone, and dofetilide, have poor selectivity and serious adverse reactions, which can cause more serious ventricular arrhythmias and cannot meet the treatment needs of clinical atrial fibrillation patients. Therefore, the development of safe and efficient atrial selective therapeutic drugs has important scientific significance and economic value.

[0005] CN105753822A discloses a benzofuran derivative, a preparation method and application thereof, and the structural formula thereof is:

[0006]

[0007] CN106432159A discloses a novel benzofuran derivative, its preparation method and application, and its general structural formula is:

[0008]

[0009] However, there is still a need to develop new drugs for the preparation of antiarrhythmic drugs. Summary of the Invention

[0010] The first object of the present invention is to provide the compound I shown.

[0011] The structure of compound I is as follows:

[0012]

[0013] The compound of formula I described in the present invention is (4-(2-hydroxy-3-(pyridin-4-ylamino)propoxy)phenyl)(2-(3-(pyrrolidin-1-yl)propyl)benzofuran-3-yl)methanone.

[0014] The second object of the present invention is to provide a method for preparing the benzofuran derivatives represented by formula I.

[0015] The synthetic route of the compound of formula I described in the present invention is as follows:

[0016] (1) reacting the compound of formula II with methylsulfonyl chloride in the presence of a base to produce a compound of formula III:

[0017]

[0018] (2) reacting the compound represented by formula III with tetrahydropyrrole to produce the compound represented by formula IV:

[0019]

[0020] (3) The compound represented by formula IV and p-hydroxybenzoyl chloride are reacted with aluminum chloride to generate the compound represented by formula V:

[0021]

[0022] (4) reacting the compound represented by Formula V with epichlorohydrin under alkaline conditions to produce the compound represented by Formula VI;

[0023]

[0024] (5) The compound represented by Formula VI was stirred with tetraaminopyridine, isopropyl alcohol and aluminum trichloride and reacted at 80-100°C. After the reaction was completed, the mixture was cooled and evaporated under reduced pressure to obtain a yellow oil. The target compound was obtained by column chromatography:

[0025]

[0026] Specifically, the steps include:

[0027] (1) Preparation of 3-(benzofuran-2-yl)propyl methanesulfonate, a compound of formula III:

[0028] Dissolve 3-(Benzofuran-2-yl)propan-1-ol (Formula II) in dichloromethane, use triethylamine as a base, cool to 0°C in an ice-salt bath, and under nitrogen, dropwise add methanesulfonyl chloride. After the reaction, add water, wash with dilute hydrochloric acid and then sodium bicarbonate solution, dry the organic phase, and evaporate under reduced pressure to obtain a solid.

[0029] (2) Preparation of the compound of formula IV, 1-(3-(benzofuran-2-yl)propyl)pyrrolidine:

[0030] An appropriate amount of tetrahydropyrrole was added to acetonitrile, and the acetonitrile solution of 3-(benzofuran-2-yl)propyl methanesulfonate was dripped into the reaction flask under nitrogen protection, and the mixture was heated to reflux. After the reaction was completed, column chromatography was performed to obtain a white solid.

[0031] (3) Preparation of the compound of formula V (4-hydroxyphenyl)(2-(3-(pyrrolidin-1-yl)propyl)benzofuran-3-yl)methanone:

[0032] 1-(3-(Benzofuran-2-yl)propyl)pyrrolidine and p-hydroxybenzoyl chloride were added to a toluene solution, cooled to 0 degrees in an ice-water bath, and aluminum chloride was added in batches. The mixture was kept warm for reaction. After the reaction was completed, the reaction solution was quenched in dilute hydrochloric acid, the phases were separated, the aqueous phase was extracted with toluene, the organic phase was collected, dried, and evaporated under reduced pressure to obtain a light yellow solid.

[0033] (4) Preparation of the compound of formula VI (4-(oxiran-2-ylmethoxy)phenyl)(2-(3-(pyrrolidin-1-yl)propyl)benzofuran-3-yl)methanone:

[0034] Add an appropriate amount of sodium hydroxide aqueous solution to the reaction flask, then add (4-hydroxyphenyl)(2-(3-(pyrrolidin-1-yl)propyl)benzofuran-3-yl)methanone and an appropriate amount of tetrabutylammonium bromide, add an appropriate amount of epichlorohydrin dropwise, heat to reflux after the addition is complete, cool to room temperature after the reaction is complete, extract three times with ethyl acetate, wash with water until neutral, dry the organic phase, and evaporate under reduced pressure to obtain the target compound.

[0035] (5) Preparation of the compound of formula I (4-(2-hydroxy-3-(pyridin-4-ylamino)propyloxy)phenyl)(2-(3-(pyrrolidin-1-yl)propyl)benzofuran-3-yl)methanone:

[0036] Add (4-hydroxyphenyl)(2-(3-(pyrrolidin-1-yl)propyl)benzofuran-3-yl)methanone, tetraaminopyridine and isopropanol to the reaction flask and stir to dissolve. Add aluminum chloride while stirring, then heat to 90 degrees to react. After the reaction is completed, cool and evaporate under reduced pressure to obtain a yellow oil, which is then purified by column chromatography to obtain the target compound.

[0037] A third object of the present invention is to provide a pharmaceutical composition comprising at least one benzofuran derivative represented by Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, as a pharmaceutically active ingredient. Optionally, the pharmaceutical composition of the present invention may further comprise one or more acceptable carriers or excipients.

[0038] The compounds of the present invention can be prepared into pharmaceutical compositions with various commonly used pharmaceutical additives. Depending on the therapeutic purpose, the pharmaceutical compositions can be prepared into various types of dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions).

[0039] In order to form the pharmaceutical composition in tablet form, any excipient known and widely used in the art can be used. For example, carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; binders such as water, ethanol, propanol, ordinary syrup, glucose solution, starch solution, albuterol solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinyl pyrrolidone, etc.; disintegrants such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, calcium carbonate, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceride of stearic acid, starch and lactose, etc.; disintegration inhibitors such as white sugar, glyceryl tristearate, stearic acid, and hydrogenated oil; adsorption promoters such as quaternary ammonium alkali and dodecane. Tablets may also contain sodium sulfate, wetting agents such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol. If desired, conventional coating materials may be used to make tablets into sugar-coated tablets, gelatin-film-coated tablets, enteric-coated tablets, film-coated tablets, double-layer film-coated tablets, or multi-layer tablets.

[0040] In order to shape the pharmaceutical composition into a pill form, any excipient known and widely used in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.; binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, etc.; disintegrants such as agar and kelp powder, etc.

[0041] In order to shape the pharmaceutical composition into a suppository form, any excipient known and widely used in the art may be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides and the like.

[0042] To prepare a pharmaceutical composition in the form of an injectable, the solution or suspension can be sterilized and preferably added with an appropriate amount of sodium chloride, glucose, or glycerol to produce an injectable formulation isotonic with blood. Any commonly used carrier in the art can be used in the preparation of the injectable formulation, such as water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan. Furthermore, conventional dissolving agents, buffers, and analgesics may be added.

[0043] In the present invention, there is no particular limitation on the method of administration of the pharmaceutical composition. Various dosage forms can be selected for administration according to the patient's age, sex, and other conditions and symptoms. For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are for oral administration; injections can be administered alone or mixed with an injectable delivery fluid (such as a glucose solution and an amino acid solution) for intravenous injection. If necessary, the injection can be used alone for intramuscular, subcutaneous, or intraperitoneal injection; suppositories are administered into the rectum. The dosage of the present invention can vary according to the route of administration, the patient's age, weight, type and severity of the disease, etc. The usual dosage can be: a daily dose of 0.1 to 10 mg / kg body weight.

[0044] The fourth object of the present invention is to provide the use of the benzofuran derivatives represented by formula I in the preparation of antiarrhythmic drugs.

[0045] Compared with existing products, the present invention improves the antiarrhythmic therapeutic effect, reduces adverse drug reactions, reduces the risk of inducing ventricular arrhythmias, and enhances drug stability. In addition, the synthesis process is simpler to operate, greatly reducing costs and being suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 This is a graph showing the inhibitory effect of the compound of formula I on IKAch ion channel current;

[0047] Figure 2 For the compound of formula I 1 H NMR;

[0048] Figure 3 For the compound of formula I 13 C NMR;

[0049] Figure 4 The high resolution mass spectrometry (HRMS) of the compound of formula I is shown in FIG. DETAILED DESCRIPTION

[0050] The technical solution of the present invention is further described below through specific implementation methods. The examples listed therein are for illustration of the present invention but do not limit its protection scope in any way.

[0051] Example 1 Preparation of 3-(Benzofuran-2-yl)propyl methanesulfonate.

[0052] 3-(Benzofuran-2-yl)propan-1-ol (5 g, 28.4 mmol) was dissolved in 100 mL of dichloromethane, and triethylamine (3.5 g, 34.1 mmol) was added. The mixture was stirred magnetically and cooled to -5 to 0°C in an ice-salt bath. A solution of methylsulfonyl chloride (3.6 g, 31.2 mmol) in dichloromethane was added dropwise under nitrogen protection. The reaction was allowed to proceed for 1 h. The completion of the reaction was monitored by thin-layer chromatography. The mixture was washed three times with 100 mL of 1 M dilute hydrochloric acid and then three times with 100 mL of a saturated sodium bicarbonate solution. The organic phase was collected and evaporated under reduced pressure to obtain 6.8 g of a solid, i.e., 3-(benzofuran-2-yl)propyl methanesulfonate, with a yield of 94.7%. 1 H NMR(500MHz, CDCl3)δ7.49–7.42(m,2H),7.28(td,J=7.4,1.6Hz,1H),7.22(td,J=7.4,1.6Hz,1H), 6.23(d,J=1.3Hz,1H),3.51(t,J=5.0Hz,2H),3.00(s,3H),2.38(t,J=5.7Hz,2H),1.91 (p,J=5.3Hz,2H).

[0053] Example 2 Preparation of 1-(3-(Benzofuran-2-yl)propyl)pyrrolidine.

[0054] 3-(Benzofuran-2-yl)propyl methanesulfonate (6 g, 23.6 mmol) was dissolved in 100 mL of acetonitrile, and tetrahydropyrrole (3.4 g, 47.2 mmol) was added. The mixture was heated to reflux and monitored for completion by thin-layer chromatography. After cooling, silica gel sand was added and column chromatography was performed to obtain 4.1 g of the target compound in a yield of 75.6%. 1 H NMR (500MHz, CDCl3) δ7.45 (ddd, J= 10.6, 6.5, 1.6Hz, 1H), 7.25 (dtd, J= 30.9, 7.5, 1.6Hz, 1H), 2.66–2.60 (m, 1H), 2.63 (s, 1H), 2.48(t,J=5.3Hz,1H), 2.38(t,J=7.9Hz,1H), 1.89(tt,J=5.9,4.3Hz,1H), 1.84(td,J=7.5,6.7,4.2Hz,2H).

[0055] Example 3 Preparation of (4-hydroxyphenyl)(2-(3-(pyrrolidin-1-yl)propyl)benzofuran-3-yl)methanone

[0056] Dissolve 1-(3-(Benzofuran-2-yl)propyl)pyrrolidine (4 g, 17.4 mmol) in 100 mL of toluene, add p-hydroxybenzoyl chloride (3.55 g, 22.6 mmol), stir magnetically, cool to 0°C in an ice-water bath, add aluminum chloride (3.0 g, 22.6 mmol) in batches, maintain the internal temperature at 0-15°C, stir for 1 h after the addition is complete, monitor the reaction completion by thin-layer chromatography, slowly pour the reaction solution into 10% dilute hydrochloric acid, raise the internal temperature, separate the phases while hot, extract the aqueous phase with toluene three times (50 mL × 3), wash the organic phase with saturated brine three times (100 mL × 3), dry, and evaporate under reduced pressure to obtain 4.76 g of a light yellow solid with a yield of 78.1%. 1 H NMR (500MHz, CDCl3) δ9.95 (s, 1H), 7.74–7.63 (m, 3H), 7.47 (dd, J= 7.2,1.9Hz,1H),7.37–7.26(m,2H),6.82–6.76(m,2H),2.66–2.60(m,4H),2.48(t,J=7.6Hz,2H),2.38(t,J=7.9Hz,2H),1.94–1.78(m,6H).

[0057] Example 4 Preparation of (4-(oxiran-2-ylmethoxy)phenyl)(2-(3-(pyrrolidin-1-yl)propyl)benzofuran-3-yl)methanone

[0058] (4-Hydroxyphenyl)(2-(3-(pyrrolidin-1-yl)propyl)benzofuran-3-yl)methanone (4 g, 11.4 mmol) was added to 50 mL of 10% sodium hydroxide solution, and tetrabutylammonium bromide (0.4 g, 1 mmol) was added dropwise. Epichlorohydrin (3 mL, 30.8 mmol) was added dropwise. After the addition was complete, the mixture was heated to 80°C and reacted for 2 h. The reaction was completed after monitoring by thin-layer chromatography. The heating was stopped and the mixture was cooled to room temperature. The reaction solution was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried, and evaporated under reduced pressure to obtain 4.3 g of an oily substance with a yield of 92.3%. 1H NMR(500MHz, CDCl3)δ7.86–7.80(m,2H),7.66(dd, J=7.1,1.8Hz,1H),7.47(dd,J=7.2,1.9Hz,1H),7.37–7.26(m,2H),7.13–7.06(m,2H), 4.36(dd,J=12.5,6.9Hz,1H), 3.93(dd,J=12.5,6.9Hz,1H), 3.01(p,J=7.0Hz,1H), 2.72(dd,J=7.0,5.1Hz,1H),2.68–2.58(m,4H),2.51–2.42(m,3H),2.38(t,J=7.9Hz, 2H),1.94–1.78(m,6H).

[0059] Example 5 Preparation of (4-(2-hydroxy-3-(pyridin-4-ylamino)propyloxy)phenyl)(2-(3-(pyrrolidin-1-yl)propyl)benzofuran-3-yl)methanone.

[0060] (4-(Oxiran-2-ylmethoxy)phenyl)(2-(3-(pyrrolidin-1-yl)propyl)benzofuran-3-yl)methanone (4.3 g, 10.6 mmol) was added to 50 mL of isopropanol, and tetraaminopyridine (5 g, 53 mmol) was added. The mixture was stirred magnetically, and aluminum chloride (1 g, 7.4 mmol) was added in batches. The temperature was raised to 90°C and the reaction was allowed to react for 5 h. The reaction was monitored for completion by thin-layer chromatography. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain 7 g of an oily substance. Dichloromethane was added for redissolution, and silica gel sand was added. Column chromatography was performed to obtain 3.1 g of a white solid with a yield of 59.7%.

[0061] 1H NMR (500MHz, CDCl3): δ=8.18–8.17 (d, J=5.0Hz, 2H), 7.84–7.82 (d, J=10.0Hz, 2H),7.67(d,J=5.0Hz,1H),7.48-7.46(d,J=5.0Hz,1H),7.33-7.30(m,2H),7.12–7.10(d,J =10.0Hz,2H),6.63–6.62(d,J=5.0Hz,2H),4.65(s,1H),4.44–4.40(m,1H),4.10–3.86 (m,3H),3.57–3.54(m,1H),3.44–3.41(m,1H),3.29–3.26(m,2H),2.58-2.57(d,J=5.0Hz, 1H),2.41-2.20(m,3H),2.22-1.90(m,3H),1.85-1.67(m,2H),1.43–1.32(m,1H). 13 C NMR (125MHz, CDCl3) δ190.63,168.85,159.92,153.88,152.63,150.88,133.02,132.35,129.73, 124.60,123.46,122.61,118.89,114.69,111.39,109.95,70.11,69.12,54.30,54.16,46.35, 25.15,24.74,23.56.ESI-HRMS:m / z calcd for C 33 H 33 N3O4[(M+H) + ], 499.6110, found 500.6093.

[0062] Example 6 Effects of the compound of formula I and amiodarone on GIRK1 / 4 ion channels in humans.

[0063] Xenopus oocytes were isolated by collagenase treatment (30 mg collagenase in 15 mL ND96 solution for 1 h at room temperature) and incubated at 17°C for 1 day in ND96 solution supplemented with 100 units / mL penicillin, 100 μg / mL streptomycin, and 2.5 mM sodium pyruvate. ND96 solution consists of 96 mM NaCl, 2 mM KCl, 1 mM MgCl₂, 1.8 mM CaCl₂, and 5 mM HEPES (pH 7.5). Oocytes were then injected with GIRK1 and GIRK4 cRNA (10 ng of each cRNA per oocyte) and incubated for an additional 2–4 days until electrophysiological measurements were performed. Two-electrode voltage clamping was performed using an OC-725 amplifier (Warner Instruments, Inc., Hamden, CT, USA) and glass microelectrodes filled with 3 M KCl (0.5–2.0 M). The oocytes were placed in a recording chamber perfused with ND96 solution, and the membrane potential was maintained at 80 mV. The perfusate was changed to high potassium solution (96 mM KCl, 2 mM NaCl, 1 mM MgCl2, 1.8 mM CaCl2, 5 mM HEPES, pH 7.5) to induce inward currents, and 3 mM BaCl2 was added to the recording chamber to induce inward currents. + Can inhibit more than 90%. + The sensitive current was considered to be IKAch. The current-voltage relationship was recorded using a voltage ramp pulse from 120 to +50 mV within 500 ms. All experiments were performed at room temperature. Data acquisition and analysis were performed using pClamp software (Axon Instruments, Foster City, CA, USA). Figure 1 .

[0064] The experimental results show that the compound of formula I can block the current of the IKAch ion channel in a dose-dependent manner, and the degree of inhibition of the IKAch current is stronger than that of amiodarone.

[0065] Experimental Example 7: The compound of formula I was applied to the aconitine-induced rabbit atrial fibrillation model.

[0066] Rabbits were anesthetized with an intravenous injection of urethane at a dose of 1 g / kg body weight. Endotracheal intubation and artificial respiration were performed, and the thoracotomy was performed. Bipolar electrodes were placed on the right lower atrium and right ventricular free wall for recording. Atrial fibrillation was induced by placing a cotton ball soaked in 0.05 mL of aconitine solution (0.05%) on the atrium, or by placing a small amount of aconitine crystals directly on the atrium. Two minutes after the onset of atrial fibrillation, an intravenous bolus was administered. Doses of the compound of Formula I were 10, 20, and 50 μg / kg / min, amiodarone was 10, 20, and 50 μg / kg / min, and dofetilide was 50 μg / kg / min. The experimental results are shown in Table 1.

[0067] Table 1: Effects of the compound of formula I on aconitine-induced rabbit atrial fibrillation model

[0068]

[0069] It can be seen from the above table that the compound of formula I exhibits a good effect in treating atrial fibrillation, and the therapeutic effect is better than amiodarone and significantly stronger than dofetilide.

[0070] Experimental Example 8 Effects of the compound of formula I on the action potential of atrial cells in beagle dogs.

[0071] Left atrial myocardium was isolated from beagle dogs weighing 8 to 11 kg and suspended in an organ bath containing Krebs-Henseleit solution. External electrical stimulation at a constant frequency (1 Hz) was applied using bipolar platinum electrodes and rectangular current pulses (3 milliseconds duration) from conventional microelectrodes filled with 3 M KCl. The microelectrode amplifier was connected to the analysis system. Atrial myocardium was allowed to stabilize for approximately 45 minutes before baseline measurement of action potential parameters (maximum rate of phase 0 depolarization [Vmax] and APD at 50% and 90% repolarization). The test drug and a control (0.1% DMSO) were then added to the perfusion medium for 30 minutes to allow steady-state effects. The experimental results are shown in Table 2.

[0072] Table 2: Effects of different concentrations of the compound of formula I on the action potential of beagle dog atrial cells

[0073]

[0074]

[0075] The experimental results showed that 10 μM of the compound of formula I could significantly prolong the action potential duration of the atrium of beagle dogs and had a good therapeutic effect on reentrant arrhythmias.

[0076] Experimental Example 9 Effects of the compound of formula I on ventricular action potential in beagle dogs.

[0077] Right ventricular myocardium was isolated from beagle dogs weighing 8 to 11 kg and suspended in an organ bath containing Krebs-Henseleit solution. External electrical stimulation at a constant frequency (1 Hz) was applied using bipolar platinum electrodes and rectangular current pulses (3 milliseconds duration) from conventional microelectrodes filled with 3 M KCl. The microelectrode amplifier was connected to the analysis system. The ventricular myocardium was allowed to stabilize for approximately 45 minutes before baseline measurements of action potential parameters (maximum rate of phase 0 depolarization [Vmax] and APD at 50% and 90% repolarization) were performed. The test drug and a control (0.1% DMSO) were then added to the perfusion medium for 30 minutes to allow steady-state effects to be achieved. The experimental results are shown in Table 3.

[0078] Table III: Effects of Formula I compound and amiodarone on ventricular myocyte action potential in beagle dogs

[0079]

[0080] The results show that 10 μM of Formula I compound has no significant effect on the ventricular myocyte action potential parameters in beagle dogs, 10 μM of amiodarone significantly prolongs the action potential duration of ventricular myocyte, increases APD 50 and APD 90 by 7.3% and 17% respectively, and has a risk of causing arrhythmia. Formula I compound is safer and more effective than amiodarone.

[0081] Experimental Example 10: Application of Formula I compound to a rabbit model of arrhythmia.

[0082] Thirty-two female New Zealand white rabbits weighing 2.5-3.5 kg were selected, anesthetized by intramuscular injection of ketamine (35 mg / kg) and xylazine (5 mg / kg), and supplemented as needed during the experiment. The electrocardiogram was continuously monitored using a polygraph system, and analyzed using an electrocardiogram processor. More than 6 consecutive Torsades de Pointes (TdP) was defined as polymorphic ventricular tachycardia. After baseline measurement, intravenous infusion of methoxamine (15 mg / kg / min) was started. After 10 minutes, Formula I compound (500 μg / kg / min), amiodarone (500 μg / kg / min), and dofetilide (5, 10 μg / kg / min) were continuously intravenously infused. The experimental results are shown in Table IV.

[0083] Table IV: Effects of Formula I compound, amiodarone, and dofetilide on a rabbit model of arrhythmia

[0084]

[0085]

[0086] The results show that a large dose of Formula I compound only rarely causes premature ventricular contractions (PVC), does not induce Torsades de Pointes (TdP) and ventricular fibrillation (VF), and an equivalent dose of amiodarone induces TdP and has a risk of causing arrhythmia. Dofetilide induces TdP in 75% of rabbits and ventricular fibrillation in 25% of rabbits at a dose of 10 μg / kg / min, and has a high risk of causing arrhythmia. In comparison, Formula I compound is safer and more effective than amiodarone and dofetilide.

[0087] In summary, the present invention provides compounds represented by Formula I and their use in the preparation of low-toxicity antiarrhythmic drugs. Experimental results show that the compounds provided by the present invention have excellent antiarrhythmic activity, primarily by prolonging the action potential of cardiomyocytes by inhibiting the potassium ion current affected by acetylcholine, and without affecting the action potential duration of ventricular myocardium. The anti-atrial fibrillation effect of the compounds is even better than that of amiodarone and dofetilide. More importantly, compared with amiodarone and dofetilide, the compounds of the present invention have a significantly reduced risk of causing arrhythmias and are safer. The present invention provides a new option for the preparation of low-toxicity antiarrhythmic drugs.

Claims

1. A benzofuran derivative, wherein the structural formula of the benzofuran derivative is as shown in Formula I: 。 2. The method for preparing the benzofuran derivatives according to claim 1, characterized in that: Its synthetic route is as follows: (1) The compound of formula II is reacted with methylsulfonyl chloride in the presence of a base to produce the compound of formula III: ； (2) reacting the compound represented by formula III with tetrahydropyrrole to produce the compound represented by formula IV: ； (3) The compound represented by formula IV and p-hydroxybenzoyl chloride are reacted with aluminum chloride to generate the compound represented by formula V: ； (4) The compound represented by formula V is reacted with epichlorohydrin under alkaline conditions to generate the compound represented by formula VI: ； (5) The compound represented by Formula VI was stirred with tetraaminopyridine, isopropyl alcohol and aluminum chloride and reacted at 80-100°C. After the reaction was completed, the mixture was cooled and evaporated under reduced pressure to obtain a yellow oil. Column chromatography was performed to obtain the compound represented by Formula I: 。 3. The preparation method according to claim 2, characterized in that The steps include: (1) Preparation of 3-(benzofuran-2-yl)propyl methanesulfonate: Dissolve 3-(benzofuran-2-yl)propan-1-ol shown in formula II in an organic solvent, use triethylamine or N,N-diisopropylethylamine as a base, cool to -5 to 0 degrees Celsius in an ice-salt bath, protect with nitrogen, slowly add methanesulfonyl chloride dropwise, add water after the reaction, wash with dilute hydrochloric acid and sodium bicarbonate solution in sequence, dry the organic phase, and evaporate under reduced pressure to obtain solid 3-(benzofuran-2-yl)propyl methanesulfonate; (2) Preparation of 1-(3-(benzofuran-2-yl)propyl)pyrrolidine: Tetrahydropyrrole was added to acetonitrile, and the acetonitrile solution of 3-(benzofuran-2-yl)propyl methanesulfonate was slowly dripped into the reaction flask under nitrogen protection, and the mixture was heated to reflux. After the reaction was completed, column chromatography was performed to obtain 1-(3-(benzofuran-2-yl)propyl)pyrrolidine as a white solid; (3) Preparation of (4-hydroxyphenyl)(2-(3-(pyrrolidin-1-yl)propyl)benzofuran-3-yl)methanone: 1-(3-(benzofuran-2-yl)propyl)pyrrolidine and p-hydroxybenzoyl chloride were added to a toluene solution, cooled to -5 to 0°C in an ice-water bath, and aluminum chloride was added in batches. The reaction was kept warm. After the reaction was completed, the reaction solution was poured into 5% to 10% dilute hydrochloric acid to quench. The phases were separated, and the aqueous phase was extracted with toluene. The organic phase was collected and dried, and vacuum rotary evaporation was performed to obtain a light yellow solid (4-hydroxyphenyl)(2-(3-(pyrrolidin-1-yl)propyl)benzofuran-3-yl)methanone. (4) Preparation of (4-(oxiran-2-ylmethoxy)phenyl)(2-(3-(pyrrolidin-1-yl)propyl)benzofuran-3-yl)methanone: A sodium hydroxide aqueous solution was added to the reaction flask, followed by the addition of (4-hydroxyphenyl)(2-(3-(pyrrolidin-1-yl)propyl)benzofuran-3-yl)methanone and an appropriate amount of tetrabutylammonium bromide, and epichlorohydrin was added dropwise. After the addition was complete, the mixture was heated to reflux. After the reaction was complete, the mixture was cooled to room temperature and extracted three times with ethyl acetate. The mixture was washed with water until neutral, and the organic phase was dried and evaporated under reduced pressure to obtain (4-(oxiran-2-ylmethoxy)phenyl)(2-(3-(pyrrolidin-1-yl)propyl)benzofuran-3-yl)methanone. (5) Preparation of (4-(2-hydroxy-3-(pyridin-4-ylamino)propyloxy)phenyl)(2-(3-(pyrrolidin-1-yl)propyl)benzofuran-3-yl)methanone: (4-Hydroxyphenyl)(2-(3-(pyrrolidin-1-yl)propyl)benzofuran-3-yl)methanone, tetraaminopyridine, and isopropanol were added to a reaction flask and stirred to dissolve. Aluminum trichloride was added while stirring, and the temperature was raised to 80-100°C for reaction. After completion of the reaction, the mixture was cooled and evaporated under reduced pressure to obtain a yellow oil, which was then purified by column chromatography to obtain the compound of Formula I.

4. The preparation method according to claim 3, characterized in that In step (1), the molar ratio of 3-(benzofuran-2-yl)propan-1-ol, triethylamine or N,N-diisopropylethylamine, and methanesulfonyl chloride is 25-30:30-36:30-35, and the organic solvent is dichloromethane.

5. The preparation method according to claim 3, characterized in that In step (2), the molar ratio of 3-(benzofuran-2-yl)propyl methanesulfonate to tetrahydropyrrole is 20-25:45-50.

6. The preparation method according to claim 3, characterized in that In step (3), the molar ratio of 1-(3-(benzofuran-2-yl)propyl)pyrrolidine, p-hydroxybenzoyl chloride, and aluminum chloride is 15-18:20-25:20-25.

7. The preparation method according to claim 3, characterized in that In step (4), the molar ratio of (4-hydroxyphenyl)(2-(3-(pyrrolidin-1-yl)propyl)benzofuran-3-yl)methanone, tetrabutylammonium bromide, and epichlorohydrin is 10-12:1:30-32; in step (5), the molar ratio of (4-(oxiran-2-ylmethoxy)phenyl)(2-(3-(pyrrolidin-1-yl)propyl)benzofuran-3-yl)methanone, tetraaminopyridine, and aluminum chloride is 10-12:50-55:5-8.

8. A pharmaceutical composition, characterized in that The benzofuran derivative according to claim 1 is used as a pharmaceutical active ingredient.

9. Use of the benzofuran derivative according to claim 1 or the pharmaceutical composition according to claim 8 in the preparation of an antiarrhythmic drug.

10. The use according to claim 9, characterized in that The related indications corresponding to the arrhythmia are selected from paroxysmal or persistent atrial fibrillation or atrial flutter, sinus rhythm or cardioversion or a combination thereof.

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