Use of a pyridine sulfonamide phosphate compound for the preparation of a medicament for the treatment of asthma

Abstract

The use of a pyridine sulfamide phosphate compound or a pharmaceutical composition containing the same in the preparation of a drug for treating asthma. The pyridine sulfamide phosphate compound has a dual effect of reducing bronchial edema and anti-inflammatory, which can reduce the inflammatory response of the airway and lung while improving ventilation function, and has the advantages of treating the symptoms and the root cause. The drug has high safety, can significantly reduce the tissue distribution in the kidney, thereby reducing the adverse effects such as electrolyte disturbance caused by strong diuretics, and is expected to become a new drug for clinical treatment of asthma, and has a very broad clinical application prospect.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically to the use of a pyridine sulfonamide phosphate compound or a pharmaceutical composition containing the same in the preparation of an asthma treatment drug. Background Technology

[0002] Asthma is a heterogeneous disease defined by a history of respiratory symptoms such as wheezing, shortness of breath, chest tightness, and cough. These symptoms vary over time and intensity and are accompanied by varying degrees of expiratory airflow limitation. This airflow limitation may persist. It is currently considered a chronic inflammatory airway disorder involving multiple cells and cellular components, typically associated with airway hyperresponsiveness and airway inflammation. It is estimated that approximately 262 to 358 million people worldwide suffer from asthma annually, and about 461,000 die from it each year. The incidence of asthma in my country is showing an increasing trend year by year. A 2019 study showed that the prevalence of asthma in people aged 20 and above in my country was 4.2%, estimating 45.7 million adult patients.

[0003] Many risk factors can induce asthma. In childhood and adolescence, these factors are related to genetics, allergens, microorganisms, air pollution, respiratory viral infections, and passive smoking. In adulthood, in addition to the same risk factors as in childhood and adolescence, factors such as stress, sex hormones, occupational exposure, obesity, and active smoking also play a role. Currently, the principles for asthma prevention and treatment both domestically and internationally are mainly based on the Global Initiative for Asthma (GINA). The primary treatments are inhaled formulations, including inhaled corticosteroids (ICS), short-acting β2 receptor agonists (SABA), long-acting β2 receptor agonists (LABA), long-acting M receptor antagonists (LAMA), and ICS+LABA. Oral or injectable formulations are used as adjuncts, including oral corticosteroids, leukotriene antagonists, theophylline, and β2 receptor agonists. Injectable formulations are used for severe or refractory asthma, including anti-IgE monoclonal antibodies, anti-interleukin-5 / anti-interleukin-5 receptor monoclonal antibodies (anti-IL5 / R), anti-interleukin-4 receptor / anti-interleukin-13 receptor monoclonal antibodies (anti-IL-4 / IL-13R), anti-thymocyte stromal lymphopoietin monoclonal antibodies (anti-TSLP), theophylline, and corticosteroids. Therefore, inhaled formulations are the main treatments and routes of administration for asthma because they have a rapid onset of action, high local concentrations in target organs, and low systemic exposure, ensuring efficacy while reducing systemic adverse reactions and exhibiting good safety. Prior to 2020, GINA recommended on-demand inhaled SABA as the first-line reliever. However, after 2020, GINA no longer recommends on-demand inhaled SABA as the first-line reliever. Instead, it recommends ICS + formoterol as the first-line reliever, with inhaled SABA as an alternative. ICS remains the first-line medication for controlling airway inflammation once a patient is diagnosed with asthma.

[0004] Glucocorticoids are primarily used for systemic administration during acute severe asthma attacks and for local inhalation therapy during remission. However, continuous use of glucocorticoids can lead to numerous adverse reactions, such as altered visual acuity, glaucoma, growth inhibition, osteoporosis, and even fractures. They are best avoided, especially by the elderly, infants, and pregnant women. Beta-2 receptor agonists are bronchodilators with rapid and potent effects, mainly used for acute asthma and dyspnea. However, long-term use of beta-2 receptor agonists can inhibit the responsiveness of beta-2 receptors, reducing their efficacy. Therefore, seeking new therapeutic targets for asthma to improve symptoms, lung function, and quality of life is of significant clinical importance.

[0005] Furosemide is an old diuretic drug that is still widely used clinically. In China, Li Yanhong et al. searched the China Hospital Knowledge Database and Wanfang Database for randomized controlled trials of furosemide nebulized inhalation for asthma in the Chinese population. They conducted a quality assessment of 21 included studies, extracted data, and performed a meta-analysis using a random-effects model. The results showed that furosemide nebulization for asthma in the Chinese population was well-tolerated and had some efficacy. However, to date, no furosemide formulations for asthma treatment have been marketed. Barnes commented on furosemide nebulization for asthma treatment in *Nature Reviews Drug Discovery*, stating that "furosemide nebulized inhalation in a metered-dose inhaler (MDI) is not very effective for asthma, but there is potential for more effective and longer-lasting chloride channel blockers to be developed in the future." Therefore, while furosemide inhalation formulations have some effect on asthma, the efficacy is weak and has not met the requirements for market approval as a therapeutic drug.

[0006] Therefore, there is an urgent clinical need to develop new asthma drugs that are more effective and safer. Summary of the Invention

[0007] To address the lack of effective and low-side-effect asthma medications in existing technologies, this invention provides the use of pyridine sulfonamide phosphate compounds or pharmaceutical compositions containing them in the preparation of asthma medications. In previous research, the inventors discovered that the pyridine sulfonamide phosphate compounds represented by Formula 1 have good diuretic effects (Patent Publication No.: CN110606860B). Based on this research and the aforementioned background, the inventors conducted in-depth research on this type of compound for asthma treatment. Experimental studies confirmed that this pyridine sulfonamide phosphate compound has significant activity towards one subtype of the Na+-K+-2Cl- cotransporter, namely NKCC1.

[0008] The pyridine sulfonamide phosphate compounds of Formula 1 of this invention have the following inventiveness and significant advantages compared with traditional NKCC inhibitors such as furosemide and torasemide: (1) The inhibitory activity of the compounds of this invention against NKCC1 is significantly better than that of furosemide and torasemide. NKCC1 is highly expressed in the airways and lungs. Drugs that inhibit this target have a dual effect of reducing bronchial edema and anti-inflammation. While improving ventilation function, they can reduce the inflammatory response of the airways and lungs, which has the advantage of treating both the symptoms and the root cause. (2) The compounds of this invention directly reach the lungs to exert a therapeutic effect and significantly reduce the tissue distribution of the drug in the kidneys, thereby reducing the serious adverse effects such as electrolyte disturbances caused by potent diuretics such as furosemide and torasemide injections. Compared with existing clinical treatment drugs, they have significant clinical advantages of better efficacy and fewer side effects.

[0009] This invention is achieved through the following technical solution:

[0010] A first aspect of the present invention provides the use of a pyridine sulfonamide phosphate compound of Formula 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating asthma;

[0011]

[0012] Where X is O or CH2, or X does not exist; Y is CH2, or Y does not exist; when neither X nor Y exists, O is directly connected to P; when X exists but Y does not exist, X is directly connected to O; when Y exists but X does not exist, Y is directly connected to P.

[0013] The pharmaceutically acceptable salts include salts formed by a compound of formula 1 and an organic base, or salts formed by a compound of formula 1 and a basic amino acid, or metal salts of a compound of formula 1.

[0014] The organic base is selected from trimethylamine, triethylamine, tripropylamine, tributylamine, or diisopropylethylamine;

[0015] Optionally, the metal salt of the compound of Formula 1 is selected from the alkali metal salt, alkaline earth metal salt or aluminum salt of the compound of Formula 1.

[0016] Optionally, the alkali metal salt of the compound of formula 1 is selected from the sodium or potassium salt of the compound of formula 1;

[0017] Optionally, the alkaline earth metal salt of the compound of Formula 1 is selected from the calcium, magnesium, or barium salts of the compound of Formula 1.

[0018] Furthermore, in the uses described in the first or second aspect of the present invention, the pyridine sulfonamide phosphate compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:

[0019]

[0020] A second aspect of the present invention provides the use of a pharmaceutical composition in the preparation of a medicament for treating asthma, said pharmaceutical composition comprising a pyridine sulfonamide phosphate compound of formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier;

[0021]

[0022] Where X is O, CH2, or X does not exist; Y is CH2, or Y does not exist; when neither X nor Y exists, O is directly connected to P; when X exists but Y does not exist, X is directly connected to O; when Y exists but X does not exist, Y is directly connected to P.

[0023] Further, the pyridine sulfonamide phosphate compound or its pharmaceutically acceptable salt in the pharmaceutical composition accounts for 0.01 to 100% of the mass of the pharmaceutical composition; preferably, the pyridine sulfonamide phosphate compound or its pharmaceutically acceptable salt in the pharmaceutical composition accounts for 0.05 to 70% (preferably liquid formulation) or 30 to 100% (preferably solid formulation) of the pharmaceutical composition; more preferably, the pyridine sulfonamide phosphate compound or its pharmaceutically acceptable salt in the pharmaceutical composition accounts for 0.1 to 50% (preferably liquid formulation) or 50 to 100% (preferably solid formulation) of the pharmaceutical composition; preferably, the pyridine sulfonamide phosphate compound or its pharmaceutically acceptable salt in the pharmaceutical composition accounts for 0.1 to 30% (preferably liquid formulation) or 70 to 100% (preferably solid formulation) of the pharmaceutical composition;

[0024] More preferably, the pharmaceutically acceptable carrier is selected from one or more of propellants, fillers, flow aids, lubricants, binders, disintegrants, osmotic pressure regulators, and solvents.

[0025] More preferably, the propellant is selected from one or more of the following: compressed gases (such as CO2, N2), hydrofluoroalkane (such as tetrafluoroethane HFA-134a, trifluoroethane HFC-143a, etc.), chlorofluoroalkane (such as trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethane, etc.), and hydrocarbons (such as propane, isobutane, n-butane, etc.);

[0026] More preferably, the filler is selected from one or more of starch, microcrystalline cellulose, sucrose, dextrin, mannitol, lactose, powdered sugar, and glucose; and the flow aid is selected from one or more of talc and colloidal silica.

[0027] More preferably, the lubricant is selected from one or more of magnesium stearate, stearic acid, sodium chloride, sodium oleate, sodium lauryl sulfate, and poloxamer; the adhesive is selected from one or more of water, ethanol, starch paste, syrup, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, sodium alginate, and polyvinylpyrrolidone.

[0028] More preferably, the disintegrant is selected from one or more of starch, sodium bicarbonate, citric acid, tartaric acid, and low-substituted hydroxypropyl cellulose; the osmotic pressure regulator is selected from one or more of sodium chloride, glucose, phosphate, or citrate; and the solvent includes water and / or a balanced salt solution.

[0029] More preferably, the pharmaceutically acceptable carrier may also include a flavoring agent or a sweetener;

[0030] More preferably, the pharmaceutical composition comprising pyridine sulfonamide phosphate compounds and their pharmaceutically acceptable salts is an inhaled formulation, an injectable formulation, or an oral formulation.

[0031] More preferably, the inhaled formulation is its solution, powder, or suspension.

[0032] Preferably, the injectable preparation is its injection solution or lyophilized powder for injection.

[0033] Preferably, the oral preparation is a tablet, capsule, granule, or oral solution.

[0034] The present invention has the following outstanding effects:

[0035] (1) Pyridine sulfonamide phosphate compounds or their pharmaceutically acceptable salts are the sole active ingredients of the drug and can directly act on the NKCC1 target in the lungs.

[0036] Specifically, Example 1 of this invention shows that the inhibitory activity (IC50) of pyridine sulfonamide phosphate compounds on NKCC1 is significant. 50 The concentration was 2.1–3.3 μM, and the inhibitory activity was approximately 6–10 times that of furosemide and 3–5 times that of torasemide.

[0037] (2) Pyridine sulfonamide phosphate compounds have significant therapeutic effects on asthma.

[0038] Specifically, studies in Examples 2-3 of this invention show that the inventors established two asthma models: ① an asthma model induced by ovalbumin-sensitized guinea pig antigen challenge; and ② an asthma model induced by ovalbumin-sensitized mouse antigen challenge. The results show that compounds I-1, I-3, II-1, and III-1 of this invention have good therapeutic effects on both asthma models, significantly treating allergic airway inflammation and reducing airway hyperresponsiveness, with significantly better activity than torasemide.

[0039] (3) Pyridine sulfonamide phosphate compounds can be administered directly to the lungs to exert a therapeutic effect, significantly reducing the distribution of drugs in the kidney tissues, thereby reducing serious adverse effects such as electrolyte disturbances caused by potent diuretics such as furosemide and torasemide injection.

[0040] Specifically, Example 4 of this invention shows that after compound I-1 is administered, the active ingredient M3 is mainly distributed in respiratory tissues such as the lungs and larynx (including the epiglottis), while the drug content in the liver and kidneys is very low. This indicates that compound I-1 mainly acts on the airways and lungs, and the diuretic effect of the drug in the kidneys will be significantly reduced. Attached Figure Description Figure 1 The image shown is an H&E staining diagram illustrating the effect of the compound on eosinophil infiltration in the lung tissue of a model guinea pig in Example 2. Figure 2 The image shown is a PAS staining diagram illustrating the effect of the compound on the metaplasia and proliferation of goblet epithelial cells in the airways of a guinea pig model, as described in Example 2. Figure 3 The image shown is an H&E staining diagram illustrating the effect of the compound on eosinophil infiltration in the lung tissue of a model mouse in Example 3. Detailed Implementation

[0041] The present invention will now be described in further detail with reference to specific embodiments.

[0042] Example 1: In vitro inhibitory activity of the compound against NKCC1

[0043] HT29 cell suspension was seeded into PDL-coated 384-well plates and incubated overnight. The compound was diluted with DMSO to prepare a stock solution and stored at -20°C. The compound plating program was set up on an ECHO liquid workstation to prepare the plating plates. 2.1 mM Tl₂SO₄ and a 340.5 mM / kg hypertonic solution were used to stimulate the opening of NKCC1 target sites. Once the cell confluence reached 80-90%, the cell detection plates were removed from the incubator for analysis. Using discarded Bravo medium, 25 μL of FLIPR thallium ion dye was added to each well. After 1.5 hours of incubation, the cell plates, stimulation plates, compound plates, and FLIPR microplate pipette tips were placed in FLIPRENTA, and the FLIPR program was run for analysis. Data were analyzed using Excel 2013 (Microsoft) and GraphPad Prism 7.0. The IC₀²⁻¹ of the compound's in vitro inhibitory activity against NKCC1 was obtained. 50 The results are summarized in Table 1.

[0044] Table 1. In vitro inhibitory activity of compounds against NKCC1 (IC50)50 (μM)

[0045]

[0046]

[0047] Example 2: Pharmacodynamic test of the compound on a guinea pig asthma model

[0048] A certain amount of the compound was weighed and prepared into a 10 mg / mL solution using sodium chloride injection for aerosol nebulization. The drug solution was sprayed into the nebulizer chamber using a compressor nebulizer. After the aerosol was filled, the sampling flow rate was set to 0.53 L / min, and the sampling time was 10 min. A glass fiber filter membrane was used to collect the aerosol within the exposure system. The nebulized inhalation dose was calculated based on the average drug concentration in the sample and the average body weight of the animals at the time of administration.

[0049] Guinea pigs were randomly divided into 9 groups: a control group, a model group, groups containing compounds I-1, I-3, II-1, and III-1, a torsemide group, a salbutamol sulfate (SAL) group, and a dexamethasone sodium phosphate (DEX) intraperitoneal injection group. On Day 0, each guinea pig received an intramuscular injection of 0.5 mL of 10 mg / mL OVAA1(OH)3 gel solution in each leg. On Day 21, the first four male and female guinea pigs from each group were challenged by nebulized inhalation of 50 mg / mL OVA solution for 30 seconds, while the remaining eight guinea pigs were challenged by nebulized inhalation of 50 mg / mL OVA solution for 1 minute. Drug administration began on Days 15-21, once daily for 10.5 minutes each time, for 7 consecutive days.

[0050] On Day 21, guinea pigs were anesthetized and intubated, then placed in a pulmonary function recording chamber equipped with a MedLab biosignal acquisition system. A baseline was established after a period of recording. The guinea pigs were then challenged with 50 mg / mL OVA solution via nebulization for 30 seconds. Tidal volume, airway flow rate, and transpulmonary pressure were recorded at 0.5, 1, 2, 3, and 4 minutes after challenge. Airway resistance (R0) was calculated using a formula. aw ) and lung dynamic compliance (C dyn On Day 22, guinea pigs that had been challenged for 1 minute were ligated in the upper lobe of the left lung and bronchoalveolar lavage was performed. The number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) was counted under a microscope. The BALF precipitate was centrifuged, smeared, and stained with Wright-Giemsa. The number of eosinophils was counted under a microscope. Part of the left lung tissue was fixed in 10% neutral buffered formalin, embedded in paraffin, sectioned, and stained with H&E to observe changes in lung structure and inflammatory cell infiltration under a microscope. PAS staining was used to observe goblet cell metaplasia and proliferation of airway epithelial cells.

[0051] Research findings:

[0052] (1) Effects of the compound on the number of inflammatory cells in BALF of model guinea pigs

[0053] The results showed that the total number of leukocytes and eosinophils in the BALF of guinea pigs in the model group were significantly increased (P<0.001). The I-1, I-3, II-1, III-1, SAL and DEX groups significantly reduced the increase in the total number of leukocytes and eosinophils (P<0.05-0.001). No significant activity was observed in the torasemide group. See Table 2 for details.

[0054] Table 2. Effects of compounds on the number of inflammatory cells in BALF of model guinea pigs (Mean ± SEM)

[0055]

[0056]

[0057] Statistics: One-way ANOVA, compared with the control group. ### P < 0.001; compared with the Model, * P<0.05, ** P<0.01, *** P<0.001.

[0058] (2) The diastolic effect of the compound on the OVA-induced bronchoconstriction response in guinea pigs

[0059] The results showed that the R... 1, 2, and 3 min after OVA nebulization stimulation in the model group guinea pigs... aw The percentage increase was significantly higher (P<0.05–0.01), and the 1- and 2-minute C values ​​were significantly higher. dyn The percentage decrease was significantly increased (P<0.01). Compounds I-1, I-3, II-1, and III-1 significantly inhibited OVA-induced R... aw Increase and C dyn The activity was reduced (P<0.05-0.01), and no significant activity was observed in the torasemide group. See Tables 3 and 4 for details.

[0060] Table 3. Effects of compounds on OVA-induced airway resistance (R) in guinea pigs. aw The effect of the increase (%, Mean±SEM)

[0061]

[0062] Statistical analysis: Mean±SEM, one-way ANOVA, comparison with the control group. #P<0.05, ## P<0.01, compared with the Model group, * P<0.05, ** P<0.01.

[0063] Table 4. Effects of compounds on OVA-induced dynamic lung compliance in guinea pigs (C dyn The effect of the decrease (%, Mean±SEM)

[0064]

[0065]

[0066] Statistical analysis: Mean±SEM, one-way ANOVA, comparison with the control group. ## P<0.01, compared with the Model group, * P<0.05, ** P<0.01, *** P<0.001

[0067] (3) Effects of the compound on eosinophil infiltration in lung tissue of model guinea pigs H&E staining results showed that a large number of eosinophils infiltrated the airways, peri-airways, and perivascular areas of the lung tissue in the model group guinea pigs. P <0.001), groups I-1, II-1, and III-1 significantly reduced eosinophil infiltration ( P <0.05~0.01), see details Figure 1 .

[0068] (4) Effects of the compound on metaplasia and proliferation of goblet epithelial cells in the airway of model guinea pigs PAS staining results showed that the model group had a large amount of mucus secretion and goblet epithelial cell metaplasia and proliferation on the inner side of the airway lumen. P <0.001). Groups I-1, II-1, III-1, and SAL significantly inhibited the metaplasia and proliferation of airway goblet epithelial cells. P <0.05~0.001), see details Figure 2 .

[0076] Example 3: Pharmacodynamic test of the compound in a mouse asthma model

[0077] A certain amount of the compound was weighed and prepared into a 10 mg / mL solution using sodium chloride injection for aerosol nebulization. The drug solution was sprayed into the nebulizer chamber using a compressor nebulizer. After the aerosol was filled, the sampling flow rate was set to 0.53 L / min, and the sampling time was 10 min. A glass fiber filter membrane was used to collect the aerosol within the exposure system. The nebulized inhalation dose was calculated based on the average drug concentration in the sample and the average body weight of the animals at the time of administration.

[0078] ICR mice were randomly divided into 9 groups: a control group, a model group, groups I-1, I-3, II-1, III-1, a torsemide group, a salbutamol sulfate (SAL) group, and a dexamethasone sodium phosphate (DEX) intraperitoneal injection group. On Day 0, each mouse was sensitized by multiple subcutaneous and intraperitoneal injections of a 2 mg / mL OVA / Al(OH)3 mixture, totaling 0.5 mL per mouse. On Day 14, each mouse received a booster sensitization injection of 0.2 mL of the 2 mg / mL OVA / Al(OH)3 mixture intraperitoneally. From Day 21 to 27, an appropriate amount of OVA was added to sodium chloride injection to prepare a 10 mg / mL solution, and the mice were placed in a nebulizer for challenge, 30 min / day. OVA was administered before challenge each day from Day 21 to 27, inhaled for 11 min daily for 7 consecutive days.

[0079] Day 28: Airway hyperresponsiveness (AHR) in mice was assessed using the EMKA animal lung function monitoring system. Mice were placed in a chamber and, after stabilization, baseline values ​​were recorded. Then, acetylcholine (Mch) at concentrations of 0.5, 1, 2, 4, 8, 12, and 16 mg / mL was nebulized sequentially, with each concentration administered for 20 seconds. Penh values ​​(simulated airway resistance values) were recorded. The left lung and part of the right lung were ligated, and bronchoalveolar lavage (BALF) was performed. The number of inflammatory cells in the BALF was counted microscopically. The BALF sediment was centrifuged, smeared, and stained with Wright-Giemsa stain. The number of eosinophils, macrophages, and lymphocytes was counted microscopically. Left lung hilar tissue was fixed in 10% neutral buffered formalin, embedded in paraffin, sectioned, and stained with H&E for microscopic observation of lung structural changes and inflammatory cell infiltration.

[0080] Research Results

[0081] (1) Effects of the compound on airway hyperresponsiveness (AHR) in Mch-induced model mice

[0082] The results showed that Mch nebulized inhalation induced an increase in airway resistance (Penh) in asthmatic mice in a dose-dependent manner. Groups I-1, I-3, II-1, III-1, SAL, and DEX all inhibited the increase in Penh in model mice (P<0.05–0.01), while no significant activity was observed in the torasemide group. See Table 7 for details.

[0083]

[0084] (2) Effects of the compound on the number of inflammatory cells in BALF of model mice

[0085] The results showed that the total number of leukocytes, eosinophils, macrophages, and lymphocytes in the BALF of the model group mice was significantly increased (P<0.05–0.001), with the total number of leukocytes, macrophages, and lymphocytes being 41.06, 25.96, and 1.78 times that of the blank control group, respectively. Compounds I-1, I-3, II-1, III-1, SAL, and DEX groups significantly reduced the increase in total leukocytes, eosinophils, and macrophages (P<0.05–0.001), while no significant activity was observed in the torasemide group. See Table 8 for details.

[0086] Table 8. Effects of compounds on the number of inflammatory cells in BALF of model mice (Mean ± SEM)

[0087]

[0088] Statistics: One-way ANOVA, compared with the control group. # P<0.05, ### P < 0.001; compared with the Model, * P<0.05, ** P<0.01, *** P<0.001.

[0089] (3) Effects of the compound on eosinophil infiltration in lung tissue of model mice H&E staining results showed that a large number of eosinophils infiltrated the airways, peri-airways, and perivascular areas of the lung tissue in the model group mice. P <0.001), groups I-1, II-1, and III-1 significantly reduced eosinophil infiltration ( P <0.05~0.001, the SAL (5 mg / kg, ih) group showed an inhibitory trend on inflammatory cell infiltration ( P >0.05), see details Figure 3 .

[0092] Example 4: Tissue distribution study of the compound

[0093] A single-dose parallel-dose design was used. Twenty-four SD rats, weighing 211.0–263.2 g (half male and half female), were administered a single dose of I-1 inhalation solution (14 mg / kg) via oral-nasal inhalation. Sampling points were half the dosing time, 5 min after the end of dosing, 1 h after the end of dosing, and 8 h after the end of dosing. Brain, heart, spleen, liver, kidneys, as well as nasopharynx (including turbinates), larynx (including epiglottis), main trachea, bronchi, lungs, and bronchoalveolar lavage fluid (2 mL physiological saline lavage) were collected. Tissue content was determined at different time points using LC-MS / MS.

[0094] The results showed that after administration, M3 was mainly distributed in respiratory tissues such as the lungs and larynx (including the epiglottis), while the drug content in the liver and kidneys was very low. This indicates that compound I-1 mainly acts on the lungs. The distribution of the drug in the kidney tissues was significantly reduced, which can reduce serious adverse effects such as electrolyte disturbances caused by potent diuretics such as furosemide and torasemide injection. See Table 10 for details.

[0095] Table 10. Mean M3 content (ng / g, ng / mL) in tissues of SD rats after administration of I-1 solution - time (h)

[0096]

[0097] Note: Only the concentration of bronchoalveolar lavage fluid is expressed in "ng / 2mL". "ND" indicates below the lower limit of quantitation; "NA" indicates that the concentration of all samples is below the lower limit of quantitation and cannot be calculated.

[0098] The embodiments described above are merely illustrative of some specific implementations of the present invention, and while the descriptions are detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. Use of a pyridine sulfonamide phosphate compound of Formula 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating asthma: in, X is O or CH2, or X does not exist; Y is CH2, or Y does not exist; when neither X nor Y exists, O is directly connected to P; when X exists but Y does not exist, X is directly connected to O; when Y exists but X does not exist, Y is directly connected to P.

2. The use according to claim 1, characterized in that, The pharmaceutically acceptable salts include salts formed by a compound of formula 1 and an organic base, or salts formed by a compound of formula 1 and a basic amino acid, or metal salts of a compound of formula 1.

3. The use according to claim 2, characterized in that, The organic base is selected from trimethylamine, triethylamine, tripropylamine, tributylamine, or diisopropylethylamine; Optionally, the metal salt of the compound of Formula 1 is selected from the alkali metal salt, alkaline earth metal salt or aluminum salt of the compound of Formula 1. Optionally, the alkali metal salt of the compound of formula 1 is selected from the sodium or potassium salt of the compound of formula 1; Optionally, the alkaline earth metal salt of the compound of Formula 1 is selected from the calcium, magnesium, or barium salts of the compound of Formula 1.

4. The use according to any one of claims 1-3, characterized in that, The pyridine sulfonamide phosphate compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:

5. The use of a pharmaceutical composition in the preparation of a medicament for treating asthma, characterized in that, The pharmaceutical composition comprises a pyridine sulfonamide phosphate compound of Formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; Where X is O, CH2, or X does not exist; Y is CH2, or Y does not exist; when neither X nor Y exists, O is directly connected to P; when X exists but Y does not exist, X is directly connected to O; when Y exists but X does not exist, Y is directly connected to P.

6. The use according to claim 5, characterized in that, The pharmaceutically acceptable carrier is selected from one or more of propellants, osmotic pressure regulators, and solvents; Optionally, the propellant is selected from one or more of the following: compressed gas (preferably CO2 or N2), hydrofluoroalkane (preferably tetrafluoroethane HFA-134a or trifluoroethane HFC-143a), chlorofluoroalkane (preferably trichlorofluoromethane, dichlorodifluoromethane or dichlorotetrafluoroethane), and hydrocarbons (preferably propane, isobutane, or n-butane); Optionally, the filler is selected from one or more of starch, microcrystalline cellulose, sucrose, dextrin, mannitol, lactose, powdered sugar, and glucose; Optionally, the flow aid is selected from one or more of talc and colloidal silica; Optionally, the lubricant is selected from one or more of magnesium stearate, stearic acid, sodium chloride, sodium oleate, sodium lauryl sulfate, and poloxamer; Optionally, the adhesive is selected from one or more of water, ethanol, starch paste, syrup, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, sodium alginate, and polyvinylpyrrolidone. Optionally, the disintegrant is selected from one or more of starch, sodium bicarbonate, citric acid, tartaric acid, and low-substituted hydroxypropyl cellulose; Optionally, the osmotic pressure regulator is selected from one or more of sodium chloride, glucose, phosphate, and citrate; Optionally, the solvent includes water and / or a balanced salt solution; Optionally, the pharmaceutically acceptable carrier may also include flavoring agents or sweeteners.

7. The use according to claim 5 or 6, characterized in that, The dosage form of the pharmaceutical composition is an inhaled formulation, an injectable formulation, or an oral formulation.

8. The use according to claim 7, characterized in that, The inhaled preparation is its solution, powder, or suspension.

9. The use according to claim 7, characterized in that, The injectable preparation is its injection solution or lyophilized powder for injection.

10. The use according to claim 7, characterized in that, The oral preparation is its tablet, capsule, granule, or oral solution.

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