Kv7 potassium ion channel opener as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of heterocyclic compounds, and particularly relates to a Kv7 potassium ion channel opener as well as a preparation method and application thereof. The method comprises the following steps: adding a compound 1, a compound 2 and triethylamine into ethyl acetate, and carrying out a first reaction to obtain a reaction solution; performing extraction, water washing, drying and vacuum concentration on the reaction liquid, and then adding the reaction liquid into a mixed solution of a sodium hydroxide aqueous solution and isopropanol to perform a second reaction to obtain a compound 3; adding the compound 3, a catalyst and NH4HCO2 into the mixed solvent, and carrying out amination reaction to obtain a compound 4; and adding the compound 4, the compound 5 and triethylamine into ethyl acetate for reaction to obtain the Kv7 potassium ion channel opener. The metabolic stability and the structural rigidity are improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of heterocyclic compounds, and in particular relates to a Kv7 potassium ion channel opener and a preparation method and application thereof. Background Art

[0002] Currently, there are more than 30 anti-epileptic drugs on the market, but these drugs have side effects and are ineffective in about 30% of patients. Therefore, it is urgent to develop a new, safer and more effective anti-epileptic drug.

[0003] Studies have shown that Kv7 potassium channel openers, such as Kv7.2 / 7.3 openers, can be used to treat epilepsy. Oral administration of Kv7.2 / 7.3 channel openers retigabine (RTG), SCR2682, HN37, and c60 can significantly inhibit epileptic seizures in mice; the results of a phase IIb clinical trial showed that the Kv7.2 / 7.3 opener XEN1101 can reduce the frequency of seizures in patients with focal epilepsy by 50%. Among the reported Kv7.2 / 7.3 openers, RTG was launched in Europe and the United States in 2011 and was approved for adjuvant treatment of partial seizures in adults. Although the marketed drug RTG has excellent anti-epileptic efficacy, it was withdrawn from the market in 2017 due to drug metabolic toxicity (blue pigment deposition in the skin and retina) caused by the triamino aromatic ring skeleton. Therefore, finding a safe and effective Kv7.2 / 7.3 opener with a new mother core structure is the key to the current development of anti-epileptic drugs targeting the Kv7.2 / 7.3 channel.

[0004] Chinese patent CN 118084710A discloses a Kv7 potassium channel opener and its pharmaceutical composition and application. The basic structural formula of the Kv7 potassium channel opener is shown in Formula I:

[0005] Wherein, ring A is selected from Any one of; wherein R1 is selected from N-benzyl, O-benzyl, S-benzyl, N-benzyl heterocycle, O-benzyl heterocycle or S-benzyl heterocycle, and the benzyl or benzyl heterocycle is optionally substituted by 1-3 halogen, cyano, nitro, amino, hydroxyl, carboxyl, trifluoromethyl, amide, methoxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl; wherein R2 and R3 are each independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, carboxyl, trifluoromethyl, amide, methoxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl; wherein R is selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy. The rigidity and stability of the Kv7 potassium channel opener structure in this patent are poor.

[0006] Chinese patent CN 102971307A discloses a piperidinyl pyrimidine amide as a KV7 potassium channel opener, a dimethoxy-pyrimidine amide compound of formula I, which exhibits activity as a Kv7.2-5 channel opener. The pharmaceutical composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof or a stereoisomer of a compound of formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0007]

[0008] Where: n is an integer of 1 or 2; t is 0 or 1; each R 1 Independently selected from C 1-3 Alkoxy, C 1-3 Alkyl, C 1-3 Alkyl-OC 1-3 Alkyl; R 2 and R 3 Independently C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl, provided that at least one is C 1-3 Alkoxy; R 4 It is C 1-6 Alkyl, C 1-3 Alkyl-C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl; or a pharmaceutically acceptable salt thereof. The parent nucleus of the KV7 potassium channel opener in the patent is a pyrimidine group, which has poor lipophilicity and is not conducive to passing through the blood-brain barrier to produce anti-epileptic effects. Summary of the invention

[0009] The purpose of the present invention is to provide a Kv7 potassium ion channel opener, which improves metabolic stability and structural rigidity; the present invention also provides a preparation method and application of the Kv7 potassium ion channel opener.

[0010] The Kv7 potassium channel opener of the present invention has the following structural formula: .

[0011] The preparation method of the Kv7 potassium channel opener of the present invention comprises the following steps: (1) Compound 1, Compound 2 and triethylamine are added to ethyl acetate for a first reaction to obtain a reaction solution; the reaction solution is extracted, washed with water, dried, and concentrated under reduced pressure, and then added to a mixed solution of sodium hydroxide aqueous solution and isopropanol for a second reaction to obtain compound 3; Wherein, the structural formula of compound 1 is as follows: ; The structural formula of compound 2 is as follows: ; (2) Compound 3, a catalyst and NH4HCO2 are added to a mixed solvent for an amination reaction to obtain compound 4; Among them, the structural formula of compound 3 is as follows: ; (3) adding compound 4, compound 5 and triethylamine to ethyl acetate to react and obtain a Kv7 potassium channel opener; Among them, the structural formula of compound 4 is as follows: ; The structural formula of compound 5 is as follows: .

[0012] In step (1), the ratio of compound 1, compound 2, triethylamine and ethyl acetate is 2-2.6:2.1-2.7:1.6-1.9:50, wherein compound 1, compound 2 and triethylamine are all measured in g, and ethyl acetate is measured in mL; the ratio of compound 1 to a mixed solution of sodium hydroxide aqueous solution and isopropanol is 2-2.6:80, wherein compound 1 is measured in g, and a mixed solution of sodium hydroxide aqueous solution and isopropanol is measured in mL; the mass concentration of sodium hydroxide in the mixed solution of sodium hydroxide aqueous solution and isopropanol is 5-10wt.%, and the volume ratio of sodium hydroxide aqueous solution to isopropanol is 1:1.

[0013] In step (1), the first reaction temperature is room temperature and the first reaction time is 4-5 hours; the second reaction temperature is 25-40° C. and the second reaction time is 2-6 hours.

[0014] In step (2), the mixed solvent is a mixture of methanol and tetrahydrofuran, and the volume ratio of methanol to tetrahydrofuran is 1-3:1; the ratio of compound 3 to the mixed solvent is 2-2.4:100, wherein compound 3 is measured in g and the mixed solvent is measured in mL.

[0015] In step (2), the catalyst is a palladium-carbon catalyst, and the mass ratio of compound 3, catalyst and NH4HCO2 is 2-2.4:0.2-0.5:5-10.

[0016] In step (2), the amination reaction temperature is 25-40° C., and the amination reaction time is 2-6 hours.

[0017] In step (3), the ratio of compound 4, compound 5, triethylamine and ethyl acetate is 1-2:1.1-2:1.1-1.2:100, wherein compound 4, compound 5 and triethylamine are all measured in g, and ethyl acetate is measured in mL.

[0018] In step (3), the reaction temperature is 20-60° C. and the reaction time is 4-10 hours.

[0019] The use of the Kv7 potassium channel opener of the present invention comprises a pharmaceutical composition of the Kv7 potassium channel opener or a pharmaceutically acceptable salt thereof. The pharmaceutical composition may also include a pharmaceutically acceptable excipient.

[0020] The pharmaceutical composition comprises a Kv7 potassium channel opener, a Kv7 potassium channel opener solvate, a Kv7 potassium channel opener stereoisomer, a Kv7 potassium channel opener hydrate, a Kv7 potassium channel opener prodrug, a Kv7 potassium channel opener pharmaceutically acceptable inorganic acid salt or a Kv7 potassium channel opener pharmaceutically acceptable organic acid salt; wherein the Kv7 potassium channel opener pharmaceutically acceptable inorganic acid salt comprises one or more of its hydrochloride, sulfonate, carbonate, nitrate, hydroiodide, hydrobromide, sulfate, phosphate or perchlorate; the Kv7 potassium channel opener pharmaceutically acceptable inorganic acid salt comprises one or more of its hydrochloride, sulfonate, carbonate, nitrate, hydroiodide, hydrobromide, sulfate, phosphate or perchlorate; the Kv7 potassium channel opener pharmaceutically acceptable inorganic acid salt comprises one or more of its hydrochloride, sulfonate, carbonate, nitrate, hydroiodide, hydrobromide, sulfate, phosphate or perchlorate; the Kv7 potassium channel opener pharmaceutically acceptable inorganic acid salt comprises one or more of its hydrochloride, sulfonate, carbonate, nitrate, hydroiodide, hydrobromide, sulfate, phosphate or perchlorate; the Kv7 potassium channel opener pharmaceutically acceptable organic ... The pharmaceutically acceptable organic acid salt of the radioactive agent includes one or more of its maleate, salicylate, acetylsalicylate, tartrate, fumarate, mandelate, malate, glutamate, lactate, oxalate, 2-hydroxyethanesulfonate, cinnamate, benzoate, phthalate, methanesulfonate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate, 1,5-naphthalenedisulfonate, formate, acetate, propionate, malonate, camphorate, camphorsulfonate, aspartate, gluconate, vitamin C salt, gallate, sorbate, trifluoroacetate, taurine, homotaurine, succinate or citrate.

[0021] The Kv7 potassium channel opener or pharmaceutical composition of the present invention can be used as a KCNQ potassium channel opener and applied to the preparation of drugs for treating neurological diseases.

[0022] The synthetic route of the present invention is as follows:

[0023] In the present invention, compound 1, compound 2 and triethylamine are first reacted and then reacted under alkaline conditions to obtain compound 3; the nitro group of compound 3 is aminated to obtain compound 4; compound 4, compound 5 and triethylamine are reacted in ethyl acetate to obtain a Kv7 potassium ion channel opener, which is recorded as A9.

[0024] The beneficial effects of the present invention are as follows: The Kv7 potassium ion channel opener provided by the present invention is a drug for treating epilepsy. The Kv7 potassium ion channel opener, as a Kv7.2 / 7.3 channel agonist, can alleviate epileptic symptoms by activating the Kv7.2 / 7.3 channel.

[0025] The existing Kv7 channel openers RTG and flupirtine have been withdrawn from the market due to metabolic toxicity, and no related drugs have been listed yet. In order to improve the metabolic stability of the structure of this type of drug, the present invention cyclizes the secondary amine on the benzene ring to improve the rigidity of the structure, and the carbonyl substitution on the five-membered ring further reduces the electronegativity of N, further improving the stability of the structure to avoid the problem of poor metabolic stability of the Kv7 potassium ion channel opener. Compared with Chinese patent CN 118084710 A, the present invention further cyclizes the secondary amine group on the benzene ring, increases the rigidity and stability of the structure, thereby further avoiding the metabolic toxicity of the Kv7 potassium ion channel opener. Compared with Chinese patent CN 102971307 A, the present invention adopts a benzene ring mother core, which is beneficial to improve the lipophilicity of the compound relative to the pyrimidine group, and is beneficial for the compound to penetrate the blood-brain barrier to exert an anti-epileptic effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is the H NMR spectrum of the Kv7 potassium channel opener prepared in Example 1.

[0027] Figure 2 This is the NMR carbon spectrum of the Kv7 potassium channel opener prepared in Example 1.

[0028] Figure 3 This is a graph showing the experimental results of the activation effect of A9 on Kv7.2 / 7.3 channels, where a, A9; b, experimental baseline.

[0029] Figure 4 This is the experimental result diagram of the protective effect of A9 on the maximum electric shock model.

[0030] Figure 5 This is a graph showing the latency period of generalized tonic-clonic seizures in mice.

[0031] Figure 6 This is a graph showing the survival rate of mice with generalized tonic-clonic seizures. DETAILED DESCRIPTION

[0032] The present invention is further described below with reference to the embodiments.

[0033] Example 1 (1) 2.59 g of compound 1 was dissolved in 50 mL of ethyl acetate, and 1.9 g of triethylamine and 2.52 g of compound 2 were added under ice bath, and the mixture was reacted at room temperature for 4 hours. After the reaction, 200 mL of ethyl acetate / water (volume ratio of 1:1) was added to the reaction solution for extraction. The organic phases were combined, washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was added to 80 mL of a mixed solution of sodium hydroxide aqueous solution and isopropanol (the volume ratio of sodium hydroxide aqueous solution and isopropanol was 1:1, and the mass concentration of sodium hydroxide was 6%) and reacted at 25°C for 5 hours. 200 mL of ethyl acetate / water (volume ratio of 1:1) was added for extraction. The organic phases were combined, washed with 5% citric acid aqueous solution, washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 2.4 g of compound 3 was separated by column chromatography (volume ratio of petroleum ether to ethyl acetate was 1:1). (2) 2.4 g of compound 3 was added to a mixed solvent consisting of 100 mL of methanol and tetrahydrofuran (the volume ratio of methanol to tetrahydrofuran was 2:1), and then 240 mg of 10% Pd / C catalyst and 6.8 g of NH4HCO2 were added. The amination reaction was carried out at 35°C for 3 hours, filtered, and the filtrate was concentrated under reduced pressure. Then, 200 mL of ethyl acetate / water (volume ratio was 1:1) was added for extraction. The organic phases were combined, washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (200 mesh silica gel, volume ratio of petroleum ether to ethyl acetate was 1:2) to obtain 2 g of compound 4; (3) 2 g of compound 4, 1.9 g of compound 5 and 1.17 g of triethylamine were added to 100 mL of ethyl acetate and reacted at 50° C. for 4 h. After the reaction was completed, 200 mL of ethyl acetate / water (volume ratio of 1:1) was added to the resulting reaction solution for extraction. The organic phases were combined, washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, and purified by column chromatography (200 mesh silica gel) (volume ratio of petroleum ether to ethyl acetate was 1:1) to obtain 1.4 g of Kv7 potassium channel opener A9.

[0034] The H NMR spectrum of Kv7 potassium channel opener is shown in Figure 1 , NMR carbon spectrum see Figure 2 . 1 H NMR (600 MHz, DMSO- d6) δ 10.21 (s, 1H), 7.54 (s, 1H), 7.36 (t, J = 6.8 Hz, 3H), 7.19 (d, J= 8.3 Hz, 1H), 7.15 (t, J = 8.8 Hz, 2H), 3.62 (d, J = 5.1 Hz, 4H), 2.40 (t, J= 8.0 Hz, 2H), 2.10 (dd, J= 14.9, 7.7 Hz, 2H), 2.08 (s, 3H). 13 C NMR (151 MHz, DMSO- d 6) δ 173.86, 169.47, 161.67 (d, J = 242.1 Hz), 138.37 (d, J = 65.4Hz), 132.63, 131.50 (d, J = 8.0 Hz), 131.22, 130.49, 118.70, 117.93, 115.59,115.45, 50.50, 42.79, 31.24, 19.24, 17.60.

[0035] Example 2 (1) 2.59 g of compound 1 was dissolved in 50 mL of ethyl acetate, and 1.9 g of triethylamine and 2.7 g of compound 2 were added under ice bath, and the mixture was reacted at room temperature for 5 hours. After the reaction, 200 mL of ethyl acetate / water (volume ratio of 1:1) was added to the reaction solution for extraction. The organic phases were combined, washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was added to 80 mL of a mixed solution of sodium hydroxide aqueous solution and isopropanol (the volume ratio of sodium hydroxide aqueous solution and isopropanol was 1:1, and the mass concentration of sodium hydroxide was 10%) and reacted at 40°C for 2 hours. 200 mL of ethyl acetate / water (volume ratio of 1:1) was added for extraction. The organic phases were combined, washed with 5% citric acid aqueous solution, washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Compound 3 was isolated by column chromatography (volume ratio of petroleum ether to ethyl acetate was 1:1). (2) 2.4 g of compound 3 was added to a mixed solvent consisting of 100 mL of methanol and tetrahydrofuran (the volume ratio of methanol to tetrahydrofuran was 1:1), and then 480 mg of 10% Pd / C catalyst and 10 g of NH4HCO2 were added. The reaction was carried out at 40°C for 2 hours for amination, and the filtrate was filtered. After the filtrate was concentrated under reduced pressure, 200 mL of ethyl acetate / water (volume ratio was 1:1) was added for extraction. The organic phases were combined, washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (300 mesh silica gel, the volume ratio of petroleum ether to ethyl acetate was 1:2) to obtain compound 4; (3) 2 g of compound 4, 2 g of compound 5 and 1.2 g of triethylamine were added to 100 mL of ethyl acetate and reacted at 20° C. for 10 h. After the reaction was completed, 200 mL of ethyl acetate / water (volume ratio of 1:1) was added to the resulting reaction solution for extraction. The organic phases were combined, washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, and then purified by column chromatography (300 mesh silica gel) (volume ratio of petroleum ether to ethyl acetate was 1:1) to obtain Kv7 potassium channel opener A9.

[0036] Example 3 (1) 2 g of compound 1 was dissolved in 50 mL of ethyl acetate, and 1.6 g of triethylamine and 2.1 g of compound 2 were added under ice bath, and the mixture was reacted at room temperature for 4.5 hours. After the reaction, 200 mL of ethyl acetate / water (volume ratio of 1:1) was added to the reaction solution for extraction. The organic phases were combined, washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was added to 80 mL of a mixed solution of sodium hydroxide aqueous solution and isopropanol (the volume ratio of sodium hydroxide aqueous solution and isopropanol was 1:1, and the mass concentration of sodium hydroxide was 7%) and reacted at 35°C for 4 hours. 200 mL of ethyl acetate / water (volume ratio of 1:1) was added to the mixture for extraction. The organic phases were combined, washed with 5% citric acid aqueous solution, washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Compound 3 was isolated by column chromatography (volume ratio of petroleum ether to ethyl acetate was 1:1). (2) 2 g of compound 3 was added to a mixed solvent consisting of 100 mL of methanol and tetrahydrofuran (the volume ratio of methanol to tetrahydrofuran was 3:1), and then 250 mg of 10% Pd / C catalyst and 5 g of NH4HCO2 were added. The amination reaction was carried out at 25°C for 6 hours, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and then extracted with 200 mL of ethyl acetate / water (volume ratio was 1:1). The organic phases were combined, washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (200 mesh silica gel, volume ratio of petroleum ether to ethyl acetate was 1:2) to obtain compound 4; (3) 1 g of compound 4, 1.1 g of compound 5 and 1.2 g of triethylamine were added to 100 mL of ethyl acetate and reacted at 60° C. for 5 h. After the reaction was completed, 200 mL of ethyl acetate / water (volume ratio of 1:1) was added to the resulting reaction solution for extraction. The organic phases were combined, washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, and then purified by column chromatography (200 mesh silica gel) (volume ratio of petroleum ether to ethyl acetate was 1:1) to obtain Kv7 potassium channel opener A9.

[0037] 1. Experiment on the activation of Kv7.2 / 7.3 channels by A9: The experiment used the whole-cell patch clamp technique to record channel currents. The experiment was completed by the HEKA EPC10 amplifier and HEKAPatchMaster software. A9 solution (A9 solution was prepared with 10% DMSO solution, with a concentration of 10μM) was administered by gravity through a gravity perfusion system (VM8 ALA Scientific Instruments). The electrode was pulled and polished by an electrode puller. The resulting electrode had a resistance range of 3-5MΩ and the membrane potential was maintained at 0mV. The corresponding electrode internal solution was added to the drawn electrode, and the electrode was mounted on a support. The glass slide filled with HEK293 cells prepared in advance was placed in a bath containing the electrode external solution. Before entering the solution, a positive pressure was applied to the recording electrode, and then the electrode was immersed in the solution. At this time, the electrode resistance should be 3-5MΩ and a square wave was formed. After the electrode was infinitely close to the cell, a negative pressure was applied until a high-resistance seal was formed and the fast capacitance was compensated. At this time, the whole-cell recording mode was formed, the electrode internal solution was connected to the cell intracellular solution, and the whole-cell current after the addition of A9 solution was recorded under voltage clamp. The cell was clamped at -120 mV for 100 ms, then depolarized from -120 mV to +30 mV in 10 mV steps for 1 s, and then repolarized to -120 mV for 400 ms. Intracellular solution: 65 mM KCl, 75 mM KF, 2 mM MgCl2, 10 mM HEPES, 5 mM EGTA, pH adjusted to 7.2 with KOH. Extracellular solution: 137 mM NaCl, 4 mM KCl, 1 mM MgCl2, 1.8 mM CaCl2, 10 mM HEPES, 10 mM Glucose, pH adjusted to 7.4 with NaOH.

[0038] The experimental results are shown in Figure 3 In HEK293 cells stably expressing Kv7.2 / 7.3 channels, A9 solution can activate Kv7.2 / 7.3 channels.

[0039] 2. Experiment on the protective effect of A9 on the maximum electric shock model (MES experiment): 24 h before the test, mice were subjected to electrical stimulation to screen mice that were easily induced to have epileptic seizures. The electrical stimulation parameters were set as: positive continuous pulse stimulation, frequency of 50 Hz, time of 0.25 s, and voltage of 120 V. Animals that had epileptic seizures after electrical stimulation (the epilepsy indicator was hind limb extension) were selected for further testing. 24 h later, epilepsy-induced mice were divided into 6 groups, 8 mice in each group: model group (administered with 10% DMSO solution), RTG 50 mg / kg group, A9 10 mg / kg group, A9 30 mg / kg group, A9 50 mg / kg group, and A9 100 mg / kg group. The mice in the A9 10mg / kg group, A9 30mg / kg group, A9 50mg / kg group and A9 100mg / kg group were intraperitoneally injected with the corresponding concentration of A9 solution (A9 solution was prepared with 10% DMSO solution) at an injection volume of 0.1mL / 10g, the model group was intraperitoneally injected with 10% DMSO solution, and the RTG 50mg / kg group was intraperitoneally administered with RTG. After 1 hour, the animals were electrically stimulated (positive continuous pulse stimulation, frequency of 50Hz, time of 0.25s, voltage of 120V), their epileptic seizure behavior was observed, and the protection rate was calculated, the protection rate = mice without epilepsy / total number of mice.

[0040] The experimental results are shown in Figure 4 In the MES experiment, RTG and A9 inhibited the epileptic behavior of electrically stimulated mice compared with the model group, among which A9's protection against epileptic seizures was dose-dependent.

[0041] 3. Experiment on the effect of A9 on PTZ-induced acute epilepsy model: The mice were divided into 6 groups, 8 mice in each group, namely model group, RTG 50mg / kg group, A9 10mg / kg group, A9 30mg / kg group, A9 50mg / kg group, and A9 100mg / kg group. The model group was administered with 10% DMSO solution (dosage 0.1mL / 10g), and the A9 10mg / kg group, A9 30mg / kg group, A9 50mg / kg group, and A9 100mg / kg group were administered with A9 solutions of various concentrations (dosage 0.1mL / 10g). One hour after administration, the mice in each group were intraperitoneally administered with the modeling drug PTZ (pentylenetetrazole). After PTZ injection, the animals were immediately placed in a transparent plexiglass box to observe the epileptic seizure activity, and the latency of the mice to generalized tonic-clonic seizure (GCST) within 30 minutes and the survival rate were calculated. Survival rate = surviving mice / total number of mice, and the latency is the time when epilepsy occurs after PTZ administration.

[0042] The experimental results are shown in Figure 5 and Figure 6 . Figure 5In the experiment, compared with the model group, each dose of A9 could delay GCST in a dose-dependent manner, and the A9 50 mg / kg group was stronger than the RTG 50 mg / kg group. Figure 6 The results showed that the survival rate of mice in the A9 50 mg / kg group and the A9 100 mg / kg group was higher.

Claims

1. A Kv7 potassium channel opener, characterized in that The structural formula is as follows: 。 2. A method for preparing the Kv7 potassium channel opener according to claim 1, characterized in that The steps include: (1) Compound 1, Compound 2 and triethylamine are added to ethyl acetate for a first reaction to obtain a reaction solution; the reaction solution is extracted, washed with water, dried, and concentrated under reduced pressure, and then added to a mixed solution of sodium hydroxide aqueous solution and isopropanol for a second reaction to obtain compound 3; Wherein, the structural formula of compound 1 is as follows: ； The structural formula of compound 2 is as follows: ； (2) Compound 3, a catalyst and NH4HCO2 are added to a mixed solvent for an amination reaction to obtain compound 4; Among them, the structural formula of compound 3 is as follows: ； (3) adding compound 4, compound 5 and triethylamine to ethyl acetate to react and obtain a Kv7 potassium channel opener; Among them, the structural formula of compound 4 is as follows: ； The structural formula of compound 5 is as follows: 。 3. The method for preparing the Kv7 potassium channel opener according to claim 2, characterized in that In step (1), the ratio of compound 1, compound 2, triethylamine and ethyl acetate is 2-2.6:2.1-2.7:1.6-1.9:50, wherein compound 1, compound 2 and triethylamine are all measured in g, and ethyl acetate is measured in mL; the ratio of compound 1 to a mixed solution of sodium hydroxide aqueous solution and isopropanol is 2-2.6:80, wherein compound 1 is measured in g, and a mixed solution of sodium hydroxide aqueous solution and isopropanol is measured in mL; the mass concentration of sodium hydroxide in the mixed solution of sodium hydroxide aqueous solution and isopropanol is 5-10wt.%, and the volume ratio of sodium hydroxide aqueous solution to isopropanol is 1:

1.

4. The method for preparing the Kv7 potassium channel opener according to claim 2, characterized in that In step (1), the first reaction temperature is room temperature and the first reaction time is 4-5 hours; the second reaction temperature is 25-40° C. and the second reaction time is 2-6 hours.

5. The method for preparing the Kv7 potassium channel opener according to claim 2, characterized in that In step (2), the mixed solvent is a mixture of methanol and tetrahydrofuran, and the volume ratio of methanol to tetrahydrofuran is 1-3:1; the ratio of compound 3 to the mixed solvent is 2-2.4:100, wherein compound 3 is measured in g and the mixed solvent is measured in mL.

6. The method for preparing the Kv7 potassium channel opener according to claim 2, characterized in that In step (2), the catalyst is a palladium-carbon catalyst, and the mass ratio of compound 3, catalyst and NH4HCO2 is 2-2.4:0.2-0.5:5-10.

7. The method for preparing a Kv7 potassium channel opener according to claim 2, characterized in that In step (2), the amination reaction temperature is 25-40° C., and the amination reaction time is 2-6 hours.

8. The method for preparing the Kv7 potassium channel opener according to claim 2, characterized in that In step (3), the ratio of compound 4, compound 5, triethylamine and ethyl acetate is 1-2:1.1-2:1.1-1.2:100, wherein compound 4, compound 5 and triethylamine are all measured in g, and ethyl acetate is measured in mL.

9. The method for preparing a Kv7 potassium channel opener according to claim 2, characterized in that In step (3), the reaction temperature is 20-60° C. and the reaction time is 4-10 hours.

10. A use of the Kv7 potassium channel opener according to claim 1, characterized in that A pharmaceutical composition comprising a Kv7 potassium channel opener or a pharmaceutically acceptable salt thereof.

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