Kv7 Potassium Ion Channel Openers and Their Preparation Methods and Applications

Abstract

The present invention belongs to the technical field of heterocyclic compounds, and particularly relates to a Kv7 potassium ion channel opener, a preparation method thereof and an application thereof. Compound 1, compound 2 and triethylamine are added to ethyl acetate for a first reaction to obtain a reaction solution; the reaction solution is subjected to extraction, washing with water, drying, and concentration under reduced pressure, and then added to a mixed solution of an aqueous sodium hydroxide solution and isopropanol for a second reaction to obtain compound 3; compound 3, a catalyst and NH4HCO2 are added to a mixed solvent for an amination reaction to obtain compound 4; compound 4, compound 5 and triethylamine are added to ethyl acetate for a reaction to obtain a Kv7 potassium ion channel opener. The present invention improves the metabolic stability and the rigidity of the structure.

Description

Technical Field

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

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

[0003] Studies have shown that Kv7 potassium ion 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 clinical phase IIb trial showed that the Kv7.2 / 7.3 opener XEN1101 can reduce the seizure frequency of 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 the adjuvant treatment of partial-onset epilepsy 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 Although the marketed drug RTG has excellent anti-epileptic efficacy, it was withdrawn from the market in 2017 due to drug metabolic toxicity (skin and retinal blue pigment deposition) caused by the triamino aromatic ring skeleton. Therefore, finding a safe and effective Kv7.2 / 7.3 opener with a new parent nucleus structure is the key to developing anti-epileptic drugs targeting the Kv7.2 / 7.3 channel currently.

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

[0005]

[0006] Among them, ring A is selected from any one of; among them, 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 halogens, cyano, nitro, amino, hydroxyl, carboxyl, trifluoromethyl, amido, methoxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl; among them, R2 and R3 are each independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, carboxyl, trifluoromethyl, amido, methoxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl; among them, R is selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy. The rigidity and stability of the structure of the Kv7 potassium ion channel opener in this patent are poor.

[0007] Chinese Patent CN 102971307A discloses a piperidinyl pyrimidine amide as a Kv7 potassium channel opener, a dimethoxy-pyrimidine amide compound of Formula I, which shows 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.

[0008]

[0009] Wherein: n is an integer of 1 or 2; t is 0 or 1; each R 1 is independently selected from C 1-3 alkoxy, C 1-3 alkyl, C 1-3 alkyl-O-C 1-3 alkyl; R 2 and R 3 are 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 is C 1-6 alkyl, C 1-3 alkyl-C 3-6 cycloalkyl, C 3-6 heterocycloalkyl; or a pharmaceutically acceptable salt thereof. In this patent, the parent nucleus of the Kv7 potassium channel opener is a pyrimidine group, which has poor lipophilicity and is not conducive to crossing the blood-brain barrier to produce an anti-epileptic effect. Summary of the Invention

[0010] The object of the present invention is to provide a Kv7 potassium ion channel opener, which improves metabolic stability and the rigidity of the structure; the present invention also provides a preparation method and application of the Kv7 potassium ion channel opener.

[0011] The Kv7 potassium ion channel opener described in the present invention has the following structural formula:

[0012] .

[0013] The preparation method of the Kv7 potassium ion channel opener described in the present invention comprises the following steps:

[0014] (1) Adding compound 1, compound 2 and triethylamine to ethyl acetate for the first reaction to obtain a reaction solution; after the reaction solution is extracted, washed with water, dried, and concentrated under reduced pressure, it is added to a mixed solution of sodium hydroxide aqueous solution and isopropanol for the second reaction to obtain compound 3;

[0015] Among them, the structural formula of compound 1 is as follows:

[0016] ;

[0017] The structural formula of Compound 2 is as follows:

[0018] ;

[0019] (2) Add Compound 3, a catalyst, and NH4HCO2 to the mixed solvent for an amination reaction to obtain Compound 4;

[0020] Among them, the structural formula of Compound 3 is as follows:

[0021] ;

[0022] (3) React Compound 4, Compound 5, and triethylamine in ethyl acetate to obtain a Kv7 potassium ion channel opener;

[0023] Among them, the structural formula of Compound 4 is as follows:

[0024] ;

[0025] The structural formula of Compound 5 is as follows:

[0026] .

[0027] 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, where Compound 1, Compound 2, and triethylamine are in g, and ethyl acetate is in mL; the ratio of Compound 1 to the mixed solution of sodium hydroxide aqueous solution and isopropanol is 2 - 2.6:80, where Compound 1 is in g, and the mixed solution of sodium hydroxide aqueous solution and isopropanol is in mL; the mass concentration of sodium hydroxide in the mixed solution of sodium hydroxide aqueous solution and isopropanol is 5 - 10 wt.%, and the volume ratio of sodium hydroxide aqueous solution to isopropanol is 1:1.

[0028] 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.

[0029] 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, where Compound 3 is in g, and the mixed solvent is in mL.

[0030] In step (2), the catalyst is palladium carbon catalyst, and the mass ratio of Compound 3, the catalyst, and NH4HCO2 is 2 - 2.4:0.2 - 0.5:5 - 10.

[0031] In step (2), the amination reaction temperature is 25 - 40 °C, and the amination reaction time is 2 - 6 hours.

[0032] 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, where compound 4, compound 5 and triethylamine are all in g, and ethyl acetate is in mL.

[0033] In step (3), the reaction temperature is 20 - 60 °C, and the reaction time is 4 - 10 hours.

[0034] The application of the Kv7 potassium channel opener described in the present invention includes a pharmaceutical composition containing a Kv7 potassium channel opener or a pharmaceutically acceptable salt thereof. The pharmaceutical composition may further include pharmaceutically acceptable excipients.

[0035] The pharmaceutical composition contains one of a Kv7 potassium channel opener, a solvent complex of a Kv7 potassium channel opener, a stereoisomer of a Kv7 potassium channel opener, a hydrate of a Kv7 potassium channel opener, a prodrug of a Kv7 potassium channel opener, a pharmaceutically acceptable inorganic acid salt of a Kv7 potassium channel opener, or a pharmaceutically acceptable organic acid salt of a Kv7 potassium channel opener; wherein, the pharmaceutically acceptable inorganic acid salts of a Kv7 potassium channel opener include one or more of its hydrochloride, sulfonate, carbonate, nitrate, hydroiodide, hydrobromide, sulfate, phosphate or perchlorate; the pharmaceutically acceptable organic acid salts of a Kv7 potassium channel opener include 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, ascorbate, gallate, sorbate, trifluoroacetate, taurate, hypotaurate, succinate or citrate.

[0036] The Kv7 potassium channel opener or pharmaceutical composition described in the present invention can be used as a KCNQ potassium channel opener and applied to the preparation of drugs for treating neurological diseases.

[0037] The synthetic route of the present invention is as follows:

[0038]

[0039] In the present invention, Compound 1, Compound 2 and triethylamine first react and then react 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 react in ethyl acetate to obtain a Kv7 potassium ion channel opener, denoted as A9.

[0040] The beneficial effects of the present invention are as follows:

[0041] The Kv7 potassium ion channel opener provided by the present invention is a drug for treating epilepsy. As a Kv7.2 / 7.3 channel agonist, the Kv7 potassium ion channel opener can alleviate epilepsy symptoms by activating the Kv7.2 / 7.3 channel.

[0042] The existing Kv7 channel openers RTG and flupirtine were withdrawn from the market due to metabolic toxicity, and currently no related drugs have been launched. 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 increase 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, increasing 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 uses a benzene ring mother nucleus, which is beneficial to improving the lipophilicity of the compound and facilitating the penetration of the compound through the blood-brain barrier to exert an anti-epileptic effect. Description of the Drawings

[0043] Figure 1 It is the 1H NMR spectrum of the Kv7 potassium ion channel opener prepared in Example 1.

[0044] Figure 2 It is the 13C NMR spectrum of the Kv7 potassium ion channel opener prepared in Example 1.

[0045] Figure 3 It is the experimental result graph of the activation effect of A9 on the Kv7.2 / 7.3 channel. In the figure, a, A9; b, experimental baseline.

[0046] Figure 4 It is the experimental result graph of the protective effect of A9 on the maximal electroshock model.

[0047] Figure 5 It is the result graph of the latency of generalized tonic-clonic seizures in mice.

[0048] Figure 6 It is the result graph of the survival rate of generalized tonic-clonic seizures in mice. Detailed Embodiments

[0049] The present invention will be further described below in conjunction with embodiments.

[0050] Example 1

[0051] (1) Dissolve 2.59 g of Compound 1 in 50 mL of ethyl acetate. Add 1.9 g of triethylamine and 2.52 g of Compound 2 under an ice bath, and react at room temperature for 4 hours. After the reaction is completed, add 200 mL of a mixed solution of ethyl acetate / water (volume ratio 1:1) to the obtained reaction solution for extraction. Combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Then add it to a mixed solution of 80 mL of sodium hydroxide aqueous solution and isopropanol (volume ratio of sodium hydroxide aqueous solution to isopropanol is 1:1, and the mass concentration of sodium hydroxide is 6%) and react at 25 °C for 5 h. Add 200 mL of a mixed solution of ethyl acetate / water (volume ratio 1:1) for extraction. Combine the organic phases, wash with 5% citric acid aqueous solution, saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography (volume ratio of petroleum ether to ethyl acetate is 1:1) to obtain 2.4 g of Compound 3;

[0052] (2) Add 2.4 g of Compound 3 to a mixed solvent composed of 100 mL of methanol and tetrahydrofuran (volume ratio of methanol to tetrahydrofuran is 2:1), then add 240 mg of 10% Pd / C catalyst and 6.8 g of NH4HCO2, and carry out an amination reaction at 35 °C for 3 hours. Filter, concentrate the filtrate under reduced pressure, add 200 mL of a mixed solution of ethyl acetate / water (volume ratio 1:1) for extraction. Combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography (200-mesh silica gel, volume ratio of petroleum ether to ethyl acetate is 1:2) to obtain 2 g of Compound 4;

[0053] (3) Add 2 g of Compound 4, 1.9 g of Compound 5, and 1.17 g of triethylamine to 100 mL of ethyl acetate and react at 50 °C for 4 h. After the reaction is completed, add 200 mL of a mixed solution of ethyl acetate / water (volume ratio 1:1) to the obtained reaction solution for extraction. Combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and after evaporation, purify by column chromatography (200-mesh silica gel) (volume ratio of petroleum ether to ethyl acetate is 1:1) to obtain 1.4 g of Kv7 potassium ion channel opener A9.

[0054] The 1H NMR spectrum of the Kv7 potassium ion channel opener is shown in Figure 1 , and the 13C NMR spectrum is shown in 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 J = 242.1 Hz), 138.37 (d, J J = 65.4 Hz), 132.63, 131.50 (d, J 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.

[0055] Example 2

[0056] (1) Dissolve 2.59 g of Compound 1 in 50 mL of ethyl acetate. Add 1.9 g of triethylamine and 2.7 g of Compound 2 under an ice bath, and react at room temperature for 5 hours. After the reaction is completed, add a mixed solution of 200 mL of ethyl acetate / water (volume ratio 1:1) to the obtained reaction solution for extraction. Combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Then add it to a mixed solution of 80 mL of an aqueous sodium hydroxide solution and isopropanol (volume ratio of aqueous sodium hydroxide solution to isopropanol is 1:1, and the mass concentration of sodium hydroxide is 10%) and react at 40 °C for 2 h. Add a mixed solution of 200 mL of ethyl acetate / water (volume ratio 1:1) for extraction. Combine the organic phases, wash with 5% aqueous citric acid solution, saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography (volume ratio of petroleum ether to ethyl acetate is 1:1) to obtain Compound 3;

[0057] (2) 2.4 g of Compound 3 was added to a mixed solvent composed of 100 mL of methanol and tetrahydrofuran (the volume ratio of methanol to tetrahydrofuran was 1:1), then 480 mg of 10% Pd / C catalyst and 10 g of NH4HCO2 were added, and the amination reaction was carried out at 40 °C for 2 hours. After filtration, the filtrate was concentrated under reduced pressure, then 200 mL of a mixed solution of ethyl acetate / water (volume ratio 1:1) was added for extraction. The organic phases were combined, washed with saturated sodium chloride solution, 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;

[0058] (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 a mixed solution of ethyl acetate / water (volume ratio 1:1) was added to the obtained reaction solution for extraction. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and after rotary evaporation, it was purified by column chromatography (300-mesh silica gel) (the volume ratio of petroleum ether to ethyl acetate was 1:1) to obtain Kv7 potassium channel opener A9.

[0059] Example 3

[0060] (1) 2 g of Compound 1 was dissolved in 50 mL of ethyl acetate, 1.6 g of triethylamine and 2.1 g of Compound 2 were added under ice bath, and the reaction was carried out at room temperature for 4.5 hours. After the reaction ended, 200 mL of a mixed solution of ethyl acetate / water (volume ratio 1:1) was added to the obtained reaction solution for extraction. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then added to a mixed solution of 80 mL of sodium hydroxide aqueous solution and isopropanol (the volume ratio of sodium hydroxide aqueous solution to isopropanol was 1:1, and the mass concentration of sodium hydroxide was 7%) and reacted at 35 °C for 4 h. 200 mL of a mixed solution of ethyl acetate / water (volume ratio 1:1) was added for extraction. The organic phases were combined, washed with 5% citric acid aqueous solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (the volume ratio of petroleum ether to ethyl acetate was 1:1) to obtain Compound 3;

[0061] (2) 2 g of Compound 3 was added to a mixed solvent composed of 100 mL of methanol and tetrahydrofuran (the volume ratio of methanol to tetrahydrofuran was 3:1), then 250 mg of 10% Pd / C catalyst and 5 g of NH4HCO2 were added, and the amination reaction was carried out at 25 °C for 6 hours. After filtration, the filtrate was concentrated under reduced pressure, then 200 mL of a mixed solution of ethyl acetate / water (volume ratio 1:1) was added for extraction. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (200-mesh silica gel, the volume ratio of petroleum ether to ethyl acetate was 1:2) to obtain Compound 4;

[0062] (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 a mixture of ethyl acetate / water (volume ratio 1:1) was added to the resulting reaction solution for extraction. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and after evaporation to dryness, 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.

[0063] I. Experiment on the activation effect of A9 on Kv7.2 / 7.3 channels:

[0064] The whole-cell patch-clamp technique was used to record channel currents in this experiment. The experiment was completed by a HEKA EPC10 amplifier and HEKAPatchMaster software. The A9 solution (the A9 solution was prepared with a 10% DMSO solution and had a concentration of 10 μM) was administered by gravity through a gravity perfusion system (VM8 ALA Scientific Instruments). An electrode puller was used for pulling and polishing the electrodes. The resistance of the obtained electrodes in the solution ranged from 3 - 5 MΩ, and the membrane potential was maintained at 0 mV. The corresponding electrode internal solution was added to the pulled electrodes, and the electrodes were installed on a holder. The glass slide pre-seeded with HEK293 cells was placed in a bath containing the electrode external solution. Before the electrodes entered the solution, a positive pressure was applied to the recording electrodes, and then the electrodes entered the solution. At this time, the electrode resistance should be 3 - 5 MΩ and a square wave should be formed. After the electrodes were infinitely close to the cells, 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 in communication with the intracellular solution, and the whole-cell current after adding the A9 solution was recorded under voltage clamp conditions. The cell clamp was at -120 mV for 100 ms, and then stepped in 10-mV increments from -120 mV to +30 mV 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.

[0065] The experimental results are shown in Figure 3 , in HEK293 cells stably expressing Kv7.2 / 7.3 channels, the A9 solution can activate the Kv7.2 / 7.3 channels.

[0066] II. Experiment on the protective effect of A9 on the maximal electroshock model (MES experiment):

[0067] Twenty-four hours before the test, the mice were subjected to electrical stimulation to screen for mice prone to epileptic seizures. The electrical stimulation parameters were set as follows: positive continuous pulse stimulation, frequency of 50 Hz, duration of 0.25 s, and voltage of 120 V. Animals with epileptic seizures after electrical stimulation (the epileptic index was hind limb extension) were selected for further testing. Twenty-four hours later, the epileptic seizure-induced mice were divided into 6 groups, with 8 mice in each group: the model group (administered 10% DMSO solution), the RTG 50 mg / kg group, the A9 10 mg / kg group, the A9 30 mg / kg group, the A9 50 mg / kg group, and the A9 100 mg / kg group. In the A9 10 mg / kg group, the A9 30 mg / kg group, the A9 50 mg / kg group, and the A9 100 mg / kg group, the mice were intraperitoneally injected with the corresponding concentration of A9 solution (the A9 solution was prepared with 10% DMSO solution) at a dose of 0.1 mL / 10 g. The model group was intraperitoneally injected with 10% DMSO solution, and the RTG 50 mg / kg group was intraperitoneally administered RTG. One hour later, the animals were electrically stimulated (positive continuous pulse stimulation, frequency of 50 Hz, duration of 0.25 s, voltage of 120 V), and their epileptic seizure behaviors were observed. The protection rate was calculated as follows: protection rate = mice without epileptic seizures / total number of mice.

[0068] The experimental results are shown in Figure 4 , in the MES experiment, compared with the model group, RTG and A9 inhibited the epileptic behaviors of electrically stimulated mice, and the protection of A9 against epileptic seizures was dose-dependent.

[0069] III. Experiment on the effect of A9 on the PTZ-induced acute epilepsy model:

[0070] The mice were divided into 6 groups, with 8 mice in each group, namely the model group, the RTG 50 mg / kg group, the A9 10 mg / kg group, the A9 30 mg / kg group, the A9 50 mg / kg group, and the A9 100 mg / kg group. The model group was administered 10% DMSO solution (dose of 0.1 mL / 10 g), and the A9 10 mg / kg group, the A9 30 mg / kg group, the A9 50 mg / kg group, and the A9 100 mg / kg group were administered A9 solutions at each concentration (dose of 0.1 mL / 10 g). One hour after administration, each group of mice was intraperitoneally administered the modeling drug PTZ (pentylenetetrazol). After injecting PTZ, the animals were immediately placed in a transparent plexiglass box, and their epileptic seizure activities were observed. The latency of generalized tonic-clonic seizures (GCST) and the survival rate of the mice within 30 minutes were calculated. The survival rate = surviving mice / total number of mice, and the latency was the time when epileptic seizures occurred after administering PTZ.

[0071] The experimental results are shown in Figure 5 and Figure 6 . Figure 5Among them, compared with the model group, each dose of A9 could delay GCST, and showed a dose-dependence. Among them, the A9 50mg / kg group was stronger than the RTG 50mg / kg group. Figure 6 It was shown that the survival rates of the mice in the A9 50mg / kg group and the A9 100mg / kg group were relatively high.

Claims

1. Use of a compound in the preparation of a Kv7 potassium channel opener, wherein the compound has the following structural formula: 。

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