Nuciferine derivatives, methods of making and using the same

Abstract

The application discloses a nuciferine derivative, a preparation method and application thereof, and relates to the technical field of medicines.The application provides a nuciferine derivative, and further provides a preparation method of the nuciferine derivative.The nuciferine derivative provided by the application greatly improves the treatment effect of arrhythmia, reduces the adverse reaction of the drug, and reduces the risk of inducing ventricular arrhythmia; in addition, the raw material is cheap and easy to obtain, the production cost is greatly reduced, the nuciferine derivative is suitable for large-scale production, and the nuciferine derivative has a certain treatment effect on QT syndrome, and has a wide application prospect in the preparation of drugs for resisting arrhythmia and treating QT syndrome.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to lotus leaf alkaloid derivatives, their preparation methods, and applications. Background Technology

[0002] Cardiac arrhythmia refers to cardiovascular diseases caused by abnormalities in the frequency, rhythm, origin of the heartbeat, and direction and sequence of conduction in the atria and ventricles. Common clinical symptoms include palpitations, and in severe cases, dizziness, blurred vision, and even sudden death can occur. Arrhythmias can exist alone or accompany other organic heart disease attacks, and their prognosis is closely related to their etiology, precipitating factors, and hemodynamics. The main pathogenesis of arrhythmias is the obstruction of the origin and conduction function of cardiac activity, thus leading to problems with the rhythm or frequency of heartbeats. The occurrence of arrhythmias is usually accompanied by receptor blockade and changes in the current of ion channels in myocardial cells. Ideally, antiarrhythmic drugs should act gently on the optimal target, such as sodium ion channels and calcium ion channels.

[0003] There are two main approaches to treating arrhythmias: medication and pacemaker implantation. Beta-adrenergic agonists, M-cholinergic receptor blockers, and phosphodiesterase inhibitors are commonly used clinical medications. Isoproterenol, epinephrine, and ephedrine are all beta-adrenergic receptor agonists, while M-cholinergic receptor blockers, including atropine, can enhance myocardial contractility and increase heart rate using cyclic adenosine monophosphate. Additionally, aminophylline, glucocorticoids, and thyroxine can improve atrioventricular conduction by specifically stimulating the sinoatrial junction. While Western medicine can significantly increase heart rate, it also has side effects such as dry mouth, facial flushing, difficulty urinating, nausea, vomiting, restlessness, insomnia, and tachycardia, and is generally not recommended for long-term use. Pacemaker implantation is an effective strategy for treating arrhythmias, but it is expensive, requires lifelong follow-up, and has limitations in implantation techniques, hindering its widespread adoption. Furthermore, it carries certain surgical risks, leading to complications such as pacemaker failure and electrode dislocation.

[0004] In the field of Traditional Chinese Medicine (TCM), arrhythmia falls under the category of "palpitation," and this condition is one of the areas where TCM has a strong advantage in treatment. Within the realm of Chinese herbal medicine, prescriptions for treating arrhythmia are essentially composed of safe natural compounds. Therefore, TCM has a significant advantage in treating arrhythmia.

[0005] Therefore, developing a safe and effective antiarrhythmic drug is of great scientific and economic significance. Summary of the Invention

[0006] The purpose of this invention is to provide lotus leaf alkaloid derivatives, their preparation methods, and applications.

[0007] To achieve the above-mentioned objectives, the technical solution of the present invention is as follows:

[0008] On one hand, the present invention provides a lotus leaf alkaloid derivative, the structure of which is shown below:

[0009]

[0010] The R-based structure can be any one of the following structures:

[0011]

[0012] In another aspect, the present invention provides a method for preparing the above-mentioned lotus leaf alkaloid derivative, the chemical reaction formula of which is as follows:

[0013]

[0014] The reaction conditions were: (a) EDCI, HOBt, DCM, rt, 24hrs; (b)(i) PCl5, DCM, reflux, 20mins; (ii) NaBH4, MeOH, 0℃ to rt, 2hrs; (c) Et3N, TFAH, CH2Cl2, 1.5hrs; (d) Pd(OAc)2, Phosphine, K2CO3, DMA, 130℃, rt to N2, 4hrs; (e) EtOH, NaBH4, rt to N2, 4hrs.

[0015] Specifically, the preparation method of compound 2-(2-bromophenyl)-N-(3,4-dimethoxyphenethyl)acetamide shown in Formula 1 is as follows: 2-bromophenylacetic acid is dissolved in dichloromethane (DCM), and 1-hydroxyphenyltriazole (HOBT), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 3,4-dimethoxyphenethylamine, and triethylamine (ET3N) are added and reacted to obtain the compound shown in Formula 1; the chemical reaction formula is as follows:

[0016]

[0017] The preparation method of compound 1-(2-bromobenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline shown in Formula 2 is as follows: The compound shown in Formula 1 is dissolved in DCM, phosphorus pentachloride (PCl5) is added, and after reflux, the DCM is evaporated to dryness. MeOH and sodium borohydride are then added, and the reaction proceeds to obtain the compound shown in Formula 2. Specifically, the reflux reaction time is 10-30 min; further, the reflux reaction time is 20 min. The chemical reaction formula is as follows:

[0018]

[0019] The preparation method of compound 1-(1-(2-bromobenzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one shown in Formula 3 is as follows: The compound shown in Formula 2 is dissolved in DCM, and trifluoroacetic anhydride (TFAH) and Et3N are added, followed by a reaction to obtain the compound shown in Formula 3. Specifically, the reaction temperature is 0-5℃, and the reaction time is 1-3 h; further, the reaction temperature is 0℃, and the reaction time is 2 h. The chemical reaction formula is as follows:

[0020]

[0021] The compound 1-(1,2-dimethoxy-4,5,6a,7-tetrahydro-6H-dibenzo[de,g]quinolin-6-yl)-2,2,2-trifluoroethane-1-one shown in Formula 4 was prepared by dissolving the compound shown in Formula 3 in N,N-dimethylacetamide (DMA), followed by adding tris(4-fluorophenyl)phosphine ((FC6H4)3P), K2CO3, and palladium acetate (Pd(OAc)2) to the reaction to obtain the compound shown in Formula 4. Specifically, the reaction temperature was 100-150℃, and the reaction time was 5-10 h; further, the reaction temperature was 130℃, and the reaction time was 6 h. The chemical reaction formula is as follows:

[0022]

[0023] The preparation method of compound 1,2-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline shown in Formula 5 is as follows: The compound shown in Formula 4 is dissolved in DCM, NaBH4 is added, and the reaction proceeds to obtain the compound shown in Formula 5. Specifically, the temperature at which NaBH4 is added is 0℃, and the reaction time is 3-5 h; further, the reaction time is 4 h. The chemical reaction formula is as follows:

[0024]

[0025] The compound shown in Formula 5, under the action of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIEPA), or triethylamine, generates a series of lotus leaf alkaloid derivatives: the chemical reaction formulas are as follows:

[0026]

[0027] Specifically, when the R-group structure is 6a, the preparation method of compound 2-(2-bromophenyl)-1-(1,2-dimethoxy-4,5,6a,7-tetrahydro-6H-dibenzo[de,g]quinolin-6-yl)ethyl-1-one shown in formula 6a is as follows: the compound shown in formula 5 is dissolved in DMF, and 2-bromophenylacetic acid, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIEPA) are added, and the reaction is carried out to obtain the compound shown in formula 6a; specifically, the reaction time is 15-20 h, and further, the reaction time is 18 h.

[0028] When the R-group structure is 6b, the preparation method of compound (4-chloromethylphenyl)(1,2-dimethoxy-4,5,6a,7-tetrahydro-6H-dibenzo[de,g]quinoline-6-yl) ketone shown in formula 6b is as follows: the compound shown in formula 5 is dissolved in DMF, 4-(chloromethyl)benzoic acid, HATU and DIEPA are added, and the reaction is carried out to obtain the compound shown in formula 6b; specifically, the reaction temperature is room temperature, the reaction time is 15-20 h, and further, the reaction time is 18 h.

[0029] When the R-group structure is 6c, the preparation method of compound (1,2-dimethoxy-4,5,6a,7-tetrahydro-6H-dibenzo[de,g]quinoline-6-yl)(4-fluorophenyl) methyl ketone shown in formula 6c is as follows: the compound shown in formula 5 is dissolved in DMF, 4-fluorobenzoic acid, HATU and DIEPA are added, and the reaction is carried out to obtain the compound shown in formula 6c; specifically, the reaction temperature is room temperature, the reaction time is 15-20 h, and further, the reaction time is 18 h.

[0030] The synthesis of compound (1,2-dimethoxy-4,5,6a,7-tetrahydro-6H-dibenzo[de,g]quinoline-6-yl)(4-methoxyphenyl) ketone, with R-group structure 6d, is as follows: The compound shown in Formula 5 is dissolved in DMF, and 4-methoxybenzoic acid, HATU, and DIEPA are added. After reaction, the compound shown in Formula 6d is obtained. Specifically, the reaction temperature is room temperature, and the reaction time is 15-20 h, further, the reaction time is 18 h.

[0031] The synthesis of compound 1-(1,2-dimethoxy-4,5,6a,7-tetrahydro-6H-dibenzo[de,g]quinolin-6-yl)prop-2-en-1-one with R-group structure 6g: The compound shown in formula 5 was dissolved in DMF, and acrylic acid, HATU and DIEPA were added. After reaction, the compound shown in formula 6g was obtained. Specifically, the reaction temperature was room temperature, and the reaction time was 15-20 h. Further, the reaction time was 18 h.

[0032] The synthesis of compound (1,2-dimethoxy-4,5,6a,7-tetrahydro-6H-dibenzo[de,g]quinoline-6-yl)(2-methylfuran-3-yl) ketone, with R-group structure 6h, is as follows: The compound shown in Formula 5 is dissolved in DMF, and 2-methylfuran-3-carboxylic acid, HATU, and DIEPA are added. The reaction is carried out to obtain the compound shown in Formula 6h. Specifically, the reaction temperature is room temperature, and the reaction time is 15-20 h, further, the reaction time is 18 h.

[0033] When the R-group structure is 6e, the compound shown in formula 6e (1,2-dimethoxy-6-toluenesulfonyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline) is synthesized by dissolving the compound shown in formula 5 in DCM, adding p-toluenesulfonyl chloride and Et3N, and then reacting to obtain the compound shown in formula 6e; specifically, the reaction temperature is room temperature, the reaction time is 20-25 h, and further, the reaction time is 24 h.

[0034] The synthesis of compound (1,2-dimethoxy-4,5,6a,7-tetrahydro-6H-dibenzo[de,g]quinoline-6-yl)(pyrrolidine-1-yl) ketone, when the R-group structure is 6f, is as follows: the compound shown in formula 5 is dissolved in DMF, and then pyrrolidine-1-formyl chloride, potassium carbonate, and potassium iodide are added and reacted to obtain the compound shown in formula 6f; specifically, the reaction temperature is room temperature, and the reaction time is 40-50 h, further, the reaction time is 48 h.

[0035] When the R-group structure is 6i, the synthesis of compound 1,2-dimethoxy-6-(methanesulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline shown in formula 6i is as follows: the compound shown in formula 5 is dissolved in DCM, and after adding methanesulfonyl chloride and Et3N, the reaction is carried out to obtain the compound shown in formula 6i; specifically, the reaction temperature is room temperature, the reaction time is 40-50 h, and further, the reaction time is 48 h.

[0036] When the R-group structure is 6j, the synthesis of the compound shown in formula 6j ((1,2-dimethoxy-4,5,6a,7-tetrahydro-6H-dibenzo[de,g]quinoline-6-yl)(4-methylpiperazin-1-yl) methyl ketone) is as follows: the compound shown in formula 5 is dissolved in DCM, and 4-methylpiperazin-1-formyl chloride, K2CO3 and KI are added and reacted to obtain the compound shown in formula 6j; specifically, the reaction temperature is room temperature and the reaction time is 40-50 h, further, the reaction time is 48 h.

[0037] When the R-group structure is 6l, the synthesis of the compound shown in formula 6l ((1,2-dimethoxy-4,5,6a,7-tetrahydro-6H-dibenzo[de,g]quinoline-6-yl)(morpholino) ketone) is as follows: the compound shown in formula 5 is dissolved in DCM, and morpholino-4-formyl chloride, K2CO3 and KI are added and reacted to obtain the compound shown in formula 6l; specifically, the reaction temperature is room temperature and the reaction time is 40-50 h, further, the reaction time is 48 h.

[0038] The synthesis of the compound (N,N-diethyl-1,2-dimethoxy-4,5,6a,7-tetrahydro-6H-dibenzo[de,g]quinoline-6-carboxamide) with the R-group structure 6m is as follows: The compound shown in Formula 5 is dissolved in DCM, and then diethylcarbamoyl chloride, K2CO3 and KI are added and reacted to obtain the compound shown in Formula 6m; specifically, the reaction temperature is room temperature and the reaction time is 40-50 h, further, the reaction time is 48 h.

[0039] The synthesis of the compound (N,N-dimethyl-1,2-dimethoxy-4,5,6a,7-tetrahydro-6H-dibenzo[de,g]quinoline-6-carboxamide) with the R-group structure of 6n is as follows: The compound shown in Formula 5 is dissolved in DCM, and dimethylcarbamoyl chloride, K2CO3 and KI are added and reacted to obtain the compound shown in Formula 6n; specifically, the reaction temperature is room temperature and the reaction time is 40-50 h, further, the reaction time is 48 h.

[0040] The synthesis of compound 6k (1,2-dimethoxy-6-(4-methoxybenzyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline) with the R-group structure 6k is as follows: The compound shown in formula 5 is dissolved in DCM, and then p-methoxybenzaldehyde and sodium triacetylborohydride are added, followed by reaction to obtain the compound shown in formula 6k. Specifically, the reaction temperature is room temperature, and the reaction time is 20-30 h; further, the reaction time is 24 h.

[0041] In another aspect, the present invention provides the application of the lotus leaf alkaloid derivative prepared by the above-mentioned preparation method in the preparation of drugs for treating arrhythmia.

[0042] Specifically, the arrhythmias include sinus arrhythmias, atrial arrhythmias, supraventricular arrhythmias, and ventricular arrhythmias.

[0043] Furthermore, the sinus arrhythmias include sinus bradycardia, sinus tachycardia, sinus arrhythmia, sinus arrest, and sinoatrial block; the atrial arrhythmias include premature atrial contractions, atrial tachycardia, and premature atrial contractions; the supraventricular arrhythmias include paroxysmal supraventricular tachycardia; and the ventricular arrhythmias include premature ventricular contractions, ventricular tachycardia, and ventricular fibrillation.

[0044] Furthermore, the aforementioned arrhythmia is a barium chloride-induced arrhythmia or aconitine-induced arrhythmia.

[0045] Preferably, the R-group structure of the lotus leaf alkaloid derivative is 6a.

[0046] Specifically, the lotus leaf alkaloid derivative is used as an active ingredient in the drug.

[0047] Specifically, the dosage form of the drug is drops, mixture, tincture, injection, tablet, powder, oral liquid, capsule, granule, ointment, suspension, powder, emulsion, solution, drop pill, pill, lozenge, lyophilized powder for injection, gel, suppository or aerosol.

[0048] Furthermore, the dosage form of the drug is an injection.

[0049] Specifically, the dosage of the drug, calculated based on the dosage of lotus leaf alkaloid derivatives, is 1.5-15 mg / kg;

[0050] Furthermore, the dosage of the drug, calculated based on the dosage of lotus leaf alkaloid derivatives, is 2.5-10 mg / kg.

[0051] In another aspect, the present invention provides the application of the lotus leaf alkaloid derivative prepared by the above-mentioned preparation method in the preparation of drugs for treating QT syndrome.

[0052] Specifically, the QT syndromes mentioned include long QT syndrome and short QT syndrome.

[0053] Preferably, the R-group structure of the lotus leaf alkaloid derivative is 6a.

[0054] Furthermore, the dosage form of the drug is an injection.

[0055] The beneficial effects of this invention are as follows:

[0056] The lotus leaf alkaloid derivative provided by this invention greatly improves the therapeutic effect of antiarrhythmia, reduces adverse drug reactions, and reduces the risk of inducing ventricular arrhythmias compared with existing products. Moreover, the raw materials are inexpensive and readily available, which greatly reduces production costs and makes it suitable for large-scale production.

[0057] The lotus leaf alkaloid derivative of this invention can shorten the recovery time of arrhythmia, prolong the time after the heart rate returns to normal, reduce heart rate, shorten QT interval and QRS duration, increase RR interval, QTc and R voltage, and increase the duration of ventricular premature beats, ventricular tachycardia, ventricular fibrillation and cardiac arrest. It can significantly reduce the amplitude of action potential and resting potential, and has a strong affinity for the inactivation and activation process of Nav and Cav channels. It has a certain therapeutic effect on short QT syndrome and long QT syndrome. Attached Figure Description

[0058] Figure 1 The image shows the hydrogen spectrum of compound 1.

[0059] Figure 2 This is the carbon spectrum of compound 1.

[0060] Figure 3 The image shows the hydrogen spectrum of compound 2.

[0061] Figure 4 The image shows the carbon spectrum of compound 2.

[0062] Figure 5 The image shows the hydrogen spectrum of compound 3.

[0063] Figure 6 This is the carbon spectrum of compound 3.

[0064] Figure 7 This is the hydrogen spectrum of compound 4.

[0065] Figure 8 This is the carbon spectrum of compound 4.

[0066] Figure 9 This is the hydrogen spectrum of compound 5.

[0067] Figure 10 This is the carbon spectrum of compound 5.

[0068] Figure 11 This is the hydrogen spectrum of compound 6a.

[0069] Figure 12 This is the carbon spectrum of compound 6a.

[0070] Figure 13 The image shows the proton NMR spectrum of compound 6b.

[0071] Figure 14 This is the carbon spectrum of compound 6b.

[0072] Figure 15 This is the hydrogen spectrum of compound 6c.

[0073] Figure 16 This is the carbon spectrum of compound 6c.

[0074] Figure 17 This is the proton NMR spectrum of the compound of formula 6d.

[0075] Figure 18 This is the carbon spectrum of the compound of formula 6d.

[0076] Figure 19 This is the hydrogen spectrum of the compound of formula 6e.

[0077] Figure 20 This is the carbon spectrum of the compound of formula 6e.

[0078] Figure 21 This is the proton NMR spectrum of compound 6f.

[0079] Figure 22 This is the carbon spectrum of compound 6f.

[0080] Figure 23 The image shows the hydrogen spectrum of compound 6g.

[0081] Figure 24 The image shows the carbon spectrum of compound 6g.

[0082] Figure 25 The image shows the proton NMR spectrum of compound 6h.

[0083] Figure 26 This is the carbon spectrum of compound of formula 6h.

[0084] Figure 27 The hydrogen spectrum of compound 6i is shown.

[0085] Figure 28 This is the carbon spectrum of compound 6i.

[0086] Figure 29 The image shows the proton NMR spectrum of compound 6j.

[0087] Figure 30 The image shows the carbon spectrum of compound 6j.

[0088] Figure 31 The image shows the proton NMR spectrum of compound 6k.

[0089] Figure 32 This is the carbon spectrum of compound 6k.

[0090] Figure 33 The image shows the proton NMR spectrum of compound 6l.

[0091] Figure 34 The image shows the carbon spectrum of compound 6l.

[0092] Figure 35 The image shows the proton NMR spectrum of the compound of formula 6m.

[0093] Figure 36 This is the carbon spectrum of the compound of formula 6m.

[0094] Figure 37 This is the hydrogen spectrum of the compound of formula 6n.

[0095] Figure 38 This is the carbon spectrum of the compound of formula 6n.

[0096] Figure 39 The effect of lotus leaf alkaloid derivatives on aconitine-induced arrhythmias (n=6); In the figure, A represents the amount of aconitine required to induce VP in rats; B represents the amount of aconitine required to induce VT in rats; C represents the amount of aconitine required to induce VF in rats; D represents the amount of aconitine required to induce CA in rats; Compared with NS: #P<0.05, ##P<0.01, ###P<0.001; Compared with DMSO: ▲P<0.05, ▲▲P<0.01, ▲▲▲P<0.001; Compared with Verapamil: +P<0.05, ++P<0.01, +++P<0.001; Compared with Nucifenrine: *P<0.05, **P<0.01, ***P<0.001.

[0097] Figure 40 The effect of different concentrations of 6a on the recovery time of BaCl2-induced arrhythmias (n=6) was compared with that of NS: ###P<0.001.

[0098] Figure 41 The effect of different concentrations of 6a on the duration of normal heart rhythm induced by BaCl2 (n=6); compared with NS: ###P<0.001; compared with DMSO: ▲P<0.05, ▲▲▲P<0.001.

[0099] Figure 42 The effects of 6a on electrocardiographic parameters in normal rats (n=6); in the figure, A is the effect of 6a on rat heart rate (HR), B is the effect of 6a on rat respiratory rate (RR), C is the effect of 6a on rat QT, D is the effect of 6a on rat QTc, E is the effect of 6a on rat R voltage, and F is the effect of 6a on rat QRS. Compared with 30s: *P<0.05, **P<0.01, ***P<0.001.

[0100] Figure 43The effect of compound 6a on APD of rat cardiomyocytes (n=9) is shown in the figure. A represents the effect of 6a at a concentration of 10 μM on APD of rat cardiomyocytes; B represents the effect of 6a at a concentration of 10 μM on APA of rat cardiomyocytes; C represents the effect of 6a at a concentration of 10 μM on resting potential of rat cardiomyocytes; D represents the effect of 6a at a concentration of 10 μM on maximum depolarization rate (Vmax) of AP; E and G represent the effects of 6a at a concentration of 10 μM on repolarization of rat cardiomyocytes to 10%, 50%, and 90% (APD10, 50, 90), respectively. Compared with the control group: *p<0.05, ***p<0.001.

[0101] Figure 44 The compound shown in Formula 6a has an effect on rat cardiomyocytes I Na Effects of activation, inactivation, and recovery; A is the effect of 6a on I at a concentration of 10 μM. Na The effect of steady-state activation current curve; in B, the left side represents I in rat cardiomyocytes. Na The IV relationship diagram; the middle of B is the steady-state activation curve calculated from the IV curve; the right side of B is the I... Na A typical schematic diagram; C represents I. Na Steady-state deactivation current trajectory diagram; D represents I Na Steady-state deactivation curve; E is I Na Recovery curve current trajectory diagram after deactivation; F is N av Recovery curve after inactivation.

[0102] Figure 45 The compound shown in Formula 6a has an effect on rat ventricular myocytes I Ca Effects of activation, inactivation, and recovery; A is I Ca Steady-state activation current curve; in B, the left side represents I in rat ventricular myocytes. Ca The IV relationship diagram; the middle of B is the steady-state activation curve calculated from the IV curve; the right side of B is the I... Ca A typical schematic diagram; C represents I. Ca Steady-state deactivation current curve; D represents I Ca Steady-state deactivation curve; E is I Ca The current trajectory diagram of the recovery curve after deactivation; F is the recovery curve after Cav deactivation.

[0103] Figure 46 A represents the effect of compound 6a on Nav1.5 sodium current (INa) in HEK293 cells; A represents the effect of compound 6a (1 μM-100 μM) on I Na The influence of peaks; B represents I after treatment with compound 6a in a resting or semi-inactivated state. Na Curve; C represents the inhibitory effect of 6a on Nav1.5 in the resting or semi-inactivated state (n=4).

[0104] Figure 47 The effect of the compound shown in Formula 6a on the Cav1.2 channel; A represents the effect of the compound in V... H At -60mV, the effect of different concentrations of 6a on the Cav1.2 channel; B is the current curve of 6a acting on Cav1.2; C is the suppression effect of 6a on the current of the Cav1.2 channel.

[0105] Figure 48 A shows the effect of the compound shown in Formula 6a on the hERG channel; B shows the effect of different concentrations of compound 6a on the hERG channel; C shows the inhibitory effect of compound 6a on the IKr current; D shows the effect of different concentrations of 6a on the IKr current.

[0106] Figure 49 A shows the effect of cisapride on hERG channels; B shows the effect of different concentrations of cisapride on hERG channels; C shows the IKr current curve after cisapride treatment; and D shows the inhibitory effect of cisapride on IKr current. Detailed Implementation

[0107] To make the technical means, creative features, objectives, and effects of this invention easier to understand, the invention is further illustrated below with reference to specific embodiments. However, the following embodiments are only preferred embodiments of this invention and not all embodiments. Unless otherwise specified, the operating methods and equipment used in the following embodiments are all conventional operating methods, and the materials used in each embodiment are the same.

[0108] Example 1

[0109] 5.00 g of 2-bromophenylacetic acid was dissolved in dichloromethane (DCM). After stirring for 10 min in an ice bath, 3.15 g of 1-hydroxyphenyltriazole (HOBT) and 4.45 g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) were added. After reacting for 20 min in an ice bath, 3.80 g of 3,4-dimethoxyphenylethylamine (0.8 equivalent) and 2.25 g of triethylamine (ET3N) (1.1 equivalent) were added. After reacting for 1 h in an ice bath, the ice bath was removed, and the reaction was continued at room temperature for 24 h. The product was then extracted with a dilute hydrochloric acid aqueous solution at pH 4-5, and the organic layer was dried with anhydrous sodium sulfate and concentrated. The concentrated product was dissolved in DCM until completely dissolved, and then frozen ethyl acetate (EA) was added until crystals precipitated. The mixture was then sealed and stored at -20°C for crystallization. After 24 hours, the solution was filtered to obtain precipitated crystals, which were determined to be compound of formula 1 with relative purity. The proton NMR spectrum of compound 1 is shown below. Figure 1 As shown, the carbon spectrum of compound 1 is as follows: Figure 2 As shown.

[0110] 1 H NMR(400MHz,CHLOROFORM-d)d ppm 2.73(t,J=6.93Hz,2H)3.46-3.54(m,2H)3.69(s,2H)3.88(s,3H)3.86(s,3H)5.47(br.s.,1H)6.58-6.6 7(m,2H)6.75(d,J=8.17Hz,1H)7.13-7.20(m,1H)7.26-7.29(m,1H)7.30(s,1H)7.57(d,J=8.04Hz,1H); 13 C NMR(101MHz,CHLOROFORM-d)d ppm 35.04,40.81,44.10,55.86,55.96,111.36,111.81,120.61,124.98,127. 97,129.09,131.11,131.68,133.10,134.82,147.66,149.04,169.48; HRMS m / z calcd for[C 18 H 20 BrNO3+H] + 380.0627, found 380.0657.

[0111] Example 2

[0112] Compound 1 (3.50 g) was dissolved in DCM. Three times the amount of phosphorus pentachloride (PCl5), 5.80 g, was added under ice bath conditions. The reaction was carried out for 10 min under ice bath conditions, then the ice bath was removed, and the mixture was heated under reflux for 2 h. The pH was adjusted to neutral with saturated sodium bicarbonate (NaHCO3). The mixture was extracted with water and DCM, and the organic layer was dried over anhydrous sodium sulfate. The solution was concentrated using a rotary evaporator to obtain an oil. The oil was dissolved in methanol and evaporated to dryness. Three times the amount of sodium borohydride (NaBH4), 1.05 g, was added in small batches at 0 °C. The reaction was carried out for 30 min at 0 °C, then overnight at room temperature. The reaction mixture was evaporated to dryness, extracted with DCM and water, and the organic layer was dried over anhydrous sodium sulfate. The organic layer was purified by column chromatography to obtain compound 2 (2.68 g), with a yield of 79.57%. The proton NMR spectrum of compound 2 is shown below. Figure 3 As shown, the carbon spectrum of compound 2 is as follows. Figure 4 As shown.

[0113] 1H NMR(400MHz,CHLOROFORM-d)d ppm 1.75(br.s.,1H)2.72-2.84(m,2H)2.96-3.09(m,2H)3.29(dt,J=12.43,6.15Hz,1H)3.39(dd,J=13.61,3.84Hz,1H)3.89(s,3H)3.85 (s,3H)4.30(dd,J=9.90,3.71Hz,1H)6.63(s,1H)6.76(s,1H)7.15(dt,J=8.41,4.33Hz,1H)7.29-7.32(m,2H)7.63(d,J=7.92Hz,1H); 13 CNMR(101MHz,CHLOROFORM-d)d ppm29.47,40.06,43.23,54.92,55.88,55.97,109.76,111.77,124.97,127 .22,127.44,128.24,130.60,132.02,133.10,138.89,147.10,147.57; HRMS m / z calcd for[C 18 H 20 BrNO2+H] + 362.0667, found 362.0677.

[0114] Example 3

[0115] 2.68 g of compound 2 was dissolved in DCM, and 1.2 times the amount of trifluoroacetic anhydride (TFAH) (1.86 g) and 2.5 times the amount of Et3N (1.87 g) were added under ice bath conditions. After reacting at 0°C for 2 h, the mixture was extracted with dilute hydrochloric acid aqueous solution at pH 5-6. The organic layer was collected and extracted again with saturated sodium chloride (NaCl) and saturated NaHCO3 solution. The organic layer was dried over anhydrous NaSO4, concentrated, and purified by column chromatography to obtain product 3 (2.58 g) in 75.68% yield. The proton NMR spectrum of compound 3 is shown below. Figure 5 As shown, the carbon spectrum of compound 3 is as follows: Figure 6 As shown.

[0116] 1H NMR(400MHz,CHLOROFORM-d)d ppm 2.83(dt,J=16.11,3.51Hz,1H)2.98(ddd,J=16.24,11.04,5.51Hz,1H)3.21( dd,J=13.61,8.78Hz,1H)3.39-3.47(m,1H)3.75(s,3H)3.77-3.83(m,1H)3.8 8(s,3H)4.02-4.12(m,1H)5.81(dd,J=8.66,5.94Hz,1H)6.49(s,1H)6.60-6. 65(m,1H)7.09-7.18(m,2H)7.20-7.27(m,1H)7.56(dd,J=7.92,0.99Hz,1H); 13 CNMR(101MHz,CHLOROFORM-d)d ppm 28.77,40.02,40.06,41.55,53.83,55.85,55.92,110.08,111.06,124.86,12 5.40,126.62,127.36,128.71,131.48,132.86,136.54,147.71,148.32; HRMS m / z calcd for[C 20 H 19 BrF3NO3+H] + 460.0450, found 460.0500.

[0117] Example 4

[0118] Dissolve 2.58 g of compound 3 in N,N-dimethylacetamide (DMA), then add 0.35 g of tris(4-fluorophenyl)phosphine ((FC6H4)3P) and 0.78 g of K2CO3. React under N2 protection at 130 °C for 3 h, then add 0.13 g of palladium acetate (Pd(OAc)2) and continue the reaction. After 3 h, TLC analysis was performed. The reaction solution was filtered through silica gel, extracted with water and DCM, and purified by column chromatography to obtain 1.83 g of compound 4, with a yield of 89.29%. The proton NMR spectrum of compound 4 is shown below. Figure 7 As shown, the carbon spectrum of compound 4 is as follows. Figure 8 As shown.

[0119] 1 H NMR(400MHz,CHLOROFORM-d)ppm 2.76(d,J=15.65Hz,1H)2.83

[0120] -2.91(m,1H)2.94(dd,J=12.53,3.73Hz,1H)3.06(dd,J=13.45,4.03Hz,1H)3.30

[0121] -3.41(m,1H)3.68(s,3H)3.90(s,3H)4.18-4.27(m,1H)5.03(dd,J=13.75,3.85 Hz,1H)6.67(s,1H)7.23-7.26(m,1H)7.30-7.38(m,1H)8.45(d,J=7.82Hz,1H); 13 C NMR(101MHz,CHLOROFORM-d)d ppm 28.79,30.39,33.58,52.29,53.83,55.85,55.94,56.03,60.10,111.28,127.35 ,128.05,128.39,128.56,128.64,128.73,131.31,131.48,132.90,135.77; HRMS m / z calcd for[C 20 H 18 F3NO3+Na] + 400.1239, found 400.1205.

[0122] Example 5

[0123] EtOH was added to dissolve 1.83 g of compound 4, and then 20 times the amount of NaBH4 (3.82 g) was added in small, repeated batches at 0 °C. The reaction was carried out at 0 °C for 4 h. After TLC analysis, the mixture was extracted with dilute hydrochloric acid aqueous solution (pH 5-6) and DCM. The organic layer was dried over anhydrous Na2SO4 and purified by column chromatography to obtain compound 5 (1.13 g), with a yield of 79.89%. The proton NMR spectrum of compound 5 is shown below. Figure 9 As shown, the carbon spectrum of compound 5 is as follows. Figure 10 As shown.

[0124] 1 H NMR(400MHz,CHLOROFORM-d)ppm 2.65-2.80(m,3H)2.81-2.88(m,1H)2.97(s,1H)3.01(d,J=8.68Hz,2H)3.34-3.40(m,1H)3.67(s,3H)3. 89(s,3H)6.60(d,J=3.42Hz,1H)6.65(s,1H)7.21-7.25(m,2H)7.29-7.34(m,1H)8.39(d,J=7.82Hz,1H); 13C NMR(101MHz,METHANOL-d4)d ppm 27.23,35.72,42.09,53.19,55.01,59.19,111.74,126.22,126.30,126.8 0,127.39,127.61,128.03,128.17,131.78,135.18,145.25,152.65; HRMS m / z calcd for[C 18 H 19 NO2+H] + 282.1416, found 282.1497.

[0125] Example 6

[0126] Dissolve 0.20 g of compound 5 in DMF. In a 25 mL reaction flask, add 0.18 g of 2-bromophenylacetic acid (1.5 times the amount) and 0.40 g of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (1.8 times the amount), then dissolve in DMF. Stir at room temperature for 0.5 h. Add the DMF-dissolved compound V dropwise to the reaction flask, followed by the addition of 0.14 g of N,N-diisopropylethylamine (DIEPA) (1.8 times the amount). React at room temperature for 18 h with N2. After TLC detection and rotary evaporation to dryness, purify by normal silica gel column chromatography to obtain compound 6a (0.23 g), with a yield of 73.15%. The 1H NMR spectrum of compound 6a is shown below. Figure 11 As shown, the carbon spectrum of compound 6a is as follows: Figure 12 As shown.

[0127] 1 H NMR(400MHz,DMSO-d6)d ppm 2.70-3.04(m,4H)3.23-3.33(m,1H)3.61(s,3H)3.86(s,3H)3.94-4.06(m,2H)4.19-4.27(m,1H)4.79-4.91(m,1 H)6.91-6.98(m,1H)7.16-7.23(m,1H)7.27-7.32(m,2H)7.36-7.41(m,3H)7.55-7.68(m,1H)8.23-8.37(m,1H); 13C NMR(101MHz,DMSO-d6)d ppm30.49,34.09,41.16,41.36,50.62,56.30,60.05,112.75,125.19,126.10,126.98,127.35,128.07,128. 16,128.38,128.89,129.12,130.01,131.71,132.29,132.70,136.63,137.27,145.51,152.19,168.46; HRMS m / z calcd for[C 26 H 24 BrNO3+Na] + 500.0950, found 500.0917.

[0128] Example 7

[0129] In a 25 ml reaction flask, 0.18 g of 1.5 times the amount of 4-(chloromethyl)benzoic acid, 0.20 g of 1 times the amount of compound 5, 0.40 g of HATU, and 0.14 g of DIEPA were added. Other procedures were the same as in Example 6. After purification by column chromatography, compound 6b (0.25 g) was obtained in 81.52% yield. The proton NMR spectrum of compound 6b is shown below. Figure 13 As shown, the carbon spectrum of compound 6b is as follows: Figure 14 As shown.

[0130] 1 H NMR(400MHz,CHLOROFORM-d)ppm 2.64(d,J=15.41Hz,1H)2.86-3.01(m,2H)3.12(br.s.,1H)3.24(d,J=12.72Hz,1H)3.68(s,3H)3.90(s,3H)4.59-4.64(m,3H)6. 67(s,1H)7.22-7.25(m,1H)7.29-7.35(m,1H)7.46(s,3H)7.49(d,J=8.31Hz,1H)8.09(d,J=8.31Hz,1H)8.44(d,J=7.82Hz,1H); 13CNMR(101MHz,CHLOROFORM-d)d ppm 19.17,30.72,45.30,45.62,56.01,60.04,77.23,111.39,126.09,127.11,127.17,127.55,127.84,128.4 6,128.56,128.78,129.28,130.61,130.92,131.52,136.47,136.82,138.87,142.98,145.93,152.25; HRMS m / z calcd for[C 26 H 24 ClNO3+H] + 434.1455, found 434.1513.

[0131] Example 8

[0132] In a 25 ml reaction flask, 1.5 times the amount of 4-fluorobenzoic acid (0.15 g), 1 times the amount of compound 5 (0.20 g), 1.8 times the amount of HATU (0.40 g), and 1.8 times the amount of DIEPA (0.14 g) were added. Other procedures were the same as in Example 6. After purification by normal silica gel column chromatography, compound 6c (0.19 g) was obtained in a yield of 68.35%. The proton NMR spectrum of compound 6c is shown below. Figure 15 As shown, the carbon spectrum of compound 6c is as follows. Figure 16 As shown.

[0133] 1 H NMR(600MHz,CHLOROFORM-d)d ppm 2.65(d,J=15.44Hz,1H)2.86-2.97(m,2H)3.25(br.s.,1H)3.68(s,3H)3.90(s,3H)6.67(s,1H)7.11(t, J=8.45Hz,2H)7.22-7.25(m,1H)7.30-7.36(m,1H)7.46(dd,J=8.36,5.45Hz,2H)8.44(d,J=7.81Hz,1H); 13 C NMR(151MHz,CHLOROFORM-d)d ppm 18.42,30.68,55.99,60.03,111.36,115.58,115.72,126.04,127.11,127.84,128.46,128. 93,128.98,131.50,132.78,132.80,136.44,145.91,152.24,162.47,164.13,169.91; HRMS m / z calcd for[C25 H 22 FNO3+H] + 405.1617, found 405.1681.

[0134] Example 9

[0135] In a 50 mL reaction flask, add 0.16 g of 1.5 times the amount of 4-methoxybenzoic acid, 0.20 g of compound 5 (1 times the amount), 0.40 g of HATU (1.8 times the amount), and 0.14 g of DIEPA (1.8 times the amount). Other procedures are the same as in Example 6. The compound 6d (0.21 g) was purified by column chromatography in a yield of 73.36%. The proton NMR spectrum of compound 6d is shown below. Figure 17 As shown, the carbon spectrum of compound 6d is as follows. Figure 18 As shown.

[0136] 1 H NMR(400MHz,CHLOROFORM-d)d ppm 2.64(d,J=15.41Hz,1H)2.87-2.98(m,2H)3.14(d,J=11.37Hz,1H)3.20-3.31(m,1H)3.68(s,3H)3.81-3.85(m,3H) 3.90(s,3H)6.67(s,1H)6.90-6.96(m,2H)7.24(s,1H)7.26-7.35(m,2H)7.40-7.47(m,2H)8.44(d,J=7.70Hz,1H); 13 C NMR(151MHz,CHLOROFORM-d)d ppm 18.44,29.70,30.77,34.75,55.36,55.99,58.48,60.03,111.34,113.80,126.40,127.03,127.79,12 7.85,128.42,128.51,128.68,128.98,129.17,131.56,136.66,145.84,152.15,160.62,170.74; HRMS m / z calcdfor[C 26 H 25 NO4+H] + 417.1817, found 417.1876.

[0137] Example 10

[0138] Add 1 part of compound 5 (0.15 g) to a 25 ml reaction flask and dissolve it in DCM. Add 2.5 parts of Et3N (0.13 g) at 0 °C. After 10 min, add 1.1 parts of p-toluenesulfonyl chloride (0.11 g). React under N2 at 0 °C. After 15 h, analyze by TLC. Extract with saturated NaHCO3 solution and DCM. Dry the organic layer with anhydrous Na2SO4 and concentrate to obtain a yellow oil. After chromatographic purification, obtain compound 6e (0.13 g) in 55.32% yield. The 1H NMR spectrum of compound 6e is shown below. Figure 19 As shown, the carbon spectrum of compound 6e is as follows: Figure 20 As shown.

[0139] 1 H NMR(400MHz,CHLOROFORM-d)d ppm 2.41(s,3H)2.42-2.54(m,2H)3.05(t,J=13.79Hz,1H)3.20(dd,J=13.92,4 .27Hz,1H)3.32(ddd,J=14.13,11.47,3.09Hz,1H)3.67(s,3H)3.88(s,3H) 4.08-4.19(m,1H)4.63(dd,J=13.79,4.14Hz,1H)6.57(s,1H)7.27(d,J=7. 92Hz,2H)7.30-7.40(m,3H)7.73(d,J=8.29Hz,2H)8.44(d,J=7.92Hz,1H); 13 C NMR(101MHz,CHLOROFORM-d)d ppm21.52(s,1C)28.80(s,1C)37.92(s,1C)40.96,55.91,60.08,111.41,125.38,126.94,127.18 ,127.93,128.43,128.54,128.93,129.90,131.48,136.50,137.98,143.32,145.75,152.26; HRMS m / z calcd for[C 25 H 25 NO4S+Na] + 458.1504, found 458.1396.

[0140] Example 11

[0141] In a 25 mL reaction flask, add 1 part of compound 5 (0.06 g), 1.2 parts of pyrrolidine-1-carboxyl chloride (0.05 g), 1.2 parts of potassium carbonate (0.06 g), and 4 parts of potassium iodide (0.14 g). Dissolve the compounds completely in an appropriate amount of DMF. Under N2 protection, react at room temperature for 48 h. After TLC analysis, the reaction solution was extracted three times with ethyl acetate and water. The organic layer was dried over anhydrous Na2SO4 and purified by column chromatography to obtain compound 6f (0.05 g) in 63% yield. The 1H N2 spectrum of compound 6f is shown below. Figure 21 As shown, the carbon spectrum of compound 6f is as follows: Figure 22 As shown.

[0142] 1 H NMR(400MHz,METHANOL-d4)ppm 2.57-2.66(m,1H)2.72(s,2H)2.82-2.91(m,1H)3.19-3.22(m,5H)3.28(d,J=6.11Hz,3 H)3.52(s,3H)3.78(s,3H)4.48(s,1H)6.71(s,1H)7.10-7.21(m,3H)8.19-8.26(m,1H); 13 C NMR(101MHz,CHLOROFORM-d)d ppm 11.99,12.05,12.24,18.99,19.04,19.40,21.09,23.08,28.92,29.70,31.66,31. 92,36.52,37.27,42.23,42.30,50.18,51.25,71.83,121.72,138.31,121.72; HRMS m / z calcd for[C 23 H 26 N2O3+H] + 401.1943, found 401.1905.

[0143] Example 12

[0144] In a 25 ml reaction flask, dissolve 1 part of compound 5 (0.10 g), 1.5 parts of acrylic acid (0.04 g), 1.8 parts of HATU (0.21 g), and 1.8 parts of DIEPA (0.07 g) in DMF. Other procedures were the same as in Example 6. Purification by silica gel column chromatography yielded compound 6 (0.08 g), with a yield of 66.43%. The proton NMR spectrum of compound 6 is shown below. Figure 23 As shown, the carbon spectrum of compound 6g is as follows: Figure 24 As shown.

[0145] 1H NMR(400MHz,CHLOROFORM-d)ppm 2.65-2.79(m,1H)2.79-2.95(m,2H)3.67(s,3H)3.85(d,J=13.94Hz,1H)3.90(s,3H)5.69-5.75(m ,1H)6.63(br.s.,1H)6.69(s,1H)7.26-7.30(m,2H)7.33(d,J=7.58Hz,1H)8.45(d,J=7.95Hz,1H); 13 C NMR(151MHz,CHLOROFORM-d)d ppm 27.94,35.52,43.10,55.54,55.92,55.98,60.04,109.78,111.39,124.82,12 6.62,126.85,126.97,127.84,127.91,128.91,132.42,132.75,165.67; HRMS m / z calcd for[C 21 H 21 NO3+H] + 358.1521, found 358.1403.

[0146] Example 13

[0147] Dissolve 1 part of compound 5 (0.10 g), 1.5 parts of 2-methylfuran-3-carboxylic acid (0.07 g), 1.8 parts of HATU (0.21 g), and 1.8 parts of DIEPA (0.07 g) in DMF. Other procedures were the same as in Example 6. Purification by silica gel column chromatography yielded compound 6h (0.09 g), with a yield of 66.55%. The proton NMR spectrum of compound 6h is shown below. Figure 25 As shown, the carbon spectrum of compound 6h is as follows. Figure 26 As shown.

[0148] 1 H NMR(400MHz,CHLOROFORM-d)ppm 2.41(s,3H)2.59(s,1H)2.65-2.74(m,1H)2.90(t,J=12.35Hz,2H)3.25(br.s.,2H)3.65-3.70(m,3H)3.90(s, 3H)6.41(d,J=1.96Hz,1H)6.68(s,1H)7.22-7.25(m,1H)7.27(s,2H)7.30-7.35(m,1H)8.44(d,J=7.82Hz,1H); 13CNMR(101MHz,CHLOROFORM-d)dppm 13.00,30.80,56.01,60.05,77.22,109.78,110.93,111.33,116.34,126.29,127.08,1 27.81,128.45,129.10,131.56,136.54,140.38,145.87,152.19,153.49,165.71; HRMS m / z calcd for[C 24 H 23 NO4+H] + 390.1627, found 390.1685.

[0149] Example 14

[0150] 0.08 g of compound 5 was added to a 25 mL reaction flask, followed by 2.5 times the amount of Et3N (0.07 g) at 0 °C. After 10 min, 1.2 times the amount of methanesulfonyl chloride (0.04 g) was added. The reaction was carried out under N2 at 0 °C for 24 h. TLC analysis was performed, and the mixture was extracted with saturated NaHCO3 and DCM. The organic layer was collected, dried over anhydrous Na2SO4, concentrated, and purified by normal silica gel column chromatography to obtain 0.04 g of yellow-brown needle-like crystals of compound 6i, with a yield of 40.06%. The proton NMR spectrum of compound 6i is shown below. Figure 27 As shown, the carbon spectrum of compound 6i is as follows: Figure 28 As shown.

[0151] 1 H NMR(400MHz,CHLOROFORM-d)2.71(td,J=2.32,15.89Hz,1H),2.83-3.11(m,6H),3.20-3.39(m,1H),3.58-3.71(m,3H),3 .91(s,3H),4.04-4.20(m,1H),4.52(dd,J=5.62,12.23Hz,1H),6.68(s,1H),7.27-7.37(m,3H),8.42(d,J=7.82Hz,1H); 13 C NMR(101MHz,CHLOROFORM-d)d ppm 29.52,37.35,39.67,40.47,52.98,55.98,60.08,111.56,125.24,127.2 6,127.98,128.04,128.49,128.54,128.60,131.36,136.32,152.49; HRMS m / z calcd for[C 19 H 21NO4S+H] + 360.1191, found 360.1253.

[0152] Example 15

[0153] In a 25 ml reaction flask, add 1 part of compound 5 (0.10 g) dissolved in DCM, 1.2 parts of 4-methylpiperazine-1-formyl chloride (0.07 g), 4 parts of KI (0.23 g), and 1.2 parts of K₂CO₃ (0.06 g). Other procedures are the same as in Example 11. After purification by column chromatography, compound 6j (0.094 g) is obtained, with a yield of 68.21%. The proton NMR spectrum of compound 6j is shown below. Figure 29 As shown, the carbon spectrum of compound 6j is as follows: Figure 30 As shown.

[0154] 1 H NMR(400MHz,CHLOROFORM-d)2.30(s,3H),2.38-2.67(m,7H),2.71-2.86(m,2H),2.86-3.12(m,2H),3.13-3.28(m,2H),3.33-3.45(m,1H),3.67(s ,3H),3.91(s,3H),4.30(d,J=9.54Hz,1H),5.03(dd,J=3.55,13.82Hz,1H ),6.69(s,1H),7.19-7.26(m,1H),7.28-7.34(m,1H),8.40-8.51(m,1H); 13 C NMR(101MHz,CHLOROFORM-d)d ppm 29.71,30.96,33.93,41.17,46.07,50.77,53.20,53.39,55.10,55.99,60.03,62.31,77.24,1 11.26,126.39,126.97,127.76,128.38,128.62,129.19,131.50,136.77,152.08,168.33; HRMS m / z calcd for[C 24 H 29 N3O3+K] + 446.2209, found 446.2372.

[0155] Example 16

[0156] In a 25 mL reaction flask, 1 part of compound 5 (0.11 g) and 1.5 parts of p-methoxybenzaldehyde (0.08 g) were added and dissolved in DCM. Then, 1.2 parts of sodium triacetoxyborohydride (0.1 g) and N2 were added, and the reaction was carried out at room temperature. After 24 h, TLC analysis was performed. The organic layer was extracted with DCM and water, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography to obtain compound 6k (0.12 g) in a yield of 75.63%. The 1H NMR spectrum of compound 6k is shown below. Figure 31 As shown, the carbon spectrum of compound 6k is as follows: Figure 32 As shown.

[0157] 1 H NMR(400MHz,CHLOROFORM-d)ppm 3.63(br.s.,3H)3.81(s,3H)3.88(s,3H)4.09(d,J=6.60Hz,1H)6.62(s,1H)6.91(d,J=7.34Hz,2 H)7.27-7.34(m,2H)7.36(d,J=8.56Hz,2H)7.54(dd,J=5.75,3.30Hz,1H)7.72(d,J=5.62Hz,1H); 13 C NMR(101MHz,CHLOROFORM-d)d ppm 19.20,29.74,35.20,48.74,55.31,55.89,57.95,60.14,60.29,71.83,77.27,111.29,113.77, 113.98,127.10,127.23,127.44,127.85,128.39,130.29,132.18,145.19,152.04,158.84; HRMS m / zcalcd for[C 26 H 27 NO3+H] + 402.1991, found 402.2066.

[0158] Example 17

[0159] Add 1 part product 5 (0.3 g), 1.2 parts morpholine-4-formyl chloride (0.19 g), 1.2 parts K₂CO₃ (0.18 g), and 4 parts KI (0.70 g) to a 25 ml reaction flask, and dissolve completely in an appropriate amount of DMF. Other procedures are the same as in Example 11. After chromatographic purification, compound 6l (0.22 g) is obtained, with a yield of 48.11%. The proton NMR spectrum of compound 6l is shown below. Figure 33 As shown, the carbon spectrum of compound 6l is as follows: Figure 34 As shown.

[0160] 1 H NMR(400MHz,CHLOROFORM-d)ppm 2.71(t,J=13.51Hz,1H)2.76-2.91(m,2H)3.02(dd,J=13.45,4.03Hz,1H)3.21-3.32(m,3H)3.37-3.45(m,2H)3.67(s,3H)3.68- 3.79(m,5H)3.90(s,3H)4.71(dd,J=13.57,3.91Hz,1H)6.66(s,1H)7.21-7.26(m,2H)7.29-7.35(m,1H)8.40(d,J=7.70Hz,1H); 13 CNMR(101MHz,CHLOROFORM-d)d ppm 18.13,29.19,34.55,43.10,46.05,46.21,51.44,54.94,59.09,65.59,65.71,76.21,110.1 0,125.87,125.99,126.65,127.16,127.31,127.80,130.63,135.57,144.63,151.05,163.0.

[0161] Example 18

[0162] In a 25 ml reaction flask, add 1 part of compound 5 (0.15 g), 1.2 parts of diethylcarbamoyl chloride (0.09 g), 1.2 parts of K₂CO₃ (0.09 g), and 4 parts of KI (0.35 g), and add DMF to completely dissolve them. Other procedures are the same as in Example 11. After chromatographic purification, compound 6m (0.10 g) is obtained, with a yield of 50.21%. The proton NMR spectrum of compound 6m is shown below. Figure 35 As shown, the carbon spectrum of compound 6m is as follows: Figure 36 As shown.

[0163] 1 H NMR(400MHz,CHLOROFORM-d)ppm 1.11-1.20(m,6H)2.65(t,J=13.45Hz,1H)2.76-2.97(m,2H)3.04(dd,J=13.45,3.91Hz,1H)3.13-3.35(m,3H)3.38-3. 53(m,3H)3.66(s,3H)3.90(s,3H)4.48(dd,J=13.45,3.91Hz,1H)6.67(s,1H)7.18-7.35(m,3H)8.38(d,J=7.82Hz,1H); 13C NMR(101MHz,CHLOROFORM-d)d ppm 13.26,13.44,29.94,35.37,41.73,42.29,45.49,53.39,55.95,60.14,77.27,111.14,126.90, 127.56,127.62,127.67,128.16,128.29,128.95,131.75,136.82,145.45,151.97,165.00; HRMS m / z calcd for[C 23 H 28 N2O3+Na] + 403.2100, found 403.2085.

[0164] Example 19

[0165] In a 25 ml reaction flask, add 1 part of compound 5 (0.26 g), 1.2 parts of dimethylcarbamoyl chloride (0.12 g), 1.2 parts of K₂CO₃ (0.26 g), and 4 parts of KI (0.62 g), and add DMF to completely dissolve them. Other procedures are the same as in Example 11. After purification by normal silica gel chromatography, compound 6n (0.10 g) is obtained in a yield of 30.15%. The proton NMR spectrum of compound 6n is shown below. Figure 37 As shown, the carbon spectrum of compound 6n is as follows: Figure 38 As shown.

[0166] 1 H NMR(400MHz,METHANOL-d4)ppm 2.55(t,J=13.57Hz,1H)2.73(s,1H)2.75-2.80(m,1H)2.83(s,6H)2.86(d,J=3.91Hz,1H)3.23-3.28(m,1H)3.38-3.4 7(m,1H)3.52(s,3H)3.78(s,3H)4.43(dd,J=13.45,3.91Hz,1H)6.71(s,1H)7.08-7.25(m,3H)8.22(d,J=7.58Hz,1H); 13 C NMR(101MHz,METHANOL-d4)d ppm 29.53,35.47,37.02,44.44,52.68,55.03,59.05,111.36,126.52,126.55,127 .03,127.32,127.68,127.91,129.23,131.61,136.64,145.37,152.12,165.57.

[0167] Example 20: The therapeutic effect of compounds shown in formulas 4-5 and 6a-6n on BaCl2-induced arrhythmias in BaCl2-induced SD rats.

[0168] Dissolve 10g of sodium pentobarbital solution in 90ml of physiological saline to obtain a 10% sodium pentobarbital solution for later use. Dissolve 80.00mg of BaCl2 in 10ml of physiological saline to obtain an 8mg / ml BaCl2 solution for later use. Dissolve 14.81mg of verapamil solution in 2ml of DMSO to obtain a 7.41mg / ml verapamil solution for later use. Dissolve 25mg of lotus leaf alkaloid and its derivatives in 1.35ml of DMSO to obtain an 18.52mg / ml lotus leaf alkaloid and its derivatives solution for later use.

[0169] Normal male SD rats weighing 200-220g were randomly divided into groups of 6 rats each. The groups were: a saline (NS) group and a DMSO group as blank control groups; a lotus leaf alkaloid group (5mg / kg) and a verapamil group (2mg / kg) as positive control groups; and a lotus leaf alkaloid derivative group (5mg / kg) as the experimental group. After intraperitoneal injection of anesthesia, the rats were connected to a BL-420N biosignal acquisition system to record a normal electrocardiogram for 1 minute. Then, a BaCl2 solution (4mg / kg) was injected sublingually. Three minutes later, according to the grouping, saline (0.27ml / kg) and DMSO (0.27ml / kg) were injected sublingually again as blank control groups; lotus leaf alkaloid (5mg / kg) and verapamil (2mg / kg) were injected as positive control groups; and a synthetic lotus leaf alkaloid derivative (5mg / kg) was injected. Under the monitoring of the BL-420N biosignal acquisition and analysis system, 35 min of lead II electrocardiogram (ECG) was observed. The antiarrhythmic activity of lotus leaf alkaloid derivatives was evaluated by recording the time required for the heart rate to return to normal after arrhythmia, the time to maintain normality, heart rate, RR interval, QT interval, QTc interval, and R voltage.

[0170] Example 20-1 Effects of lotus leaf alkaloid derivatives on recovery time and maintenance time of BaCl2-induced arrhythmias

[0171] The experimental results, as shown in Table 1, indicate that injection of BaCl2 into rats in both the NS and DMSO groups caused cardiac arrhythmia that was difficult to reverse for a prolonged period. This suggests that BaCl2 can induce cardiac arrhythmia in rats, and the rats will remain in an arrhythmic state for an extended period. Compared with the NS and DMSO groups, all lotus leaf alkaloid derivatives, as well as lotus leaf alkaloid and verapamil, significantly shortened the time for rats to recover to normal heart rate (P < 0.001). Among them, 6a, 6c, 6f, 6g, 6j, 6m, verapamil, and lotus leaf alkaloid showed a clear trend of shortening the recovery time. Compared with the NS group, except for 6k, 6l, 6m, and 6n, all other derivatives, as well as verapamil and lotus leaf alkaloid, significantly prolonged the maintenance time of normal heart rate in rats (P < 0.05). Compared with the DMSO group, all compounds, as well as lotus leaf alkaloid and verapamil, significantly prolonged the maintenance time of normal heart rate in rats (P < 0.05). Compared with verapamil and lotus leaf alkaloids, 6a showed a significant trend in prolonging the duration of heart rate maintenance in rats, and among all groups, only 6a rats had a maintenance time of ≥20 min.

[0172] Table 1. Effects of lotus leaf alkaloid derivatives on BaCl2-induced cardiac arrhythmias in rats (n=6)

[0173]

[0174]

[0175] Compared to the NS group: # P < 0.05 ## P < 0.01, ### P < 0.001;

[0176] Compared with the DMSO group: ▲ P < 0.05 ▲▲ P < 0.01, ▲▲▲ P < 0.001.

[0177] Example 20-2 Effects of lotus leaf alkaloid derivatives on changes in heart rate (HR) in rats induced by BaCl2

[0178] As shown in Table 2, compared with the normal group, the heart rate of rats injected with BaCl2 increased significantly. This is because barium ions, after entering the body, inhibit sodium and potassium ion channels on the myocardial cell membrane, leading to a decrease in intracellular potassium ions and an increase in sodium ions. This induces increased cardiac automaticity and increased excitation of the myocardial sympathetic nervous system, thus resulting in an increased heart rate. Injection of verapamil, lotus leaf alkaloids, and lotus leaf alkaloid derivatives can decrease the heart rate, indicating that lotus leaf alkaloid derivatives have a certain therapeutic effect on the BaCl2-induced increase in heart rate.

[0179] Table 2. Effects and significance of lotus leaf alkaloid derivatives on heart rate (HR) in rats (n=6)

[0180]

[0181]

[0182] Compared with the normal group: #P<0.05, ##P<0.01, ###P<0.001;

[0183] Compared with the model group: ▲P<0.05, ▲▲P<0.01, ▲▲▲P<0.001.

[0184] Example 20-3 Effects of lotus leaf alkaloid derivatives on changes in the QT interval in rats caused by BaCl2

[0185] As shown in Table 3, compared with the normal group, the QT interval of rats injected with BaCl2 was significantly reduced, thus inducing Short QT Syndrome (SQTS), a syndrome characterized by a shortened QT interval that can lead to arrhythmic sudden death. Compared with the normal group, the QT interval of all compounds except verapamil and the lotus leaf alkaloid model group was significantly shortened (P < 0.05). After injection of lotus leaf alkaloid derivatives, NS, DMSO, verapamil, and lotus leaf alkaloid, except for NS and DMSO, the QT interval of the other groups was significantly increased (P < 0.05) and tended to return to normal. This indicates that the synthesized lotus leaf alkaloid derivatives and lotus leaf alkaloid have a certain therapeutic effect on BaCl2-induced SQTS.

[0186] Table 3. Effects of lotus leaf alkaloid derivatives on the QT interval in rats and their significance (n=6)

[0187]

[0188]

[0189] Compared with the normal group: #P<0.05, ##P<0.01, ###P<0.001;

[0190] Compared with the model group: ▲P<0.05, ▲▲P<0.01, ▲▲▲P<0.001.

[0191] Example 20-4 Effects of lotus leaf alkaloid derivatives on changes in the RR interval of BaCl2 in rats

[0192] Table 4 shows that after injecting BaCl2 into rats, the RR interval of normal rats showed a significant decreasing trend. After injecting lotus leaf alkaloid derivatives, verapamil, and lotus leaf alkaloid, the RR interval of rats showed a significant increasing trend. Among them, the RR interval of 6a, 6b, 6d, 6g, 6h, and 6n was significantly increased compared with the model group (P < 0.05), and the increased RR interval was not significantly different from that of the normal group.

[0193] Table 4. Effects of lotus leaf alkaloid derivatives on the RR interval in rats and their significance (n=6)

[0194]

[0195]

[0196] Compared with the normal group: #P<0.05, ##P<0.01, ###P<0.001;

[0197] Compared with the model group: ▲P<0.05, ▲▲P<0.01, ▲▲▲P<0.001.

[0198] Example 20-5 Effects of lotus leaf alkaloid derivatives on changes in the QTc interval in rats caused by BaCl2

[0199] Injection of BaCl2 can shorten the RR interval and increase heart rate, which in turn can shorten the QT interval. This invention investigates whether BaCl2 injection causes semi-QTS and whether lotus leaf alkaloid derivatives have a therapeutic effect on BaCl2-induced SQTS by statistically analyzing the heart rate-corrected QT interval, i.e., QTc. The results are shown in Table 5. In normal rats, BaCl2 injection leads to SQTS (P < 0.05). After administration, except for lotus leaf alkaloids, 6e, 6g, 6j, and 6n, the QTc values ​​of other lotus leaf alkaloid derivatives and verapamil were significantly increased (P < 0.05). In particular, the QTc values ​​of 4, 5, 6a, 6b, 6c, 6d, 6f, 6g, 6i, 6k, and 6m were not significantly different from those of the normal group, indicating that the above compounds have a certain corrective effect on BaCl2-induced SQTS.

[0200] Table 5. Effects of lotus leaf alkaloid derivatives on the QTc interval in rats and their significance (n=6)

[0201]

[0202]

[0203] Compared with the normal group: #P<0.05, ##P<0.01, ###P<0.001;

[0204] Compared with the model group: ▲P<0.05, ▲▲P<0.01, ▲▲▲P<0.001.

[0205] Example 20-6 Effects of lotus leaf alkaloid derivatives on changes in R voltage in rats due to BaCl2

[0206] The effects of lotus leaf alkaloid derivatives on the R voltage of rats are shown in Table 6. After injection of BaCl2, the R voltage of rats decreased significantly (P < 0.05). After injection of verapamil and lotus leaf alkaloid, the R voltage increased significantly compared with the model group (P < 0.05) and there was no significant difference compared with the normal group (P > 0.05). After injection of lotus leaf alkaloid derivatives, except for 5, 6f, 6i, 6j, 6l, and 6n, the R voltage of the other compound administration groups increased significantly compared with the model group (P < 0.05) and there was no significant difference compared with the normal group (P > 0.05).

[0207] Table 6. Effects and significance of lotus leaf alkaloid derivatives on R voltage in rats (n=6)

[0208]

[0209]

[0210] Compared with the normal group: #P<0.05, ##P<0.01, ###P<0.001;

[0211] Compared with the model group: ▲P<0.05, ▲▲P<0.01, ▲▲▲P<0.001.

[0212] Example 20-7 Effects of lotus leaf alkaloid derivatives on changes in QRS complex in rats due to BaCl2

[0213] The effects of lotus leaf alkaloid derivatives on the QRS duration in rats are shown in Table 7. After injection of barium chloride, the QRS duration in rats was significantly prolonged except for NS, 5, and 6f (P < 0.05). After injection of lotus leaf alkaloid, lotus leaf alkaloid derivatives, and verapamil, the QRS duration in all other groups except 6b and 6h was not significantly different from that in the drug-treated groups (P > 0.05). This indicates that lotus leaf alkaloid and lotus leaf alkaloid derivatives have a certain therapeutic effect on the QRS duration prolongation caused by barium chloride injection.

[0214] Table 7. Effects and significance of lotus leaf alkaloid derivatives on the QRS complex in rats (n=6)

[0215]

[0216]

[0217] Compared with the normal group: #P<0.05, ##P<0.01, ###P<0.001;

[0218] Compared with the model group: ▲P<0.05, ▲▲P<0.01, ▲▲▲P<0.001.

[0219] Example 21: The therapeutic effect of some lotus leaf alkaloid derivatives on aconitine-induced arrhythmia in rats.

[0220] After investigating the effects of lotus leaf alkaloid derivatives on aconitine-induced arrhythmia in rats, this invention screened compounds 4, 5, and 6a to investigate their effects on aconitine-induced arrhythmia in rats. The injection concentrations of compounds 4 and 5 were 5 mg / kg, and the concentrations of compound 6a were 1 mg / kg, 2.5 mg / kg, 5 mg / kg, and 10 mg / kg, respectively.

[0221] Dissolve 5.00 mg of aconitine in 5 mL of physiological saline to obtain a 1 mg / mL aconitine stock solution. Take 1 mL of the aconitine stock solution and dilute it with physiological saline to 100 mL to obtain a 0.01 mg / mL aconitine solution.

[0222] Healthy male SD rats weighing 200-220g were randomly divided into groups of 6 rats each. The saline group and DMSO group served as blank control groups, verapamil and lotus leaf alkaloids served as positive control groups, and rats aged 4, 5, and 6 years served as experimental groups.

[0223] After intraperitoneal injection of an anesthetic, rats were fixed in a supine position and connected to a BL-420N biosignal acquisition system to record normal lead II electrocardiograms (ECG) for 1 minute. The blank control group was injected sublingually with normal saline (0.27 ml / kg) and DMSO (0.27 ml / kg). The positive control group was injected sublingually with verapamil solution (2 mg / kg) and lotus leaf alkaloid solution (5 mg / kg). The experimental groups were injected sublingually with 4 (5 mg / kg), 5 (5 mg / kg), 6a (1 mg / kg), 6a (2.5 mg / kg), 6a (5 mg / kg) and 6a (10 mg / kg). Two minutes later, aconitine solution with a concentration of 0.01 mg / ml was injected into the femoral vein on one side of the rat's thigh at a constant rate of 100 uL / min using a micro-injection pump. ECG was observed, and the time of occurrence of ventricular premature beats (VP), ventricular tachycardia (VT), ventricular fibrillation (VF), and cardiac arrest (CA) in each rat was monitored, and the dosage of aconitine was calculated accordingly.

[0224] Experimental results are as follows Figure 39As shown, compared with verapamil, 5 (5 mg / kg), 6a (5 mg / kg), and 6a (10 mg / kg) significantly increased the amount of aconitine-induced VP in rats (P < 0.05); compared with verapamil, 5 (5 mg / kg), 6a (5 mg / kg), and 6a (10 mg / kg) significantly increased the amount of aconitine-induced VT in rats (P < 0.05); compared with verapamil, 4 (5 mg / kg), 5 (5 mg / kg), 6a (2.5 mg / kg), 6a (5 mg / kg), and 6a (10 mg / kg) significantly increased the amount of aconitine-induced VF in rats (P < 0.05); and compared with verapamil, 4, 5, 6a (2.5 mg / kg), 6a (5 mg / kg), and 6a (10 mg / kg) significantly increased the amount of aconitine-induced CA in rats (P < 0.05). Compared with lotus leaf alkaloids, 6a (5 mg / kg) and 6a (10 mg / kg) significantly increased the amount of VT induced by aconitine in rats (P < 0.05). Compared with lotus leaf alkaloids, 4 (5 mg / kg), 6a (2.5 mg / kg), 6a (5 mg / kg), and 6a (10 mg / kg) significantly increased the amount of VF induced by aconitine in rats (P < 0.05). Compared with lotus leaf alkaloids, 6a (5 mg / kg) and 6a (10 mg / kg) significantly increased the amount of CA induced by aconitine in rats (P < 0.01).

[0225] Example 22: The therapeutic effect of the compound shown in Formula 6a on BaCl2-induced arrhythmia in rats.

[0226] By investigating the effects of lotus leaf alkaloid derivatives on BaCl2-induced cardiac arrhythmias in rats, this invention screened out compound 6a, which had the best efficacy, to explore the effects of different concentrations of 6a on BaCl2-induced cardiac arrhythmias in rats. The experimental results are as follows: Figure 40 , Figure 41 As shown, compared with saline and DMSO, different concentrations of 6a significantly reduced the time to recovery of normal heart rate after BaCl2-induced arrhythmia in rats (P < 0.001). Compared with DMSO, 2.5 mg / kg of 6a significantly increased the maintenance time after recovery from BaCl2-induced arrhythmia (P < 0.05). Compared with saline and DMSO, 5 mg / kg and 10 mg / kg of 6a significantly increased the maintenance time after recovery from BaCl2-induced arrhythmia (P < 0.001). Compared with lotus leaf alkaloids and verapamil, 5 mg / kg and 10 mg / kg of 6a showed a clear trend of increasing the maintenance time after recovery from BaCl2-induced arrhythmia. These experimental results indicate that within a certain concentration range, the therapeutic effect of 6a on BaCl2-induced arrhythmia in rats gradually increases with increasing 6a concentration.

[0227] Example 23 Effect of the compound shown in Formula 6a on the heart rate of normal rats

[0228] SD rats were randomly assigned to groups, anesthetized, and connected to a BL-420N biosignal acquisition system. Normal ECG was recorded for 1 minute. At 60 seconds, lotus leaf alkaloid derivative 6a (5 mg / kg) was injected sublingually, followed by ECG observation for 35 minutes. Electrocardiographic parameters (HR, QT, RR, QTc, R voltage) were recorded at 30 seconds (normal), 90 seconds, 3 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, and 35 minutes. Results are as follows: Figure 42 As shown, after 6 years of injection, compared with 30 seconds (normal), the heart rate of rats decreased significantly (P<0.05), the RR interval time increased significantly (P<0.05), and the other electrocardiographic parameters (QT, QTc, R voltage) were not significantly different from those of the normal group (P>0.05).

[0229] Effects of the compound shown in Formula 6a on electrophysiological signals of rat ventricular myocytes in Example 24

[0230] Voltage-dependent calcium current (Ic) in isolated male rat cardiomyocytes was measured using the whole-cell patch-clamp method. Ca ), sodium current (I) Na ) and action potential duration (APD) and measurements of hERG.

[0231] Patch clamp data logging:

[0232] The EPC-10 amplifier and patchmaster software (HEKA Elektronik, Germany) were used to record data from whole-cell patch-clamp experiments in HEK293 cells in voltage-clamp mode and the data were analyzed using Clampfit 10.6.

[0233] The APD recordings were prepared using a cell culture medium consisting of 137 mM NaCl, 4 mM KCl, 10 mM HEPES, 10 mM D-glucose, 1 mM MgCl2, and 2 mM CaCl2, with the pH adjusted to 7.3 using NaOH. The glass electrode solution consisted of 4 mM NaCl, 1 mM MgCl2, 0.1 mM CaCl2, 138 mM K-gluconic acid, 10 mM HEPES, 1 mM EGTA, and 2 mM Mg-ATPase, with the pH adjusted to 7.3 using KOH.

[0234] The Nav1.5 recordings were prepared using a cell culture medium consisting of 137 mM NaCl, 10 mM D-glucose, 4 mM KCl, 1.8 mM CaCl2, 1 mM MgCl2, and 10 mM HEPES, adjusted to pH 7.4 with NaOH. The glass electrode solution consisted of 50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 60 mM CsF, and 20 mM EGTA, adjusted to pH 7.2 with CsOH.

[0235] Recording of Cav1.2: The glass electrode solution consisted of 110 mM CsCl, 10 mM EGTA, 5 mM HEPES, 1 mM CaCl2, 4 mM Na2-ATP and 4.5 mM Mg-ATP, with the pH adjusted to 7.2 using CsOH; the cell culture medium consisted of 140 mM TEA-Cl, 1 mM MgCl2, 4 mM KCl, 10 mM CaCl2, 5 mM D-glucose and 10 mM HEPES, with the pH adjusted to 7.4 using TEA-OH.

[0236] For hERG recording, the cell culture medium is the same as that used for ventricular myocyte recording of APD. The solution inside the glass electrode is prepared by adjusting the pH to 7.2 with KOH, consisting of 20 mM KCl, 120 mM K-aspartic acid, 10 mM HEPES, 10 mM EGTA, 5 mM MgCl2, and 5 mM Mg-ATP.

[0237] Example 24-1 Effect of the compound shown in Formula 6a on the action potential duration (APD) of rat cardiomyocytes

[0238] like Figure 43 As shown, in current-clamp mode, compound 6a (10 μM) significantly reduced the amplitude of action potential (p < 0.001) and resting potential (p < 0.05). Simultaneously, it had no effect on APD30 and APD50 in rat univentricular myocytes, but it prolonged APD90, indicating that compound 6a can prolong ventricular conduction in rats and mildly block sodium ion influx, thereby slightly reducing APA and resting potential.

[0239] Example 24-2 Effects of the compound shown in Formula 6a on Nav and Cav currents in rat cardiomyocytes

[0240] Example 24-2-1 Effect of the compound shown in Formula 6a on Nav current in rat cardiomyocytes

[0241] like Figure 44 As shown, in whole-cell patch-clamp current-clamp mode, the compound of formula 6a (10 μM) significantly blocked IgA in rat cardiomyocytes (p < 0.001).Na Current, and does not change the current-voltage relationship between the activation potential and the peak potential ( Figure 44 A in the middle. Figure 44 BF in the compound shown in Formula 6a (10 μM) does not affect the voltage-dependent recovery of I. Na steady-state activation, I Na steady-state deactivation and I Na The recovery. This result also indicates that the compound shown in formula 6a (10 μM) can alter I. Na The activation, inactivation, and recovery characteristics of channels. For example... Figure 44 The B-current-voltage curve in the figure shows that, compared with the normal group, 6a can significantly shift I upward. Na The IV curve was lowered, and the activation curve did not shift significantly to the right when the sodium current was reduced. 1 / 2 The inactivation curve shifted from (-52.94±5.446) mV to (-52.51±4.801) mV (n=13, P>0.05), and k shifted from (1.091±0.5969) mV to (12.23±17.23) mV (n=13, P<0.05), indicating that compound 6a has a slight effect on the Nav activation process. The inactivation curve shifted to the right, V 1 / 2 The value shifted from (-84.45±7.360) mV to (-103.4±3.458) mV (n=13, P<0.001), and the k value changed from (-5.076±0.9617) mV to (-4.210±0.8139) mV (n=13, P<0.05), indicating that the compound shown in Formula 6a has a strong affinity for binding to the Nav channel and accelerates the Nav inactivation process. The recovery curve of the compound shown in Formula 6a shifted to the right after treatment, with the τ value changing from 7.255±0.7848 to 34.23±7.541 (n=13, P<0.01) and the k value changing from 0.1582±0.01723 to 0.04124±0.007670 (n=13, P<0.001). This indicates that compound 6a can significantly alter the Nav recovery kinetics after inactivation and delay the reactivation process of the sodium current channel. These results demonstrate that compound 6a has a strong affinity for the Nav channel during the inactivation-to-activation process and can effectively connect with the Nav channel.

[0242] Example 24-2-2 Effect of the compound shown in Formula 6a on Cav current in rat ventricular myocytes

[0243] Results in whole-cell patch-clamp mode showed that the compound shown in Formula 6a (10 μM) did not change I Ca Under the current-voltage curve trend, I2O2 in rat ventricular myocytes can be significantly blocked. Ca Current (****p<0.001)( Figure 45A in the middle. Figure 45 BF in the figure respectively show I Ca Steady-state activation, I Ca Steady-state deactivation and I Ca Recovery curves showed that the compound shown in formula 6a (10 μM) could alter I in both inactivated and recovered states. Ca Channel. (e.g., passageway) Figure 45 The B-current-voltage curve in the figure shows that, compared with the control group, 6a can significantly shift I upward. Ca The IV curve was changed and the calcium current was reduced. The activation curve remained unchanged, V 1 / 2 The value shifted from (-6.086±2.289) mV to (-4.941±2.638) mV (n=7, P>0.05), and k changed from (4.582±0.2864) mV to (4.642±0.6666) mV (n=7, P>0.05), indicating that compound 6a had no significant effect on the activation process of Cav. In I ca The inactivation curve shifts to the left in the inactivation curve, V 1 / 2 The values ​​of τ and k changed from (-3.343±3.817) mV to (-12.860±3.633) mV (n=7, P<0.001) and k changed from (-4.025±1.065) mV to (-6.344±1.507) mV (n=7, P<0.05), indicating that compound 6a accelerated the inactivation process of Cav. After treatment with compound 6a, the recovery curve shifted positively along the time axis, with the τ value changing from 0.08245±0.009048 to 0.1921±0.03795 (n=7, P<0.05) and the k value changing from 13.16±1.618 to 6.414±1.141 (n=7, P<0.01), indicating that compound 6a can reasonably alter the recovery kinetics of inactivated Cav and can moderately delay the reactivation process of calcium current channels. This also means that compound 6a has a strong affinity for the Cav channel during the inactivation to activation process.

[0244] Example 24-2-3 Effect of the compound shown in Formula 6a on rat ventricular myocytes Nav1.5

[0245] To provide compound 6a with an inward current I Na To investigate the mechanism of action, this invention studied the effect of compound 6a on the Nav1.5 channel in HEK293 cells. The results are as follows: Figure 46 As shown, compound 6a exhibits concentration-dependent inhibition of sodium current in the Nav1.5 channel of HEK293. The IC50 at rest was calculated based on the dose-response curve. 50 The value is 23.886 μM. In the semi-inactive state, IC... 50 The value is 4.9857 μM.

[0246] Example 24-2-4 Effect of the compound shown in formula 6a on rat cardiomyocytes Cav1.2

[0247] like Figure 47 As shown, compound 6a exhibits concentration-dependent inhibition of the Cav1.2 current in HEK293 cells. With increasing 6a concentration, an Ia effect was obtained. Ca Concentration-response curve for peak suppression. The inhibitory effect of compound 6a on the Cav1.2 channel is generally determined by the state of the Cav1.2 channel. In the semi-inactivated state, the IC50 value is calculated based on the concentration-response curve. 50 The value is 4.6228 μM, from Figure 47 It can be seen that the voltage decreases after rinsing 6a, indicating that the combination of 6a and Cav1.2 is partially reversible.

[0248] Effects of the compound shown in Formula 6a on hERG / IKr in rat cardiomyocytes (Example 24-2-5)

[0249] If a drug's inhibitory effect on hERG / IKr is too strong, it can lead to a sharp prolongation of the QT interval, causing long QT syndrome. The strength of a drug's inhibitory effect on hERG / IKr is usually determined by the IC50 value. 50 To evaluate, when IC 50 <1μM indicates high risk; 1μM <IC 50 <10μM indicates medium risk, IC 50 >10μM indicates low risk, IC 50 >30μM is considered extremely low risk. In general, IC 50 The lower the level, the greater the risk of developing long QT syndrome. Figure 48 It is known that compound 6a inhibits the Kv11.1 channel in a concentration-dependent manner, thereby blocking the hERG current. The IC50 value of 6a in inhibiting the Kv11.1 channel current is [not specified]. 50 The concentration was 24.717 μM, and the inhibition was reversible. (From...) Figure 49 As shown, the calculated IC50 of the positive control drug cisapride is 13.914 nM. Compared with the positive control drug, the IC50 of 6a for the Kv11.1 channel current is... 50 The results above suggest that the risk of 6a inducing long QT syndrome is extremely low.

[0250] Based on the above experimental results, all synthesized lotus leaf alkaloid derivatives exhibited varying degrees of antiarrhythmic activity. Among them, the compound represented by formula 6a showed the best activity, demonstrating superior activity compared to the positive control drug verapamil, both in treating barium chloride-induced and aconitine-induced arrhythmias. Whole-cell patch-clamp experiments showed that the compound represented by formula 6a could bind to Nav1.5 and Cav1.2 and inhibit their protein activity, causing I... Na and I Ca Although the compound shown in Formula 6a can also bind to Kv11.1, its inhibition rate of Kv11.1 is lower than that of the positive control drug cisapride, resulting in a lower risk of long QT syndrome. Based on the above results, it can be seen that the compound shown in Formula 6a has the characteristics of good activity and low toxicity for the treatment of arrhythmia.

[0251] In summary, this invention provides a series of lotus leaf alkaloid derivatives through total synthesis for use in antiarrhythmic therapy. Experimental results show that the compounds provided by this invention have excellent antiarrhythmic effects. Furthermore, the compound represented by formula 6a exhibits stronger therapeutic effects on arrhythmias than the positive control drug verapamil, with a lower probability of causing adverse reactions (long QT syndrome). Therefore, the compounds provided by this invention offer a new option for preparing low-toxicity, highly active antiarrhythmic drugs.

[0252] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. The application of lotus leaf alkaloid derivatives in the preparation of drugs for treating arrhythmias, characterized in that, The structure of the lotus leaf alkaloid derivative is shown below: ； The R-based structure is as follows: 。 2. The application according to claim 1, characterized in that, The chemical reaction formula for the preparation method of the lotus leaf alkaloid derivative is as follows: 。 3. The application according to claim 2, characterized in that, The compound 2-(2-bromophenyl)-N-(3,4-dimethoxyphenylethyl)acetamide shown in Formula 1 is prepared by dissolving 2-bromophenylacetic acid in dichloromethane, adding 1-hydroxyphenyltriazole, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 3,4-dimethoxyphenylethylamine and triethylamine, and reacting to obtain the compound shown in Formula 1. The preparation method of compound 1-(2-bromobenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline shown in Formula 2 is as follows: Dissolve compound 1 in DCM, add phosphorus pentachloride, reflux the reaction, evaporate DCM to dryness, add MeOH and sodium borohydride, and then react to obtain compound 2. The preparation method of compound 1-(1-(2-bromobenzyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1-one shown in Formula 3 is as follows: Dissolve compound shown in Formula 2 in DCM, add trifluoroacetic anhydride and Et3N, and react to obtain compound shown in Formula 3; The compound 1-(1,2-dimethoxy-4,5,6a,7-tetrahydro-6H-dibenzo[de,g]quinolin-6-yl)-2,2,2-trifluoroethane-1-one shown in Formula 4 was prepared by dissolving the compound shown in Formula 3 in N,N-dimethylacetamide, then adding tris(4-fluorophenyl)phosphine, K2CO3 and palladium acetate to react and obtain the compound shown in Formula 4. The compound 1,2-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline shown in Formula 5 is prepared by dissolving the compound shown in Formula 4 in DCM, adding NaBH4, and reacting to obtain the compound shown in Formula 5.

4. The application according to claim 2, characterized in that, When the R-group structure is 6a, the compound 2-(2-bromophenyl)-1-(1,2-dimethoxy-4,5,6a,7-tetrahydro-6H-dibenzo[de,g]quinoline-6-yl)ethyl-1-one shown in formula 6a is prepared by dissolving the compound shown in formula 5 in DMF, adding 2-bromophenylacetic acid, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine, and reacting to obtain the compound shown in formula 6a.

5. The application according to claim 1, characterized in that, The arrhythmias mentioned are sinus arrhythmias, atrial arrhythmias, supraventricular arrhythmias, and ventricular arrhythmias.

6. The application according to claim 5, characterized in that, The sinus arrhythmias mentioned are sinus bradycardia, sinus tachycardia, sinus arrhythmia, sinus arrest, and sinoatrial block; the atrial arrhythmias mentioned are atrial premature beats, atrial tachycardia, and atrial premature contractions; the supraventricular arrhythmias mentioned are paroxysmal supraventricular tachycardia; and the ventricular arrhythmias mentioned are ventricular premature beats, ventricular tachycardia, and ventricular fibrillation.

7. The application according to claim 1, characterized in that, The drug may also include a pharmaceutically acceptable carrier; the pharmaceutically acceptable carrier is selected from one or more of excipients, buffers, emulsifiers, stabilizers, diluents, binders, preservatives, lubricants, pH adjusters, cryoprotectants, and flavoring agents.

8. The application according to claim 1, characterized in that, The dosage forms of the drug are drops, mixtures, tinctures, injections, tablets, powders, oral liquids, capsules, granules, ointments, suspensions, powders, emulsions, solutions, drop pills, pills, lozenges, lyophilized powder injections, gels, suppositories, or aerosols.

9. The application of lotus leaf alkaloid derivatives in the preparation of drugs for treating QT syndrome, characterized in that, The structure of the lotus leaf alkaloid derivative is shown below: ； The R-based structure is as follows: 。

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