4-thioamide substituted pyridine derivative and application thereof

Abstract

The invention discloses a 4-thioamide substituted pyridine derivative and application thereof, and belongs to the field of medicines. The invention provides a pyridine derivative with a structure as shown in a formula (I) or pharmaceutically acceptable salt thereof, and the compound has excellent sodium channel regulating activity and can treat, prevent or relieve voltage-gated sodium channel related diseases by regulating sodium channels.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to a 4-thioamide-substituted pyridine derivative and its applications. Background Technology

[0002] Pain is a complex sensation, usually caused by bodily injury, illness, or adverse external stimuli, resulting in discomfort. For clinical research purposes, the International Association for the Study of Pain (ISAP) defines pain as "an unpleasant sensory and emotional experience, often accompanied by actual or potential tissue damage." Pain serves as a warning signal, alerting the body to potential danger and playing an indispensable protective role in normal life activities. Pain is also a common clinical symptom; after the external stimulus causing pain disappears, intense or persistent pain can disrupt physiological functions and severely impact the quality of life. Data shows that approximately one-fifth of the world's population suffers from moderate to severe chronic pain. Pain originates from nociceptors in the peripheral nervous system. These are free nerve endings widely distributed throughout the skin, muscles, joints, and internal organs. They convert perceived thermal, mechanical, or chemical stimuli into nerve impulses (action potentials), which are transmitted via afferent nerve fibers to the cell bodies of the dorsal root ganglia (DRG), ultimately reaching higher nerve centers and causing pain sensation. The generation and conduction of action potentials in neurons depend on voltage-gated sodium channels (VGSCs) on the cell membrane. When the cell membrane depolarizes, sodium channels are activated and open, causing an influx of sodium ions, which further depolarizes the cell membrane, leading to the generation of action potentials. Therefore, inhibiting abnormal sodium channel activity can help treat and alleviate pain. Voltage-gated sodium ion channels are widely distributed on the cell membranes of excitable cells such as neurons and skeletal muscle cells. They are transmembrane glycoprotein complexes composed of a C1 subunit and several β subunits. The C1 subunit is the functional carrier of the sodium ion channel, consisting of 1700-2000 amino acids. The β subunit mainly plays an auxiliary role, modifying the kinetics and voltage-gated dependence of the ion channel. Sodium ion channels can be classified according to the different C1 subunits. Currently, nine sodium ion channel subtypes have been identified in mammals, namely NavI (NavU-Nav1.9). Different subtypes exhibit different tissue distributions and electrophysiological and pharmacological characteristics. Based on whether they can be effectively inhibited by tetrodotoxin (TTX), sodium ion channels are divided into TTX-sensitive (TTX-S) and TTX-resistant (TTX-R). Among them, NavI.1, Nav1.2, Nav1.3, and Nav1.9 are classified as TTX-sensitive, TTX-S, and TTX-resistant, respectively. 1.7 is of the TTX-S type, with the encoding gene located on human chromosome 2q23-24, and they are highly expressed in neurons. Nav 1.5, Nav 1.8, and Nav 1.9 are of the TTX-R type, with the encoding gene located on human chromosome 3p21-24.Nav1.5 is mainly found in cardiomyocytes, while Nav1.8 and Nav1.9 are found in the peripheral nervous system (PNS). Nav1.8 is an important ion channel involved in chronic pain, atrial fibrillation, and Budd-Chiari syndrome, and is a highly selective target for pain treatment. It has been shown to act as a carrier of sodium currents, maintaining the action potential emission of neurons in the dorsal root ganglia, and also participating in the spontaneous emission of electrical signals in damaged neurons, such as driving neuropathic pain. Currently reported small molecule inhibitors include A-803467, PF-06305591, VX-150, HRS-4800, JMKX-000623, HBW-004, and VX-548. PF-01247324, A-803467, and PF-06305591 have disadvantages such as poor selectivity, poor pharmacokinetic data, and low bioavailability. Summary of the Invention

[0003] To address the aforementioned problems in the prior art, the present invention provides a 4-thioamide-substituted pyridine derivative or a pharmaceutically acceptable salt thereof, which can treat, prevent, or alleviate voltage-gated sodium channel-related diseases by modulating sodium channels.

[0004] The present invention also provides a pharmaceutical composition comprising the above-described 4-thioamide-substituted pyridine compound or a pharmaceutically acceptable salt thereof.

[0005] Furthermore, the present invention provides the use of the above-mentioned 4-thioamide-substituted pyridine compounds or pharmaceutically acceptable salts thereof.

[0006] Detailed plan content:

[0007] This invention provides a 4-thioamide-substituted pyridine derivative or a pharmaceutically acceptable salt thereof with the structure shown in formula (I):

[0008]

[0009] In the above compounds, R1 and R2 are each independently selected from hydrogen and halogens (F, Cl, Br, I); R3 is selected from CH3 or CD3; and X is selected from O or S.

[0010] In one embodiment of the invention, when a chiral center is present, the compound further includes its stereoisomer, racemate, and isotope label.

[0011] In one embodiment of the present invention, the compound is specifically selected from:

[0012]

[0013] In one embodiment of the present invention, the pharmaceutically acceptable salt is an inorganic or organic salt. The inorganic salt includes hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, hydrogen sulfate, nitrate, phosphate, and acid phosphate. The organic salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, and ascorbate. Furthermore, the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, succinate, or methanesulfonate.

[0014] The present invention also provides sodium channel modulators prepared from pyridine derivatives of the present invention (I) or pharmaceutically acceptable salts, stereoisomers, racemates, or isotope-labeled derivatives thereof.

[0015] The present invention also provides pharmaceutical compositions comprising a pyridine derivative of the present invention (I) above, or a pharmaceutically acceptable salt, stereoisomer, racemate, isotope label thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0016] The present invention also provides the use of pyridine derivatives of Formula I or pharmaceutically acceptable salts, stereoisomers, racemates, or isotopic labels thereof in the preparation of medicaments for the treatment, prevention, or relief of voltage-gated sodium channel-related diseases.

[0017] In one embodiment of the present invention, the disease is pain, multiple rigidity, peroneal muscular dystrophy, incontinence, pathological cough, or arrhythmia.

[0018] In one embodiment of the present invention, the dosage form of the drug is a solid dosage form for oral administration, including, but not limited to, capsules, tablets, pills, powders, granules, etc. In these solid dosage forms, the compound of general formula (I) of the present invention is mixed as the active ingredient with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate. Or it may be mixed with the following components: (1) fillers or solubilizers, such as starch, lactose, sucrose, glucose, mannitol and silica; (2) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, gum arabic; (3) humectants, such as glycerin; (4) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginic acid, certain silicates and sodium carbonate; (5) slowing agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glyceryl monostearate; (8) adsorbents, such as kaolin; (9) lubricants, such as talc, calcium stearate, solid polyethylene glycol, sodium dodecyl sulfate, etc., or mixtures thereof. Buffers may also be included in capsules, tablets and pills.

[0019] The solid dosage forms, such as tablets, sugar pills, capsules, pellets, and granules, can be coated or microencapsulated with coating and shell materials such as enteric coatings and other materials known in the art. They may contain opaque agents, and the release of the active ingredient from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active ingredient may also be formed into microcapsules with one or more of the excipients described above.

[0020] In one embodiment of the present invention, the dosage form of the drug is a liquid dosage form for oral administration, including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, etc. In addition to the compound of general formula (I) or its pharmaceutically acceptable salt as the active ingredient, the liquid dosage form may contain inert diluents conventionally used in the art, such as water and other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn oil, olive oil, castor oil, sesame oil, etc., or mixtures of these substances. Besides these inert diluents, the liquid dosage form of the present invention may also include conventional adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0021] The suspending agent includes, for example, ethoxylated octadecyl alcohol, polyoxyethylene sorbitol, and dehydrated sorbitol, microcrystalline cellulose, agar, or mixtures thereof.

[0022] In one embodiment of the invention, the dosage form of the drug is a dosage form for parenteral injection, including, but not limited to, physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions and dispersions. Suitable carriers, diluents, solvents, and excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0023] In one embodiment of the invention, the dosage form of the drug is a dosage form for local administration, including ointments, powders, suppositories, drops, sprays, and inhalers. The active ingredient, a compound of general formula (I) of the invention or a pharmaceutically acceptable salt thereof, is mixed under sterile conditions with a physiologically acceptable carrier and optionally a preservative, buffer, and, if necessary, a propellant.

[0024] The pharmaceutical compositions of the present invention comprise a compound of general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier, excipient, and diluent. In preparing the pharmaceutical compositions, the compound of general formula (I) or a pharmaceutically acceptable salt thereof is typically mixed with a pharmaceutically acceptable carrier, excipient, or diluent. The content of the compound of general formula (I) or a pharmaceutically acceptable salt thereof can be 0.01-1000 mg, for example 0.05-800 mg, 0.1-500 mg, 0.01-300 mg, 0.01-200 mg, 0.05-150 mg, 0.05-50 mg, etc.

[0025] Beneficial effects:

[0026] The compounds provided by this invention have superior activity and higher drug potential. Detailed Implementation

[0027] Example 1: Synthesis of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-thiocarbamate)pyridine amide

[0028]

[0029] Step 1, Synthesis of intermediate a-2: Methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxylate

[0030] Add (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (a-1, 100 mg, 0.28 mmol) to a reaction flask, along with 25 mL of dichloromethane and 1 drop of N,N-dimethylformamide. Under nitrogen protection and in an ice-water bath, add 72 mg, 0.56 mmol of oxaloyl chloride dropwise. After the addition is complete, remove the ice-water bath and heat to room temperature, stirring for 1 hour. Concentrate to remove the reaction solvent. Dissolve the residue in 25 mL of dichloromethane, and add a 10 mL solution of methyl 4-aminopyridine-2-carboxylate (51.8 mg, 0.34 mmol) in dichloromethane dropwise at -10 °C. After the addition is complete, heat to room temperature and stir for 1 hour. Add water (25 mL) to the reaction solution to quench the reaction. After separation, the aqueous phase is extracted twice with DCM. Combine the organic phases and wash once with water and once with saturated brine. Dry the organic phase with anhydrous sodium sulfate and concentrate it. Column chromatography is used to separate the target product (95.6 mg, yield 70%). ESI-MS m / z 489.10(M+l)+.

[0031] Step 2, Synthesis of intermediate a-3: Methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-thiocarbamate)pyridinecarboxylate

[0032] Methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamate)pyridinecarboxylate (488.2 mg, 1.0 mmol) was added to a 100 mL round-bottom flask containing anhydrous toluene (20 mL) with stirring. The mixture was then stirred at 60 °C for 2 h. The reaction progress was monitored by TLC. After complete consumption of the starting material, the mixture was concentrated under reduced pressure. The target compound (292.3 mg, 58%) was purified by Combi Flash.

[0033] LCMS(ES)m / z=504.18[M+H]+.

[0034] Step 3: Synthesis of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-thiocarbamate)pyridine amide (Example 1)

[0035] Methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-thiocarbamate)pyridinecarboxylate (131.0 mg, 0.26 mmol) was dissolved in methanol-ammonia solution (5.0 mL, 7.0 M) and stirred at room temperature for 24 hours. The solution was concentrated under reduced pressure and purified by Combi Flash (using a gradient elution of 0-30% EtOAc in hexane) to give 99.4 mg (78%) of the target compound as a solid.

[0036] LCMS(ES)m / z=490.12[M+H]+.

[0037] 1 H-NMR (400MHz, CDCl3) δ13.75(s,1H),8.75(m,1H),8.38(m,1H),8.14(m,1H),7.85(br,1H),7.09(m,1H),6.91(m,1H ),5.70(br,1H),5.03(d,J=12.0Hz,1H),4.13(m,1H),3.99(d,J=2.2Hz,3H),2.80(m,1H),1.70(s,3H),0.80(m,3H).

[0038] Examples 2, 3, and 4 were obtained by operating in a manner similar to that of Example 1 (see Table 1).

[0039] Table 1: Structure and Data of Examples 2-4

[0040]

[0041] Synthesis of Example 5: 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-thioamino)pyridine-2-thiocarboxamide

[0042]

[0043] Phosphorus pentasulfide (78.0 mg, 0.35 mmol) was added to a 100 mL round-bottom flask containing a stirred solution of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-thiocarbamate)pyridine amide (245.2 mg, 0.5 mmol) in anhydrous toluene (15 mL), and the mixture was stirred at 60 °C for 2 h. The reaction progress was monitored by TLC. After the starting material was completely consumed, the mixture was concentrated under reduced pressure. The target compound (121.4 mg, 48%) was purified by Combi Flash.

[0044] LCMS(ES)m / z=506.08[M+H] + .

[0045] 1 H-NMR(400MHz, CDCl3)δ13.70(s,1H),8.04(m,1H),7.84(br,1H),7.07(m,1H),6.91(m,1H),6.81(m,2H),5.7 0(br,1H),5.03(d,J=12.0Hz,1H),4.13(m,1H),3.99(d,J=2.2Hz,3H),2.80(m,1H),1.70(s,3H),0.80(m,3H).

[0046] Example 6 Bioactivity Test

[0047] ①In vitro inhibitory effect of the compound on Nav 1.8:

[0048] Manual patch-clamping was used on HEK293 cells stably expressing human Nav 1.8. After the Nav 1.8 current stabilized, the magnitude of the Nav 1.8 current before and after compound administration was compared to determine the effect of the compound on the Nav 1.8 channel. The test compound was dissolved in DMSO to prepare a 9 mM stock solution, which was then dissolved in extracellular fluid at the required concentration on the day of testing. The extracellular fluid composition included (mM): NaCl, 137; KCl, 4; CaCl2, 1.8; MgCl2, 1; HEPES, 10; glucose, 10; pH 7.4 (titrated with NaOH). All reagents were purchased from Sigma (St. Louis, MO). Cells were clamped at -80 mV and depolarized to 10 mV using a 10 ms square wave to obtain the Nav 1.8 current, repeated every 5 seconds. The maximum current induced by the square wave was detected. After stabilization, the test compound (dissolved in extracellular fluid at the required concentration) was perfused. After stabilization, the blocking strength of the compound against Nav 1.8 was calculated based on the current before and after perfusion. A pCLAMP (Molecular Devices, Union City, CA) was used. Current stabilization refers to the current changing within a finite range over time.

[0049] Inhibition rate (%) = (1 - current value of experimental group / current value of control group) × 100%.

[0050] Table 2: Inhibition rate determination (inhibition rate / %) at 100 nM concentration

[0051]

[0052]

[0053] The inhibition rate (%) of Nav 1.8 at a concentration of 100 nM was determined using the same method for the control compound VX-548 and the compounds of the present invention, indicating that compounds 1, 2, 3, 4, and 5 have excellent sodium channel regulatory activity (inhibition rate of Nav 1.8 ≥ 90%) and can be used to treat diseases related to sodium channel regulation.

[0054] ② Test the in vitro inhibitory effect of the compound on Nav 1.8 (IC50):

[0055] The experiment was conducted using a CHO cell line that stably expresses the Nav1.8 sodium channel. Gene information: Sodium channel, voltage-gated, type 8, alpha (SCN1OA, cDNA strictly similar to GenBank accession number: NM 006514).

[0056] Prior to patch-clamp assay, cells were separated using 0.25% Trypsin-EDTA, and 6.5 × 10⁶ cells were collected. 3 Cells were seeded onto coverslips and cultured in 24-well plates (final volume: 500 μL). After 18 hours, the cells were tested.

[0057] Fluids used for electrophysiological recording: Extracellular fluid: K-007-1, 140mM NaCl, 3.5mM KCl, 1mM MgCl2MH2O, 2mM CaCl2·H2O, 10mM D-Glucose, 10mM HEPES, 1.25mM NaH2PO4·H2O, pH adjusted to 7.4 with NaOH. Intracellular fluid: Nav-001-2, 50mM CsCl, 10mM NaCl, 10mM HEPES, 60mM CsF, 20mM EGTA, pH adjusted to 7.2 with CsOH. Extracellular fluid was stored for 2 weeks. Intracellular fluid was prepared, aliquoted into 1mL tubes, and stored at -20°C. Freshly thawed intracellular fluid was used daily for experiments. All intracellular fluid was used within three months. After three months, the old intracellular fluid was discarded and freshly prepared.

[0058] Patch-clamp assay: The voltage stimulation protocol for recording Navl.8 sodium current using whole-cell patch-clamp was as follows: After whole-cell sealing, the cell voltage was clamped at -120mV for 30ms. The clamp voltage was then depolarized to 0mV and maintained for 50ms. The voltage was then restored to -50mV (specific voltage referenced from the half-inactivation voltage of the IV assay) and maintained for 5s. Next, the cell membrane potential was restored to -120mV and maintained for 20ms, then depolarized to 0mV and maintained for 50ms. Finally, the voltage was restored to the clamp voltage of -120mV and maintained for 30ms. Data was collected every 20ms. The effect of the drug on the peak sodium current was observed. Experimental data were acquired using an EPC 10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.

[0059] A capillary glass tube was drawn into a recording electrode using a microelectrode drawing instrument. The electrode, filled with intracellular fluid, was placed into an electrode holder. Under an inverted microscope, the microelectrode manipulator was manipulated to immerse the electrode in the extracellular fluid, and the electrode resistance (Rpip) was recorded. The electrode was then brought into contact with the cell surface, and negative pressure was applied to aspirate and form a high-resistance seal (GΩ). Fast capacitance compensation was then performed, and negative pressure was continued to rupture the cell membrane, establishing a whole-cell recording mode. Slow capacitance compensation was then performed, and experimental parameters such as membrane capacitance (Cm) and series resistance (Rs) were recorded. Leakage compensation was not applied.

[0060] Once the Navl.8 current recorded in whole cells stabilized, drug administration began. Each drug concentration was administered for 5 minutes (or until the current stabilized) before moving to the next concentration. Multiple concentrations were measured for each test compound. A coverslip containing cells was placed in a recording bath under an inverted microscope. Blank control solution and working solution of the test compound were sequentially flowed through the recording bath from low to high concentration using gravity perfusion, acting on the cells. A peristaltic pump was used for fluid exchange during recording. The current detected in the compound-free solution for each cell served as its control group. Each concentration was measured independently in triplicate using at least three cells. All electrophysiological experiments were performed at room temperature.

[0061] Data analysis: The current and blank control current after each concentration of the test compound were normalized. Then, the inhibition rate corresponding to each test compound was calculated, and the mean and standard deviation of the inhibition rate at each concentration were calculated. The IC50 was then calculated. 50 The dose-dependent effect was nonlinearly fitted, and the calculation equation is as follows:

[0062]

[0063] Among them, IC 50 This is the half-inhibitory concentration (IC50). 50 The calculations and curve fitting were performed using GraphPad Prism software.

[0064] Table 3: IC50 of compounds 1, 2, and 3 in the examples inhibiting Nav1.8 channel activity 50 (nM)

[0065] Test compound <![CDATA[IC 50 (nM)]]> VX-548 4.77 Example 1 2.07 Example 2 2.65 Example 3 2.95 Example 4 3.23 Example 5 3.07

[0066] Conclusion: In the same batch of experiments under the same testing conditions, compounds 1, 2, 3, 4, and 5 showed more significant inhibitory effects on Nav1.8 channel activity compared to VX-548.

[0067] For compounds of general formula (I), the linking and substituent groups have a significant impact on the pharmacodynamic properties of the compound. Although the invention has been described through specific embodiments above, it should not be construed as limiting; rather, the invention covers the general aspects previously disclosed. Various modifications and embodiments are possible without departing from the spirit and scope of the invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, racemate, or isotope-labeled form thereof, in: R1 and R2 are each independently H or a halogen group; R3 is selected from CH3 or CD3; X is selected from O or S.

2. The compound of claim 1 or its pharmaceutically acceptable salt, stereoisomer, racemate, or isotope label, characterized in that, The compounds are specifically selected from:

3. The compound according to claim 1, or its pharmaceutically acceptable salt, stereoisomer, racemate, or isotope label, characterized in that, The pharmaceutically acceptable salts are inorganic or organic salts; the inorganic salts are selected from hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, hydrogen sulfate, nitrate, phosphate, and acid phosphate; the organic salts are selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, and ascorbate.

4. A sodium channel modulator, characterized in that, Includes the compound of any one of claims 1-3 or its pharmaceutically acceptable salt, stereoisomer, racemate, or isotope label.

5. A pharmaceutical composition, characterized in that, This includes the compound of any one of claims 1-3 or its pharmaceutically acceptable salt, stereoisomer, racemate, isotope label, and pharmaceutically acceptable carrier, excipient, or diluent.

6. Use of the compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, racemate, isotope label thereof, or the pharmaceutical composition of claim 5 in the preparation of a medicament for treating, preventing, or alleviating voltage-gated sodium channel-related diseases.

7. The use according to claim 6, characterized in that, The diseases mentioned include pain, multiple rigidity, peroneal muscular atrophy, incontinence, pathological cough, or arrhythmia.

8. The use according to claim 6, characterized in that, The dosage form of the drug is a solid or liquid dosage form for oral administration.

9. The use according to claim 6, characterized in that, The drug is in a dosage form intended for parenteral injection.

10. The use according to claim 6, characterized in that, The drug is in a dosage form intended for local administration.

Images