Use of sulfonamide compound in preparation of drug for treating pulmonary edema

Abstract

A use of a sulfonamide compound represented by formula (I) or a pharmaceutical composition comprising same in the preparation of a drug for treating pulmonary edema.

Description

Use of a sulfonamide compound in the preparation of drugs for treating pulmonary edema

[0001] Priority information

[0002] This application claims priority and benefit to patent application 202411473654.6, filed with the China National Intellectual Property Administration on October 22, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application relates to the field of pharmaceutical technology, specifically to the use of a sulfonamide compound or a pharmaceutical composition containing the same in the preparation of a medicament for treating pulmonary edema. Background Technology

[0004] Pulmonary edema refers to an imbalance in the production and return of pulmonary tissue fluid caused by various reasons. This results in a large amount of tissue fluid that cannot be absorbed by the pulmonary lymphatic and venous systems within a short period, leaking into and accumulating in the alveoli, pulmonary interstitium, and small bronchioles, thus causing severe impairment of pulmonary ventilation and gas exchange. It can be divided into two main categories: cardiac and non-cardiac. Acute pulmonary edema caused by hypertensive heart disease, coronary heart disease, and rheumatic valvular heart disease accounts for the vast majority of cardiac pulmonary edema. Myocarditis, cardiomyopathy, congenital heart disease, and severe rapid arrhythmias can also cause cardiac pulmonary edema. Non-cardiac pulmonary edema includes many types such as infectious pulmonary edema, drowning pulmonary edema, and high-altitude pulmonary edema. It is a very common disease in respiratory medicine, and diuretics, dipropyltheophylline tablets, and vasodilators are often used to control the condition.

[0005] Current medications for treating pulmonary edema mainly consist of potent diuretics such as furosemide injection and torasemide injection. Diuretics work by dehydrating systemic tissues, thereby promoting the excretion of fluid from the lungs and treating pulmonary edema. However, these drugs can also cause a series of adverse reactions due to their strong diuretic effect, such as electrolyte imbalance, orthostatic hypotension, and shock.

[0006] Therefore, there is an urgent clinical need to develop new drugs for the treatment of pulmonary edema that are more effective and have better clinical safety. Summary of the Invention

[0007] To address the lack of effective and low-side-effect drugs for treating pulmonary edema in existing technologies, this application provides the use of a sulfonamide compound or a pharmaceutical composition containing it in the preparation of a drug for treating pulmonary edema. In previous research, the applicant discovered that the sulfonamide compound represented by Formula I has a good diuretic effect (Application No.: 202411353809.0). Based on this research and the above background, the applicant conducted in-depth research on the treatment of pulmonary edema using this type of compound. Experimental studies have confirmed that this sulfonamide compound can selectively act on Na+.+ -K + -2Cl - One subtype of the cotransporter is NKCC1. The sulfonamide compound shown in Formula I of this application is used to treat pulmonary edema through a novel mechanism of action—NKCC1 inhibitors. Currently, no drugs targeting the same target have been developed or applied for this indication. NKCC1 is highly expressed in the lungs; drugs that inhibit this target can directly regulate alveolar fluid secretion and clearance, while simultaneously inhibiting the expression of pro-inflammatory factors, thereby treating pulmonary edema and lung injury from various causes. Furthermore, the compound of this application can directly reach the lungs to exert its therapeutic effect, significantly reducing drug distribution in the kidneys, thus reducing serious adverse effects such as electrolyte disturbances caused by potent diuretics like furosemide injection and torasemide. Compared with existing clinical treatments, it has significant clinical advantages of better efficacy and fewer side effects.

[0008] This application is achieved through the following technical solution:

[0009] The first aspect of this application provides the use of a compound in the preparation of a medicament for treating pulmonary edema; said compound is selected from sulfonamide compounds of Formula I or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof.

[0010] Wherein, X is methyl, F, Cl, Br, trifluoromethyl, difluoromethyl, or monofluoromethyl; R1 is cyclopropyl, isopropyl, or R2 is H or Y is O or CH2, or Y does not exist; Z is CH2, or Z does not exist; R is H or a metallic element; metallic elements include alkali metals or alkaline earth metals; when neither Y nor Z exists, O is directly connected to P; when Y exists but Z does not exist, Y is CH2, and Y is directly connected to O; when Z exists but Y does not exist, Z is directly connected to P.

[0011] A second aspect of this application provides the use of a compound in the treatment of pulmonary edema; said compound is selected from sulfonamide compounds of Formula I or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof.

[0012] Wherein, X is methyl, F, Cl, Br, trifluoromethyl, difluoromethyl or monofluoromethyl;

[0013] R1 is cyclopropyl, isopropyl, or...

[0014] R2 is H or

[0015] Y is O or CH2, or Y does not exist;

[0016] Z is CH2, or Z does not exist;

[0017] R represents H or a metallic element; metallic elements include alkali metals or alkaline earth metals.

[0018] When neither Y nor Z exists, O is directly connected to P;

[0019] When Y exists but Z does not exist, Y is CH2, and Y is directly connected to O;

[0020] When Z exists but Y does not, Z is directly connected to P.

[0021] A third aspect of this application provides a compound for treating pulmonary edema; said compound is selected from sulfonamide compounds of Formula I or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof;

[0022] Wherein, X is methyl, F, Cl, Br, trifluoromethyl, difluoromethyl or monofluoromethyl;

[0023] R1 is cyclopropyl, isopropyl, or...

[0024] R2 is H or

[0025] Y is O or CH2, or Y does not exist;

[0026] Z is CH2, or Z does not exist;

[0027] R represents H or a metallic element; metallic elements include alkali metals or alkaline earth metals.

[0028] When neither Y nor Z exists, O is directly connected to P;

[0029] When Y exists but Z does not exist, Y is CH2, and Y is directly connected to O;

[0030] When Z exists but Y does not, Z is directly connected to P.

[0031] According to embodiments of this application, the uses of the first, second, and third aspects described above may further include at least one of the following technical features: According to embodiments of this application, the treatment of pulmonary edema may include pulmonary edema caused by various reasons, such as cardiogenic pulmonary edema, infectious pulmonary edema, high-altitude pulmonary edema, etc.

[0032] According to embodiments of this application, the pharmaceutically acceptable salt includes a salt formed by a compound of formula I and an organic base, or a salt formed by a compound of formula I and a basic amino acid, or a metal salt of a compound of formula I.

[0033] According to embodiments of this application, the organic base is selected from trimethylamine, triethylamine, tripropylamine, tributylamine, choline hydroxide, or diisopropylethylamine.

[0034] According to embodiments of this application, the metal salt of the compound of formula I is selected from alkali metal salts, alkaline earth metal salts, or aluminum salts of the compound of formula I.

[0035] According to embodiments of this application, the alkali metal salt of the compound of formula I is selected from the sodium or potassium salt of the compound of formula I.

[0036] According to embodiments of this application, the alkaline earth metal salt of the compound of formula I is selected from the calcium salt, magnesium salt, or barium salt of the compound of formula I.

[0037] According to an embodiment of this application, Y is O and Z is CH2.

[0038] According to the embodiments of this application, neither Y nor Z exists.

[0039] A fourth aspect of this application provides the use of a pharmaceutical composition in the preparation of a medicament for treating pulmonary edema, said pharmaceutical composition comprising a sulfonamide compound of formula I and its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0040] Wherein, X is methyl, F, Cl, Br, trifluoromethyl, difluoromethyl, or monofluoromethyl; R1 is cyclopropyl, isopropyl, or R2 is H or When R2 is When R is H or a metallic element, the metallic element includes alkali metals or alkaline earth metals; Y is O or CH2, or Y is not present; Z is CH2, or Z is not present; when neither Y nor Z is present, O is directly connected to P; when Y is present but Z is not present, Y is CH2 and Y is directly connected to O; when Z is present but Y is not present, Z is directly connected to P.

[0041] This application provides the use of a pharmaceutical composition in the treatment of pulmonary edema, the pharmaceutical composition comprising a sulfonamide compound of formula I and its isomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier;

[0042] Wherein, X is methyl, F, Cl, Br, trifluoromethyl, difluoromethyl, or monofluoromethyl; R1 is cyclopropyl, isopropyl, or R2 is H or When R2 is When R is H or a metallic element, the metallic element includes alkali metals or alkaline earth metals; Y is O or CH2, or Y is not present; Z is CH2, or Z is not present; when neither Y nor Z is present, O is directly connected to P; when Y is present but Z is not present, Y is CH2 and Y is directly connected to O; when Z is present but Y is not present, Z is directly connected to P.

[0043] This application provides the use of a pharmaceutical composition in the treatment of pulmonary edema, the pharmaceutical composition comprising a sulfonamide compound of formula I and its isomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier;

[0044] Wherein, X is methyl, F, Cl, Br, trifluoromethyl, difluoromethyl, or monofluoromethyl; R1 is cyclopropyl, isopropyl, or R2 is H or When R2 is When R is H or a metallic element, the metallic element includes alkali metals or alkaline earth metals; Y is O or CH2, or Y is not present; Z is CH2, or Z is not present; when neither Y nor Z is present, O is directly connected to P; when Y is present but Z is not present, Y is CH2 and Y is directly connected to O; when Z is present but Y is not present, Z is directly connected to P.

[0045] According to embodiments of this application, the use of the fourth aspect described above may further include at least one of the following technical features: According to embodiments of this application, the treatment of pulmonary edema may include pulmonary edema caused by various reasons, such as: cardiogenic pulmonary edema, infectious pulmonary edema, high-altitude pulmonary edema, etc.

[0046] According to embodiments of this application, the pharmaceutically acceptable salt includes a salt formed by a compound of formula I and an organic base, or a salt formed by a compound of formula I and a basic amino acid, or a metal salt of a compound of formula I.

[0047] According to embodiments of this application, the organic base is selected from trimethylamine, triethylamine, tripropylamine, tributylamine, choline hydroxide, or diisopropylethylamine.

[0048] According to embodiments of this application, the metal salt of the compound of formula I is selected from alkali metal salts, alkaline earth metal salts, or aluminum salts of the compound of formula I.

[0049] According to embodiments of this application, the alkali metal salt of the compound of formula I is selected from the sodium or potassium salt of the compound of formula I.

[0050] According to embodiments of this application, the alkaline earth metal salt of the compound of formula I is selected from the calcium salt, magnesium salt, or barium salt of the compound of formula I.

[0051] According to an embodiment of this application, Y is O and Z is CH2.

[0052] According to the embodiments of this application, neither Y nor Z exists.

[0053] In some alternative embodiments of this application, the sulfonamide compound or its pharmaceutically acceptable salt in the pharmaceutical composition accounts for 0.01% to 100% of the mass of the pharmaceutical composition (e.g., 0.01%, 0.05%, 0.1%, 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%). Exemplarily, the sulfonamide compound or its pharmaceutically acceptable salt in the pharmaceutical composition accounts for 0.05-70% (preferably liquid formulation) or 30-100% (preferably solid formulation) by mass of the pharmaceutical composition; exemplarily, the sulfonamide compound or its pharmaceutically acceptable salt in the pharmaceutical composition accounts for 0.1-50% (preferably liquid formulation) or 50-100% (preferably solid formulation) by mass of the pharmaceutical composition; exemplarily, the sulfonamide compound or its pharmaceutically acceptable salt in the pharmaceutical composition accounts for 0.1-30% (preferably liquid formulation) or 70-100% (preferably solid formulation) by mass of the pharmaceutical composition.

[0054] In some alternative embodiments of this application, the pharmaceutically acceptable carrier is selected from one or more of propellants, fillers, flow aids, lubricants, binders, disintegrants, osmotic pressure regulators, and solvents.

[0055] In some optional embodiments of this application, the propellant is selected from one or more of 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.).

[0056] In some optional embodiments of this application, the filler is selected from one or more of starch, mannitol, dextrin, powdered sugar, microcrystalline cellulose, sucrose, lactose, and glucose; the flow aid is selected from one or more of talc and silica.

[0057] In some optional embodiments of this application, the lubricant is selected from one or more of magnesium stearate, stearic acid, sodium oleate, sodium lauryl sulfate, poloxamer, and sodium chloride.

[0058] In some alternative embodiments of this application, the adhesive is selected from one or more of water, ethanol, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, sodium alginate, polyvinylpyrrolidone, starch paste, and syrup.

[0059] In some alternative embodiments of this application, the disintegrant is selected from one or more of starch, citric acid, tartaric acid, low-substituted hydroxypropyl cellulose, and sodium bicarbonate.

[0060] In some alternative embodiments of this application, the osmotic pressure regulator is selected from one or more of sodium chloride, glucose, citrate, or phosphate.

[0061] In some alternative embodiments of this application, the solvent includes water and / or a balanced salt solution.

[0062] In some alternative embodiments of this application, the pharmaceutically acceptable carrier may also include a flavoring agent or a sweetener.

[0063] In some alternative embodiments of this application, the pharmaceutical composition comprising sulfonamide compounds and their pharmaceutically acceptable salts is an injectable formulation, an oral formulation, or an inhaled formulation.

[0064] In some alternative embodiments of this application, the injectable formulation is its injection solution or lyophilized powder for injection.

[0065] In some alternative embodiments of this application, the oral formulation is a tablet, capsule, granule, or oral solution.

[0066] In some alternative embodiments of this application, the inhaled formulation is its solution, powder, or suspension.

[0067] A fifth aspect of this application provides a method for treating pulmonary edema with a medicament. According to an embodiment of this application, the method includes administering to a subject a therapeutically effective amount of a compound or a pharmaceutical composition containing the compound; said compound is selected from sulfonamide compounds of Formula I or their stereoisomers, tautomers, or pharmaceutically acceptable salts thereof;

[0068] Wherein, X is methyl, F, Cl, Br, trifluoromethyl, difluoromethyl or monofluoromethyl;

[0069] R1 is cyclopropyl, isopropyl, or...

[0070] R2 is H or

[0071] Y is O or CH2, or Y does not exist;

[0072] Z is CH2, or Z does not exist;

[0073] R represents H or a metallic element; metallic elements include alkali metals or alkaline earth metals.

[0074] When neither Y nor Z exists, O is directly connected to P;

[0075] When Y exists but Z does not exist, Y is CH2, and Y is directly connected to O;

[0076] When Z exists but Y does not, Z is directly connected to P.

[0077] According to embodiments of this application, the use of the fifth aspect described above may further include at least one of the following technical features: According to embodiments of this application, the treatment of pulmonary edema may include pulmonary edema caused by various reasons, such as: cardiogenic pulmonary edema, infectious pulmonary edema, high-altitude pulmonary edema, etc.

[0078] According to embodiments of this application, the pharmaceutically acceptable salt includes a salt formed by a compound of formula I and an organic base, or a salt formed by a compound of formula I and a basic amino acid, or a metal salt of a compound of formula I.

[0079] According to embodiments of this application, the organic base is selected from trimethylamine, triethylamine, tripropylamine, tributylamine, choline hydroxide, or diisopropylethylamine.

[0080] According to embodiments of this application, the metal salt of the compound of formula I is selected from alkali metal salts, alkaline earth metal salts, or aluminum salts of the compound of formula I.

[0081] According to embodiments of this application, the alkali metal salt of the compound of formula I is selected from the sodium or potassium salt of the compound of formula I.

[0082] According to embodiments of this application, the alkaline earth metal salt of the compound of formula I is selected from the calcium salt, magnesium salt, or barium salt of the compound of formula I.

[0083] According to an embodiment of this application, Y is O and Z is CH2.

[0084] According to the embodiments of this application, neither Y nor Z exists.

[0085] It should be noted that the terms "subject," "individual," and "patient" are used interchangeably herein and refer to a mammal being evaluated for treatment and / or being treated. In one implementation, the mammal is a human. The terms "subject," "individual," and "patient" include, but are not limited to, individuals with cancer, individuals with autoimmune diseases, individuals with pathogen infections, etc. Subjects can be humans, but also include other mammals, particularly mammals that can be used as laboratory models of human diseases, such as mice, rats, etc.

[0086] The effective amount of the compound or pharmaceutical composition described in this application may vary depending on the administration method and the severity of the disease to be treated. A preferred effective amount can be determined by those skilled in the art based on various factors (e.g., through clinical trials). These factors include, but are not limited to: pharmacokinetic parameters of the active ingredient, such as bioavailability, metabolism, and half-life; the severity of the disease to be treated, the patient's weight, the patient's immune status, and the route of administration. For example, due to the urgency of the treatment condition, several separate doses may be administered daily, or the dose may be reduced proportionally.

[0087] According to embodiments of this application, in the uses described in the first, second, third, and fourth aspects of this application, and in the methods described in the fifth aspect, the sulfonamide compound represented by Formula I or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:

[0088] According to embodiments of this application, in the uses described in the first, second, third, and fourth aspects of this application, and in the methods described in the fifth aspect, the sulfonamide compound represented by Formula I or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:

[0089] The beneficial effects of this application are:

[0090] (1) The technical solution of this application has a different mechanism of action for the treatment of pulmonary edema compared with diuretics.

[0091] The compounds in this application exhibit significantly superior inhibitory activity against NKCC1 compared to furosemide and torasemide. NKCC1 is highly expressed in the lungs. By inhibiting the NKCC1 target in the lungs, the compounds in this application can directly regulate alveolar fluid secretion and clearance, while simultaneously inhibiting the expression of pro-inflammatory factors, thereby treating pulmonary edema and lung injury caused by various reasons. This represents a direct therapeutic effect on lung diseases. This is fundamentally different from diuretics that inhibit the NKCC2 target in the kidneys, first producing a diuretic effect and then treating pulmonary edema through systemic tissue dehydration.

[0092] Specifically, Example 1 of this application shows that the inhibitory activity of sulfonamide compounds on NKCC1 is IC 50 The concentration ranges from 2.01 to 2.96 μM, and the inhibitory activity is approximately 6 to 10 times that of furosemide and 3 to 5 times that of torasemide.

[0093] (2) The technical solution of this application has unexpected technical effects in treating pulmonary edema.

[0094] The compounds in this application demonstrate significant therapeutic effects on pulmonary edema caused by various factors, including but not limited to cardiogenic pulmonary edema, infectious pulmonary edema, and high-altitude pulmonary edema. Under the same experimental conditions, no significant activity was observed in the torasemide group. The outstanding activity of the technical solution in treating pulmonary edema is not due to the diuretic effect of the kidneys, but rather by inhibiting the NKCC1 target in the lungs, thus achieving an unexpected technical effect.

[0095] Specifically, Examples 2-4 of this application show that three pulmonary edema models were established based on the main causes of pulmonary edema: ① a lipopolysaccharide (LPS)-induced pulmonary edema model in mice with ALI / ARDS; ② a negative pressure and hypoxia-induced high-altitude pulmonary edema model in rats; and ③ an adrenaline-induced cardiogenic pulmonary edema model in rats. The results show that the compounds in this application have good therapeutic effects on pulmonary edema models with different etiologies. Detailed Implementation

[0096] The embodiments of this application are described in detail below. The embodiments described below are exemplary and are only used to explain this application, and should not be construed as limiting this application.

[0097] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. Furthermore, in the description of this application, unless otherwise stated, "multiple" means two or more.

[0098] It should be noted that the structural and chemical formula descriptions in the embodiments or implementations of this application are intended to cover all alternatives, modifications, and equivalent technical solutions, all of which are within the scope of this application as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice this application. This application is by no means limited to the methods and materials described herein. In the event that one or more of the cited documents, patents, and similar materials differ from or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0099] It should be further appreciated that some features of this application, for clarity, have been described in multiple independent embodiments or implementations, but may also be provided in combination in a single embodiment or implementation. Conversely, various features of this application, for the sake of brevity, have been described in a single embodiment or implementation, but may also be provided individually or in any suitable sub-combination.

[0100] Unless otherwise stated, the technical and scientific terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains, and unless otherwise stated, all patent publications cited in the entirety of this application are incorporated herein by reference.

[0101] Unless otherwise stated, the following definitions will apply in this application. For the purposes of this application, chemical elements are defined according to the periodic table.

[0102] In this document, the terms “comprising” or “including” are open-ended expressions, meaning that they include the contents specified in this application but do not exclude other contents.

[0103] In this document, the compounds of this application also include isotopically labeled compounds of this application that are identical to those compounds described herein except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those of naturally common atomic masses or mass numbers. Exemplary isotopes that may also be introduced into the compounds of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 13 C 14 C 15 N、 16 O、 17 O、 31 P, 32 P, 36 S, 18 F and 37 Cl.

[0104] Compounds of this application containing other isotopes of the aforementioned isotopes and / or other atoms, as well as pharmaceutically acceptable salts of said compounds, are included within the scope of this application. Isotope-labeled compounds of this application, such as radioactive isotopes, are also included. 3 H and 14 The incorporation of tritium into the compounds of this application can be used for drug and / or substrate tissue distribution analysis. Due to its ease of preparation and detection, tritium-substituted compounds... 3 H, and carbon-14, i.e. 14 C isotopes are particularly preferred. In addition, heavier isotopes, such as deuterium, are used. 2 H substitution can offer therapeutic advantages stemming from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements. Therefore, it may be preferred in some cases.

[0105] The compounds of this application may contain asymmetric or chiral centers, and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomers of the compounds of this application, including but not limited to diastereomers, enantiomers, and atropisomers, and mixtures thereof such as racemic mixtures, are also included within the scope of this application. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral centers (or multiple chiral centers) in the molecule. The prefixes d and l or (+) and (-) are symbols used to specify the rotation of plane-polarized light caused by the compound, where (-) or l indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers can also be called enantiomers, and mixtures of such isomers are usually referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or method.

[0106] Depending on the choice of raw materials and methods, the compounds of this application may exist as one or a mixture of possible isomers, for example, as pure optical isomers, or as mixtures of isomers, such as as racemic and non-corresponding isomer mixtures, depending on the number of asymmetric carbon atoms. Optically active (R)- or (S)- isomers can be prepared using chiral synthons or chiral formulations, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may be cis or trans (cis- or trans-) configuration.

[0107] The compounds of this application may contain asymmetric or chiral centers, and thus exist in different stereoisomer forms. It is contemplated that all stereoisomer forms of the compounds of this application, including but not limited to diastereomers, enantiomers, atropisomers, and geometric (or conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of this application.

[0108] Unless otherwise stated, the structures described in this application also represent all isomers including this structure (e.g., enantiomers, diastereotropic atropisomers, and geometric (or conformational) forms; for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers). Therefore, individual stereochemical isomers of the compounds of this application, as well as mixtures of enantiomers, diastereomeric mixtures, and mixtures of geometric isomers (or conformational isomers), are all within the scope of this application.

[0109] Any asymmetric atom (e.g., carbon) in the compounds of this application may exist in a racemic or enantiomerically enriched form, such as (R)-, (S)-, or (R,S)- configuration. In some embodiments, each asymmetric atom has at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% enantiomeric excess in the (R)- or (S)- configuration. If possible, substituents on atoms having unsaturated double bonds may be present in cis-(Z)- or trans-(E)- form.

[0110] Therefore, as described in this application, the compounds of this application may exist in the form of one of the possible isomers, rotational isomers, tautomers, tautomers or mixtures thereof, for example, in the form of essentially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0111] Any mixture of isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example by chromatography and / or stepwise crystallization, based on the physicochemical differences of the components.

[0112] Racemic derivatives of any resulting end product or intermediate can be separated into optical enantiomers using known methods familiar to those skilled in the art, such as by separating salts of their diastereomers. Racemic products can also be separated by chiral chromatography, such as high-performance liquid chromatography (HPLC) using chiral adsorbents. In particular, enantiomers can be prepared via asymmetric synthesis.

[0113] In this document, the terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerization is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also known as prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. Unless otherwise stated, all tautomer forms of the compounds in this application are within the scope of this application.

[0114] In this document, the term "pharmaceutically acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with other components of the formulation and / or the mammals to which it is treated.

[0115] In this document, the term "pharmaceutically acceptable salt" refers to the organic and inorganic salts of the compounds of this application. Pharmaceutically acceptable salts are those well known and documented in the art. Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts and organic acid salts formed by reaction with amino groups, or obtained by other methods described in the literature, such as ion exchange.

[0116] In this document, the terms “optionally,” “optionally,” or “optionally” generally refer to an event or condition that may, but may not, occur, and the description includes both cases in which the event or condition occurs and cases in which the event or condition does not occur.

[0117] In this document, the term "pharmaceuticalally acceptable excipient" includes any solvent, dispersion medium, coating material, surfactant, antioxidant, preservative (e.g., antibacterial, antifungal), isotonic agent, salt, drug stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, colorant, or combination thereof, all of which are known to those skilled in the art (as described in Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except in cases where any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is covered.

[0118] In this document, the term "administration" refers to the introduction of a predetermined amount of a substance into a patient in a suitable manner. The compounds or pharmaceutical compositions of this application may be administered via any common route, as long as it can reach the intended tissue. Various routes of administration are foreseeable, including peritoneal, intravenous, intramuscular, subcutaneous, etc., but this application is not limited to these exemplified routes of administration.

[0119] In this document, the term "treatment" refers to the administration of a drug or compound to an individual to achieve a desired pharmacological and / or physiological effect. This effect may be preventative in terms of complete or partial prevention of a disease or its symptoms, and / or therapeutic in terms of partial or complete cure of a disease and / or adverse effects caused by the disease. As used herein, "treatment" encompasses diseases in mammals, particularly humans, including: (a) prevention of disease or the onset of a condition in an individual who is susceptible but has not yet been diagnosed with the disease; (b) inhibition of disease, such as blocking disease progression; or (c) relief of disease, such as reducing symptoms associated with the disease. As used herein, "treatment" encompasses any administration of a drug or compound to an individual to treat, cure, relieve, improve, reduce, or inhibit the individual's disease, including but not limited to administration of a drug containing a compound described herein to an individual in need.

[0120] The first aspect of this application provides a sulfonamide compound of Formula I, an isomer thereof, or a pharmaceutically acceptable salt thereof, and its use in the preparation of a medicament for treating pulmonary edema;

[0121] Wherein, X is methyl, F, Cl, Br, trifluoromethyl, difluoromethyl, or monofluoromethyl; R1 is cyclopropyl, isopropyl, or R2 is H or When R2 is When R is H or a metallic element; metallic elements include alkali metals or alkaline earth metals; when Y is O or CH2, or Y does not exist; when Z is CH2, or Y does not exist; when neither Y nor Z exists, O is directly connected to P; when Y exists but Z does not exist, Y is CH2 and Y is directly connected to O; when Z exists but Y does not exist, Z is directly connected to P.

[0122] Furthermore, the treatment of pulmonary edema can include pulmonary edema caused by various reasons, such as: cardiogenic pulmonary edema, infectious pulmonary edema, high-altitude pulmonary edema, etc.

[0123] The pharmaceutically acceptable salts include salts formed by a compound of formula I and an organic base, or salts formed by a compound of formula I and a basic amino acid, or metal salts of a compound of formula I.

[0124] The organic base is selected from trimethylamine, triethylamine, tripropylamine, tributylamine, choline hydroxide, or diisopropylethylamine;

[0125] Optionally, the metal salt of the compound of formula I is selected from the alkali metal salt, alkaline earth metal salt or aluminum salt of the compound of formula I;

[0126] Optionally, the alkali metal salt of the compound of formula I is selected from the sodium or potassium salt of the compound of formula I;

[0127] Optionally, the alkaline earth metal salt of the compound of formula I is selected from the calcium salt, magnesium salt, or barium salt of the compound of formula I.

[0128] Furthermore, in the uses described in the first or second aspect of this application, the sulfonamide compound represented by Formula I or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:

[0129] A second aspect of this application provides the use of a pharmaceutical composition in the preparation of a medicament for treating pulmonary edema, said pharmaceutical composition comprising a sulfonamide compound of formula I and its isomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier;

[0130] Wherein, X is methyl, F, Cl, Br, trifluoromethyl, difluoromethyl, or monofluoromethyl; R1 is cyclopropyl, isopropyl, or R2 is H or When R2 is When R is H or a metallic element; metallic elements include alkali metals or alkaline earth metals; when Y is O or CH2, or Y does not exist; when Z is CH2, or Y does not exist; when neither Y nor Z exists, O is directly connected to P; when Y exists but Z does not exist, Y is CH2 and Y is directly connected to O; when Z exists but Y does not exist, Z is directly connected to P.

[0131] Further, the sulfonamide 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 sulfonamide 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 sulfonamide 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; more preferably, the sulfonamide 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.

[0132] 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.

[0133] 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.);

[0134] More preferably, the filler is selected from one or more of starch, mannitol, dextrin, powdered sugar, microcrystalline cellulose, sucrose, lactose, and glucose; and the flow aid is selected from one or more of talc and silicon dioxide.

[0135] More preferably, the lubricant is selected from one or more of magnesium stearate, stearic acid, sodium oleate, sodium lauryl sulfate, poloxamer, and sodium chloride; the adhesive is selected from one or more of water, ethanol, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, sodium alginate, polyvinylpyrrolidone, starch paste, and syrup.

[0136] More preferably, the disintegrant is selected from one or more of starch, citric acid, tartaric acid, low-substituted hydroxypropyl cellulose, and sodium bicarbonate; the osmotic pressure regulator is selected from one or more of sodium chloride, glucose, citrate, or phosphate; and the solvent includes water and / or a balanced salt solution.

[0137] More preferably, the pharmaceutically acceptable carrier may further include a flavoring agent or a sweetener; even more preferably, the pharmaceutical composition comprising a sulfonamide compound and its pharmaceutically acceptable salt is an injectable formulation, an oral formulation, or an inhaled formulation.

[0138] More preferably, the injectable formulation is its injection solution or lyophilized powder for injection.

[0139] Preferably, the oral preparation is a tablet, capsule, granule, or oral solution.

[0140] Preferably, the inhaled formulation is its solution, powder, or suspension.

[0141] The following will explain the solution of this application with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of this application. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0142] Example 1: In vitro inhibitory activity of the compound against NKCC1

[0143] 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.

[0144] Table 1. In vitro inhibitory activity of compounds against NKCC1 (IC50) 50 (μM)

[0145] Example 2: Pharmacodynamic test of the preferred compound by nebulized inhalation on LPS-induced pulmonary edema in mice

[0146] A certain amount of the compound was weighed and prepared into a 50 mg / mL solution using sodium chloride injection. The 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 collection time was 10 min. The aerosol in the exposure system was collected using a glass fiber filter membrane. The drug dose for nebulization was calculated based on the average drug concentration in the sample and the average body weight of the animal at the time of administration.

[0147] ICR mice were randomly divided into four groups of 10 mice each: a blank control group, a model group, a compound group (30 mg / kg, ih), a torasemide group (30 mg / kg, ih), and a positive control group (dexamethasone intraperitoneal injection group, 1 mg / kg, ip). After anesthesia, the neck skin was incised, the trachea was separated, and 200 μg / mouse (10 mg / mL, 20 μL / mouse) of LPS was sprayed into the airway using an aerosol lung administration kit to establish the model. The blank control group was sprayed with sodium chloride injection. After model establishment, the mice were administered the medication by inhalation once daily for 10 minutes for two consecutive days. After administration, the lower lobe of the right lung was harvested, weighed wet, and dried in a thermostatic drying oven at 60°C until constant weight. The dry / wet lung weight ratio was calculated after weighing again. The lower lobe of the left lung was harvested, and the levels of IL-1β, IL-6, and TNF-α proteins in the lung tissue were detected using ELISA.

[0148] Research findings:

[0149] (1) Effect on the dry-to-wet lung weight ratio of model mice

[0150] The results showed that the dry-to-wet lung weight ratio of the model mice was significantly reduced (P<0.05); the compound group and the DEX group could significantly inhibit the decrease in the dry-to-wet lung weight ratio of the lung tissue (P<0.05-0.01), indicating that the compound of the invention can significantly reduce pulmonary edema. No significant activity was observed in the torasemide group. See Table 2 for details.

[0151] Table 2: Effects of compounds on the dry-to-wet lung weight ratio in LPS model mice (Mean±SEM)

[0152] Statistics: One-way ANOVA, compared with the control group, #P<0.05; compared with the model group, *P<0.05, **P<0.01.

[0153] (2) Effects on the level of inflammatory factor proteins in lung tissue of model mice

[0154] The results showed that the IL-1β protein level in the lung tissue of mice was significantly increased after modeling (P<0.001), and the levels of IL-6 and TNF-α proteins showed an increasing trend. Both the compound in this application and the positive control group significantly reduced the levels of IL-1β, TNF-α, and IL-6 proteins (P<0.05–0.001), indicating that the compound in this application has anti-inflammatory effects. No significant activity was observed in the torasemide group. See Table 3 for details.

[0155] Table 3: Effects on the levels of inflammatory cytokine proteins in lung tissue of LPS model mice (Mean±SEM) Statistics: One-way ANOVA, compared with the control group, ###P<0.001; compared with the model group, *P<0.05, **P<0.01, ***P<0.001.

[0156] Example 3: Pharmacodynamic test of the compound of this application against negative pressure and hypoxia-induced high-altitude pulmonary edema in rats.

[0157] A certain amount of the compound was weighed and prepared into a 50 mg / mL solution using sodium chloride injection. The 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 collection time was 10 min. The aerosol in the exposure system was collected using a glass fiber filter membrane. The drug dose for nebulization was calculated based on the average drug concentration in the sample and the average body weight of the animal at the time of administration.

[0158] Wistar rats were randomly divided into four groups: a blank control group, a model group, the compound of this application (30 mg / kg, ih), a torasemide group (30 mg / kg, ih), and a dexamethasone intraperitoneal injection group (0.5 mg / kg, ip). The animals were placed in a low-pressure oxygen environment control system to simulate the pressure environment of a 6,000 m altitude plateau, with a pressure set at -54.0 to -59.0 kPa, and the modeling time was 72 h. Drug administration began one day before modeling (Day 1), administered via inhalation once daily for 10 min, for four consecutive days. On day 5, the left lung and part of the right lung were ligated, and alveolar lavage was performed. The lower lobe of the right lung was harvested, weighed wet, and then dried in a thermostatic drying oven at 60°C until constant weight was achieved. The dry / wet lung weight ratio was calculated after weighing again.

[0159] The results showed that the dry-to-wet lung weight ratio of the model group rats was significantly decreased (P<0.001), and both the compound of this application and the dexamethasone intraperitoneal injection group could significantly inhibit the decrease in the dry-to-wet lung weight ratio (P<0.001). This suggests that the compound of this application can alleviate pulmonary edema caused by negative pressure and hypoxia. No significant activity was observed in the torasemide group. See Table 4 for details.

[0160] Table 4: Effects of compounds on the dry-to-wet lung weight ratio in negative pressure and hypoxia-induced rat models (Mean ± SEM) Statistical analysis: Mean±SEM, one-way ANOVA, compared with the blank control group, ###P<0.001; compared with the model, ***P<0.001.

[0161] Example 4: Pharmacodynamic test of the compound on adrenaline-induced cardiogenic pulmonary edema in rats

[0162] A certain amount of the compound was weighed and prepared into a 50 mg / mL solution using sodium chloride injection. The 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 collection time was 10 min. The aerosol in the exposure system was collected using a glass fiber filter membrane. The drug dose for nebulization was calculated based on the average drug concentration in the sample and the average body weight of the animal at the time of administration.

[0163] Wistar rats were randomly divided into four groups of 10 each: a blank control group, a model group, the compound of this application (30 mg / kg, ih), a torasemide group (30 mg / kg, ih), and a furosemide intraperitoneal injection group (10 mg / kg, ip). After anesthesia, the jugular vein was isolated and cannulated, and 80 μg / mL epinephrine hydrochloride solution was injected intravenously to establish the model. Drug administration began two days before modeling, administered by inhalation once daily for 10 minutes for three consecutive days; furosemide was administered intraperitoneally 30 minutes before modeling, once daily. After the third day of administration, all lungs were removed, and the wet weight of the whole lung was measured to calculate the lung coefficient. The lower lobe of the right lung was removed, weighed, and then dried in a thermostatic drying oven at 60°C until constant weight was achieved. The dry / wet lung weight ratio was calculated after weighing again.

[0164] The results showed that the dry-to-wet lung weight ratio of rats decreased significantly after modeling (P<0.01). The compound of this application and the furosemide intracavitary injection group significantly inhibited the decrease in the dry-to-wet lung weight ratio (P<0.05-0.01). This suggests that the compound of this application can alleviate cardiogenic pulmonary edema, while no significant activity was observed in the torasemide group (see Table 5 for details).

[0165] Table 5: Effects of the compounds on the dry-to-wet lung weight ratio in rats with cardiogenic pulmonary edema (Mean ± SEM) Statistics: One-way ANOVA, compared with the blank control group, ##P<0.01; compared with the model group, *P<0.05, **P<0.01.

[0166] Although embodiments of this application have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting this application. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of this application.

Claims

1. Use of a compound or a pharmaceutical composition containing a compound in the preparation of a medicament for treating pulmonary edema; wherein the compound is selected from sulfonamide compounds of Formula I or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof; in, X is methyl, F, Cl, Br, trifluoromethyl, difluoromethyl, or monofluoromethyl; R1 is cyclopropyl, isopropyl, or... R2 is H or Y is O or CH2, or Y does not exist; Z is CH2, or Z does not exist; R represents H or a metallic element; metallic elements include alkali metals or alkaline earth metals. When neither Y nor Z exists, O is directly connected to P; When Y exists but Z does not exist, Y is CH2, and Y is directly connected to O; When Z exists but Y does not, Z is directly connected to P.

2. Use of a compound or a pharmaceutical composition containing a compound in the treatment of pulmonary edema; said compound being selected from sulfonamide compounds of formula I or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof; in, X is methyl, F, Cl, Br, trifluoromethyl, difluoromethyl, or monofluoromethyl; R1 is cyclopropyl, isopropyl, or... R2 is H or Y is O or CH2, or Y does not exist; Z is CH2, or Z does not exist; R represents H or a metallic element; metallic elements include alkali metals or alkaline earth metals. When neither Y nor Z exists, O is directly connected to P; When Y exists but Z does not exist, Y is CH2, and Y is directly connected to O; When Z exists but Y does not, Z is directly connected to P.

3. A compound or a pharmaceutical composition containing a compound for treating pulmonary edema; said compound is selected from sulfonamide compounds of formula I or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof; in, X is methyl, F, Cl, Br, trifluoromethyl, difluoromethyl, or monofluoromethyl; R1 is cyclopropyl, isopropyl, or... R2 is H or Y is O or CH2, or Y does not exist; Z is CH2, or Z does not exist; R represents H or a metallic element; metallic elements include alkali metals or alkaline earth metals. When neither Y nor Z exists, O is directly connected to P; When Y exists but Z does not exist, Y is CH2, and Y is directly connected to O; When Z exists but Y does not, Z is directly connected to P.

4. A method for treating pulmonary edema with a drug, characterized in that, include: Administering a therapeutically effective amount of a compound or a pharmaceutical composition containing the compound to a subject; The compound is selected from sulfonamide compounds of Formula I or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof; Wherein, X is methyl, F, Cl, Br, trifluoromethyl, difluoromethyl or monofluoromethyl; R1 is cyclopropyl, isopropyl, or... R2 is H or Y is O or CH2, or Y does not exist; Z is CH2, or Z does not exist; R represents H or a metallic element; metallic elements include alkali metals or alkaline earth metals. When neither Y nor Z exists, O is directly connected to P; When Y exists but Z does not exist, Y is CH2, and Y is directly connected to O; When Z exists but Y does not, Z is directly connected to P.

5. The use according to any one of claims 1 to 3 or the method according to claim 4, characterized in that, The pharmaceutically acceptable salts include salts formed by a compound of formula I and an organic base, or salts formed by a compound of formula I and a basic amino acid, or metal salts of a compound of formula I.

6. The use or method according to claim 5, characterized in that, The intended use satisfies one or more of the following conditions: 1) The organic base is selected from trimethylamine, triethylamine, tripropylamine, tributylamine, choline hydroxide, or diisopropylethylamine; 2) The metal salt of the compound of formula I is selected from the alkali metal salt, alkaline earth metal salt or aluminum salt of the compound of formula I; 3) Y is O, Z is CH2; 4) Neither Y nor Z exists.

7. The use or method according to claim 5, characterized in that, The intended use satisfies one or more of the following conditions: 1) The alkali metal salt of the compound of formula I is selected from the sodium or potassium salt of the compound of formula I; 2) The alkaline earth metal salt of the compound of formula I is selected from the calcium salt, magnesium salt, or barium salt of the compound of formula I.

8. The use according to any one of claims 1-3 or the method according to claim 4, characterized in that, The sulfonamide compounds represented by Formula I, or their pharmaceutically acceptable salts, are selected from the following compounds or their pharmaceutically acceptable salts:

9. The use according to any one of claims 1-3 or the method according to claim 4, characterized in that, The sulfonamide compounds represented by Formula I, or their pharmaceutically acceptable salts, are selected from the following compounds or their pharmaceutically acceptable salts:

10. The use according to any one of claims 1 to 3 or the method according to claim 4, characterized in that, The pharmaceutical composition further includes a pharmaceutically acceptable carrier.

11. The use or method according to claim 10, characterized in that, The pharmaceutically acceptable carrier is selected from one or more of the following: propellants, fillers, flow aids, lubricants, binders, disintegrants, osmotic pressure regulators, and solvents.

12. The use or method according to claim 11, characterized in that, The intended use satisfies one or more of the following conditions: 1) 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 hydrocarbon (preferably propane, isobutane or n-butane); 2) The filler is selected from one or more of starch, mannitol, dextrin, powdered sugar, microcrystalline cellulose, sucrose, lactose, and glucose; 3) The flow aid is selected from one or more of talc and silica; 4) The lubricant is selected from one or more of magnesium stearate, stearic acid, sodium oleate, sodium lauryl sulfate, poloxamer, and sodium chloride; 5) The adhesive is selected from one or more of water, ethanol, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, sodium alginate, polyvinylpyrrolidone, starch paste, and syrup. 6) The disintegrant is selected from one or more of starch, citric acid, tartaric acid, low-substituted hydroxypropyl cellulose, and sodium bicarbonate; 7) The osmotic pressure regulator is selected from one or more of sodium chloride, glucose, citrate, or phosphate; 8) The solvent includes water and / or a balanced salt solution; 9) Pharmaceutically acceptable carriers also include flavoring agents or sweeteners.

13. The use or method according to claim 11, characterized in that, The dosage form of the pharmaceutical composition is an injectable formulation, an oral formulation, or an inhaled formulation.

14. The use or method according to claim 13, characterized in that, The intended use satisfies one or more of the following conditions: 1) The injectable preparation is its injection solution or lyophilized powder for injection; 2) The oral preparation is its tablet, capsule, granule, or oral solution; 3) The inhaled preparation is its solution, powder, or suspension.

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