Compound as well as pharmaceutical composition and application thereof

Abstract

The invention relates to the technical field of medicines, in particular to a compound as well as a pharmaceutical composition and application thereof. Effective components of the pharmaceutical composition comprise a compound and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable auxiliary materials. The invention further provides application of the compound and the pharmaceutical composition in preparation of drugs for treating neurological and mental diseases. The structure provided by the invention has stronger activity to a Kv7.2 / 7.3 channel, and the number of amino groups which are easy to oxidize is reduced in the structure, so that the physical property is more stable, oxidative deterioration is not easy to occur, the toxicity is greatly reduced, and the structure has a larger therapeutic window, a better therapeutic effect and a good application prospect.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and in particular to a compound and a pharmaceutical composition and application thereof. Background Art

[0002] After protein kinases and G protein-coupled receptors, voltage-gated ion channels (VGICs) constitute the third largest group of signaling molecules encoded by the human genome. Potassium ion channels account for half of the VGICs superfamily and can be divided into four categories based on their activation mode and number of transmembrane spans: inward rectifiers, two transmembrane K + Channel, two-pore four-pass transmembrane K + Channels, calcium-activated six- or seven-transmembrane K + voltage-gated six-transmembrane K + Channel. Voltage-gated potassium channels (Kv) are functionally expressed on the cell membrane and are selectively permeable to potassium ions. Human Kv channels are encoded by 40 genes and are the largest class in the potassium channel family, which can be divided into 12 subfamilies (Kv1-12). Therefore, Kv channels are also the most widely distributed, most diverse, and most complex type of ion channels in organisms. Kv channels are involved in the repolarization of neuronal and cardiac action potentials, providing an effective target for the development of new drugs for the treatment of nervous system and cardiovascular diseases.

[0003] In most neurons of the central nervous system and peripheral nerves, the predominant Kv7 (also known as KCNQ) isoforms are Kv7.2, Kv7.3, and Kv7.5. The generation and firing frequency of neuronal action potentials are controlled by the natural endogenous M potassium current composed of Kv7.2-7.5, which exhibits slow activation kinetics and relatively little inactivation, thereby generating considerable hyperpolarization to counteract depolarization of the neuronal membrane potential. Activation of the M current thus leads to generalized silencing of neurons, particularly after sustained depolarizing stimulation, where it limits spike duration and subsequent high-frequency action potential bursts. Human loss-of-function mutations in Kv7.2 and Kv7.3 channel genes cause benign familial neonatal epilepsy (BFNE). Kv7.2 gene mutants are broadly characterized by hyperexcitability, ranging from mild to severe epileptic encephalopathy with cognitive impairment, neuroradiological changes, and drug-resistant seizures Neonatal epileptic encephalopathy (NEE). Variants in the Kv7.3 gene are also associated with BFNE. Kv7 channels can regulate cell excitability. Their opening can reduce nerve excitability, while functional inhibition can cause depolarization of nerve cell membrane potential, increase excitability, and induce more nerve impulses. Therefore, Kv7 channels are important drug targets for preventing and treating a variety of neuroexcitability disorders.

[0004] Based on the above characteristics of Kv7 channels, Kv7.2 / 7.3 openers reduce the excitability of nerve cells by activating potassium channels. At present, the most representative KCNQ potassium channel agonist in clinical practice is the anti-epileptic drug Retigabine (RTG) developed by GlaxoSmithKline and launched in 2011. Retigabine is the first systematically studied KCNQ potassium channel agonist. It can activate KCNQ2-5 and is mainly used for the treatment of adult patients with partial-onset epilepsy. The structure of Retigabine contains an electron-rich benzene ring substituted by three amine groups. This structural feature makes Retigabine particularly prone to oxidation and deterioration during synthesis and storage. At the same time, Retigabine has many adverse reactions in clinical applications, which limits its application effect.

[0005] Therefore, there is an urgent need to develop a compound with more stable physical properties, not easy to oxidize and deteriorate, high activity, significant efficacy, low toxicity and side effects, so as to solve the problems in the prior art. Summary of the invention

[0006] To solve the above problems, the present invention provides a compound and its pharmaceutical composition and application. The number of amino groups that are easily oxidized is reduced in the structure of the compound, so the physical properties are more stable, it is not easy to oxidize and deteriorate, the activity is high, the efficacy is greatly improved, the toxicity is greatly reduced, the side effects of application are small, and the application prospects are good.

[0007] To achieve the above object, the present invention provides the following technical solutions:

[0008] In a first aspect, the present invention provides a compound, the general structural formula of which is shown in Formula I:

[0009]

[0010] wherein Ring A is selected from C6-12 aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1-3 halogens, amino, hydroxyl, carboxyl, nitro, trifluoromethyl, amide, methoxy, cyano and C1-4 alkyl;

[0011] Wherein, R1 is selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, carboxyl, trifluoromethyl, amide, methoxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl;

[0012] wherein R2 is selected from H, C1-C6 alkyl, C1-C6 alkyl which may be optionally substituted by hydroxyl, amino, C1-C4 alkoxy, C1-C4 alkylcarbonyl, halogen atom, C6-10 aryl or halogenated C6-10 aryl, C3-C6 cycloalkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkylaminocarbonyl, C2-C8 alkenyl, which may be optionally substituted by hydroxyl, amino, C1-C4 alkoxy, C1-C4 alkylcarbonyl, halogen atom, C6-10 aryl or halogenated C6-10 aryl C2-C8 alkenyl substituted by an alkylcarbonyl group, a C1-C4 alkoxy group, a halogen atom, a C6-C10 aryl group or a halogenated C6-C10 aryl group, a C5-C7 cycloalkenyl group, a C2-C8 alkynyl group, a C2-C8 alkynyl group or a C6-C10 aryl group which may be optionally substituted by a hydroxyl group, an amino group, a C1-C4 alkylcarbonyl group, a C1-C4 alkoxy group, a halogen atom, a C6-C10 aryl group or a halogenated C6-C10 aryl group;

[0013] Wherein, R3 is selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, carboxyl, trifluoromethyl, amide, methoxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl;

[0014] Among them, n=1-3.

[0015] Furthermore, the compound has a general structural formula as shown in Formula II:

[0016]

[0017] wherein Ring A is selected from C6-12 aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1-3 halogens, amino, hydroxyl, carboxyl, nitro, trifluoromethyl, amide, methoxy, cyano and C1-4 alkyl;

[0018] wherein R1 and R2 are each independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, carboxyl, trifluoromethyl, amide, methoxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl;

[0019] Among them, n=1-3.

[0020] Furthermore, the compound has a general structural formula as shown in Formula III:

[0021]

[0022] wherein R1 and R2 are each independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, carboxyl, trifluoromethyl, amide, methoxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl;

[0023] Among them, n=1-3.

[0024] Furthermore, the compound has a general structural formula as shown in Formula VI:

[0025]

[0026] Wherein, R1 and R2 are each independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, carboxyl, trifluoromethyl, amide, methoxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl.

[0027] Furthermore, the compound has a general structural formula as shown in Formula V:

[0028]

[0029] Wherein, R1 and R2 are each independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, carboxyl, trifluoromethyl, amide, methoxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl.

[0030] Furthermore, the compound has a general structural formula as shown in Formula VI:

[0031]

[0032] Wherein, R1 and R2 are each independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, carboxyl, trifluoromethyl, amide, methoxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl.

[0033] Furthermore, the compound is selected from the following compounds HP-18 to HP-28:

[0034]

[0035] Based on the same inventive concept, the present application also provides a pharmaceutical composition, the active ingredients of which include the compound represented by the above formula (I) and its stereoisomers, prodrugs, solvates, hydrates and pharmaceutically acceptable inorganic acids or organic acid salts thereof;

[0036] Wherein, the inorganic acid includes but is not limited to any of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfonic acid, carbonic acid, sulfuric acid, phosphoric acid, nitric acid and perchloric acid;

[0037] Wherein, the organic acid includes but is not limited to any of maleic acid, succinic acid, citric acid, tartaric acid, fumaric acid, formic acid, acetic acid, propionic acid, malonic acid, oxalic acid, benzoic acid, phthalic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, camphoric acid, camphorsulfonic acid, salicylic acid, acetylsalicylic acid, aspartic acid, glutamic acid, lactic acid, gluconic acid, vitamin C acid, gallic acid, mandelic acid, malic acid, sorbic acid, trifluoroacetic acid, taurine, homotaurine, 2-hydroxyethanesulfonic acid and cinnamic acid.

[0038] Based on the same inventive concept, the present application also provides a pharmaceutical composition, the active ingredients of which include the compounds represented by the above formula (I)-(VI) and pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.

[0039] Based on the same inventive concept, the present application also provides a use of the above-mentioned compound and pharmaceutical composition as a KCNQ potassium channel opener.

[0040] Based on the same inventive concept, the present application also provides an application of the above-mentioned compound and pharmaceutical composition in the preparation of drugs for treating neurological diseases.

[0041] Furthermore, the drugs for treating neurological diseases include epilepsy drugs, convulsion drugs, neuropathic pain drugs, ischemic stroke drugs and Alzheimer's disease drugs.

[0042] Furthermore, the drugs for treating neurological diseases include epilepsy drugs, convulsion drugs, neuropathic pain drugs, ischemic stroke drugs and Alzheimer's disease drugs.

[0043] Compared with the prior art, a compound of the present invention and its pharmaceutical composition and application have the following beneficial effects:

[0044] The compounds provided by the present invention have a reduced number of amino groups that are easily oxidized in their structures, so their physical properties are more stable and they are not easily oxidized and deteriorated. Specifically, the solutions of such compounds are not easily oxidized and discolored even when exposed to air. In addition, the compounds provided by the present invention not only have stable physical properties and high activity, but also have greatly reduced toxicity. Therefore, they have a larger treatment window and better treatment effects, and have good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 It is the activation multiple of the compound prepared in the example of the present invention (100 nM) and retigabine (10 μM) on Kv7.2 / 7.3 current. DETAILED DESCRIPTION

[0046] In order to facilitate the understanding of the present invention, the present invention will be described more comprehensively by way of examples below, and preferred embodiments of the present invention are given below. However, the present invention can be implemented in a variety of different forms and is not limited to the embodiments described herein. Any other implementation schemes obtained by modifying or equivalently replacing the technical scheme of the present invention without creative results are within the protection scope of the present invention.

[0047] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention are only for describing specific embodiments and are not intended to limit the present invention.

[0048] The numerical values ​​disclosed in the embodiments of the present invention are approximate values, not definite values. When the error or experimental conditions permit, all values ​​within the error range may be included without being limited to the specific numerical values ​​disclosed in the embodiments of the present invention.

[0049] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

[0050] Description of relevant terms in this application:

[0051] Relevant terms of the present invention:

[0052] The hydrogen described in the present invention includes various isotopes of hydrogen, such as deuterium and tritium;

[0053] The term "hydrocarbon" (whether used alone or as part of another group) refers to any structure containing carbon atoms and hydrogen atoms;

[0054] The term "alkyl" refers to a linear or branched saturated hydrocarbon group, wherein the alkyl group may be optionally substituted with one or more substituents, including but not limited to methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, tert-butyl;

[0055] The term "alkoxy" is used to refer to an -O-alkyl group;

[0056] The term "aryl" refers to a monocyclic aromatic group and / or a polycyclic monovalent aromatic group containing at least one aromatic hydrocarbon ring; the aromatic group includes, but is not limited to, phenyl and biphenyl;

[0057] The term "heteroaryl" refers to a monocyclic heteroaryl containing heteroatoms N, O, S and / or a polycyclic monovalent heteroaryl containing at least one aromatic hydrocarbon ring; the heteroaryl includes but is not limited to thiophene, furan, pyrrole;

[0058] The term "halogen" is used to refer to fluorine, chlorine, bromine and iodine;

[0059] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid, including inorganic and organic acids. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids, such as maleic acid, succinic acid, citric acid, tartaric acid, fumaric acid, formic acid, acetic acid, propionic acid, malonic acid, oxalic acid, benzoic acid, phthalic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, camphoric acid, camphorsulfonic acid, salicylic acid, acetylsalicylic acid, aspartic acid, glutamic acid, lactic acid, gluconic acid, vitamin C acid, gallic acid, mandelic acid, malic acid, sorbic acid, trifluoroacetic acid, taurine, homotaurine, 2-hydroxyethanesulfonic acid, cinnamic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and perchloric acid.

[0060] The instruments used for the experiments and sample analysis in the examples of this application are:

[0061] 1 HMR was measured on a Varian Mercury plus 400 NMR spectrometer. 13 CMR was measured on a Bruker 600 MHz NMR instrument;

[0062] LS-MS was measured by Agilent 1100 Series LC / MSD1946D mass spectrometer;

[0063] Special chemical reagents were purchased from reagent companies such as Exploration, Bidex, Anaiji, Sigma, Alfa, Acros and Adamas. General chemical reagents were purchased from Sinopharm Shanghai Chemical Reagent Company. The main solvents included petroleum ether, ethyl acetate, dichloromethane, methanol, etc., which were purchased from Sinopharm Group and were all synthetic grade. Column chromatography silica gel used chemically pure silica gel from Huanghai Chemical Plant, generally 200-300 mesh. The reagent treatment method was treated with reference to Purification of Laboratory Chemicals (1988 edition).

[0064] The technical solution of the present invention is further described in detail below in conjunction with specific implementation methods.

[0065] Example 1

[0066] This embodiment provides a compound for preparing N-(4-((4-fluorobenzyl)(prop-2-yn-1-yl)amino)-2-methylphenyl)-3-phenylpropanamide hydrochloride, and its general structural formula is:

[0067]

[0068] The reaction route is:

[0069]

[0070] The reaction steps are:

[0071] Compound 1 (2g, 1eq) was dissolved in toluene (50mL), and 100mg of p-toluenesulfonic acid and p-fluorobenzaldehyde (1.88g, 1.15eq) were added. After installing a water separator, the mixture was heated to reflux and separated for 4-5h. TLC detected that the raw material reaction was complete. The reaction system was concentrated under reduced pressure and used directly in the next step. The obtained crude product was dissolved in methanol (50mL), and sodium borohydride (1.65g, 2eq) was added in batches under ice-water bath cooling. Then the ice-water bath was removed, and the reaction was carried out at room temperature for 1-2h. The reaction was completed by TLC detection. The reaction system was poured into an ice-water bath, stirred, and solid precipitated. It was filtered and dried to obtain a crude intermediate 2. The obtained crude intermediate 2 was dissolved in a small amount of dichloromethane, and petroleum ether was added dropwise under stirring. A nearly white solid precipitated, filtered, and dried to obtain the intermediate, with a two-step yield of 70%.

[0072] Compound 2 (1 g, 1 eq) was dissolved in ethanol (20 mL) and water (10 mL), and reduced iron powder (4 eq) and ammonium chloride (2 eq) were added. The mixture was refluxed for 4-5 h under nitrogen protection. TLC showed that the reaction of the raw material was complete. After filtration, the mixture was concentrated under reduced pressure and purified by column chromatography. The elution ratio was petroleum ether: ethyl acetate = 1:1. The product was obtained in an amount of 3700 mg and a yield of 79%.

[0073] Compound 3 (400 mg, 1 eq) was dissolved in dichloromethane with stirring, and the mixture was cooled to 0°C in an ice-water bath. Di-tert-butyl dicarbonate (455 mg, 1.2 eq) was added. Triethylamine (263 mg, 1.5 eq) was slowly added under stirring. The mixture was warmed to room temperature after half an hour and the reaction was continued overnight. After the reaction, the mixture was washed with water, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 8:1) to obtain product 4 as a light yellow solid (180 mg, yield 31%).

[0074] Compound 4 (180 mg, 1 eq) was dissolved in DMF, and DIPEA (141 mg, 2 eq) and propargyl bromide (97 mg, 1.5 eq) were added. The reaction system was reacted at 65°C for 4 h, and ethyl acetate was added dropwise to the system. The resulting system was washed twice with water and once with saturated brine. The mixture was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain propargyl substituted intermediate 5 (178 mg, yield 89%).

[0075] Intermediate 5 (178 mg) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added under ice bath, and the reaction was carried out for 1 h. After the reaction was completed, the mixture was concentrated under reduced pressure, washed with saturated sodium bicarbonate and saturated sodium chloride, and the organic phases were combined and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain intermediate 6 (126 mg, yield 97%).

[0076] Intermediate 6 (42 mg, 1 eq) was dissolved in tetrahydrofuran (3 mL), and EDC (42 mg, 1.4 eq), DMAP (4 mg, 0.2 eq) and phenylpropionic acid (32 mg, 1.2 eq) were added. The mixture was reacted overnight at room temperature. After the reaction, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to obtain N-(4-((4-fluorobenzyl)(prop-2-yn-1-yl)amino)-2-methylphenyl)-3-phenylpropanamide (23 mg, yield 45%). This compound is numbered 7. 1 H NMR (600MHz, CHLOROFORM-D) δ7.35 (d, J=8.6Hz, 1H), 7.32-7.27 (m, 3H), 7.27-7 .23 (m, 5H), 7.23-7.19 (m, 2H), 7.03-6.97 (m, 2H), 6.70 (dd, J=9.7, 4.7Hz, 3H), 4 .45 (s, 2H), 3.94 (d, J = 2.4Hz, 2H), 3.05 (t, J = 7.5Hz, 2H), 2.93 (dt, J = 22.1, 7.9 Hz, 1H), 2.66 (td, J=7.6, 2.4Hz, 3H), 2.22 (dt, J=14.3, 2.4Hz, 1H), 2.02 (s, 3H).

[0077] Compound 7 (23 mg, 1 eq) was dissolved in 1 mL of ethyl acetate, and 1 mL of 1M HCl-dioxane solution was added at room temperature. The mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain the final product, N-(4-((4-fluorobenzyl)(prop-2-yn-1-yl)amino)-2-methylphenyl)-3-phenylpropanamide hydrochloride (25 mg, yield 100%). This compound was numbered HP-26. 1H NMR (600MHz, METHANOL-D4) δ7.52-7.37(m,1H),7.25(p,J=10.1Hz,8H),7.22-7.09(m,6H),7. 09-6.94(m,3H),4.91(d,J=7.2Hz,33H),4.57(dd,J=25.1,7.3Hz,2H),3.66(tdd,J=47.1,11. 1,5.6Hz,3H),3.30(d,J=6.9Hz,5H),3.17(d,J=7.2Hz,1H),3.00(q,J=7.5Hz,2H),2.90(q,J= 8.0Hz,2H),2.79-2.57(m,3H),2.33(d,J=6.9Hz,1H),2.09(d,J=7.0Hz,2H),1.39-1.18(m,2H)

[0078] Example 1-1

[0079] The following compounds were obtained by similar operation as in Example 1:

[0080]

[0081]

[0082]

[0083]

[0084]

[0085] The electrophysiological experiments of the compounds prepared in the above examples are as follows:

[0086] The whole-cell patch clamp was used to record the current of Kv7.2 / 7.3 channels. The patch clamp recording system used MultiClamp700A amplifier, 1440A digital-to-analog converter and pClamp10.6 acquisition and analysis software (Moleculardevices, USA). The microelectrode was made of borosilicate hard glass electrode. The glass electrode was pulled by a puller (P-97, Sutter). After filling the electrode with internal liquid, the electrode resistance was between 2-5MΩ. The cell was placed on the microscope stage, and the cell was selected to have a clear field of view. The pulled microelectrode was fixed on the amplifier probe, and the electrode was put into the liquid by a microelectrode manipulator, and slowly approached the cell. After the electrode contacted the cell, negative pressure was applied to form a GΩ seal between the electrode tip and the cell membrane surface. After compensating the electrode capacitance, negative pressure was applied to break the cell membrane, and the series resistance and cell membrane capacitance were compensated. Electrophysiological recording was performed using a 6KHz filter.

[0087] Stimulation program for activation curve recording: In voltage clamp mode, the cell is clamped at -120mV for 100ms, then depolarized from -120mV to +30mV in 10mV steps for 1s, and then repolarized to -120mV for 400ms. The sweep interval is 1.5s.

[0088] Extracellular solution (mM): NaCl 137, KCl 4, MgCl2 1, CaCl2 1.8, HEPES 10, Glucose 10, pH adjusted to 7.4 with NaOH.

[0089] Intracellular solution (mM): KCl 65, KF 75, MgCl22, HEPES 10, EGTA 5. The pH was adjusted to 7.2 with KOH.

[0090] In summary, see Figure 1 As shown, in Figure 1 In the example, the compounds prepared in the present invention have activation multiples of Kv7.2 / 7.3 current at a dose of 100 nM, which are 1.19, 4.61, 1.93, 1.12, 3.09, 1.10, 1.79, and 2.21, respectively. Figure 1 From the comparison in the figure, it can be seen that the agonist activity of compounds HP-19, HP-23, HP-26, and HP-27 on Kv7.2 / 7.3 channels is significantly better than the activation factor of the positive drug RTG, which is 1.86.

[0091] In addition, compared with the drug retigabine, which was withdrawn from the market in 2017, the compounds provided by the present invention have more stable physical properties and are not easily oxidized and deteriorated, because the number of amino groups that are easily oxidized is reduced in their structure. This is reflected in the fact that the solution of such compounds is not easily oxidized and discolored even when exposed to air. Compared with the existing drug retigabine, the efficacy of the compounds provided by the present invention is greatly improved. For example, in in vitro electrophysiological experiments, the agonist activity of compounds HP-19, HP-23, HP-26 and HP-27 on Kv7.2 / 7.3 channels is stronger than that of retigabine.

[0092] In summary, the compounds provided by the present invention overcome many shortcomings of existing Kv7 openers, not only have stable physical properties and high activity, but also have greatly reduced toxicity, and therefore have a larger therapeutic window and better therapeutic effect, showing good application prospects.

[0093] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A compound, characterized in that Its general structural formula is shown in Formula I: wherein Ring A is selected from C6-12 aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1-3 halogens, amino, hydroxyl, carboxyl, nitro, trifluoromethyl, amide, methoxy, cyano and C1-4 alkyl; Wherein, R1 is selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, carboxyl, trifluoromethyl, amide, methoxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl; wherein R2 is selected from H, C1-C6 alkyl, C1-C6 alkyl which may be optionally substituted by hydroxyl, amino, C1-C4 alkoxy, C1-C4 alkylcarbonyl, halogen atom, C6-10 aryl or halogenated C6-10 aryl, C3-C6 cycloalkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkylaminocarbonyl, C2-C8 alkenyl, which may be optionally substituted by hydroxyl, amino, C1-C4 alkoxy, C1-C4 alkylcarbonyl, halogen atom, C6-10 aryl or halogenated C6-10 aryl C2-C8 alkenyl substituted by an alkylcarbonyl group, a C1-C4 alkoxy group, a halogen atom, a C6-C10 aryl group or a halogenated C6-C10 aryl group, a C5-C7 cycloalkenyl group, a C2-C8 alkynyl group, a C2-C8 alkynyl group or a C6-C10 aryl group which may be optionally substituted by a hydroxyl group, an amino group, a C1-C4 alkylcarbonyl group, a C1-C4 alkoxy group, a halogen atom, a C6-C10 aryl group or a halogenated C6-C10 aryl group; Wherein, R3 is selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, carboxyl, trifluoromethyl, amide, methoxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl; Among them, n=1-3.

2. The compound according to claim 1, characterized in that Its general structural formula is shown in Formula II: wherein Ring A is selected from C6-12 aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1-3 halogens, amino, hydroxyl, carboxyl, nitro, trifluoromethyl, amide, methoxy, cyano and C1-4 alkyl; wherein R1 and R2 are each independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, carboxyl, trifluoromethyl, amide, methoxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl; Among them, n=1-3.

3. The compound according to claim 1, characterized in that Its general structural formula is shown in Formula III: wherein R1 and R2 are each independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, carboxyl, trifluoromethyl, amide, methoxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl; Among them, n=1-3.

4. The compound according to claim 3, characterized in that Its general structural formula is shown in Formula VI: Wherein, R1 and R2 are each independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, carboxyl, trifluoromethyl, amide, methoxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl.

5. The compound according to claim 1, characterized in that Its general structural formula is shown in Formula V: Wherein, R1 and R2 are each independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, carboxyl, trifluoromethyl, amide, methoxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl.

6. The compound according to claim 3, characterized in that Its general structural formula is shown in Formula VI: Wherein, R1 and R2 are each independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, carboxyl, trifluoromethyl, amide, methoxy, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl.

7. The compound according to claim 1, characterized in that The compound is selected from the following compounds HP-18 to HP-28:

8. A pharmaceutical composition, characterized in that The active ingredients of the pharmaceutical composition include the compound as claimed in claim 1 and its stereoisomers, prodrugs, solvates, hydrates and pharmaceutically acceptable inorganic acids or organic acid salts thereof; Wherein, the inorganic acid includes any of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfonic acid, carbonic acid, sulfuric acid, phosphoric acid, nitric acid and perchloric acid; Wherein, the organic acid comprises any several of maleic acid, succinic acid, citric acid, tartaric acid, fumaric acid, formic acid, acetic acid, propionic acid, malonic acid, oxalic acid, benzoic acid, phthalic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, camphoric acid, camphorsulfonic acid, salicylic acid, acetylsalicylic acid, aspartic acid, glutamic acid, lactic acid, gluconic acid, vitamin C acid, gallic acid, mandelic acid, malic acid, sorbic acid, trifluoroacetic acid, taurine, homotaurine, 2-hydroxyethanesulfonic acid and cinnamic acid.

9. A pharmaceutical composition, characterized in that The active ingredients of the pharmaceutical composition include the compounds of formula (I)-(VI) as described in any one of claims 1 to 7 and pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.

10. Use of the compound according to any one of claims 1 to 7 or the pharmaceutical composition according to any one of claims 8 to 9 as a KCNQ potassium channel opener.

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