Methods of Treating Cough by Using Diaminopyrimidine Compounds

Abstract

A method for treating, suppressing, or alleviating cough or the urge to cough in the field of biomedicine, comprising administering to a subject in need thereof a therapeutically effective amount of a diaminopyrimidine compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof. [Formula 1] TIFF2022530890000045.tif35149

Description

FIELD OF THEINVENTION

[0001] The present invention belongs to the field of biomedicine, and in particular relates to a method for treating, suppressing or alleviating cough or the urge to cough, comprising administering to a subject in need thereof a therapeutically effective amount of a diaminopyrimidine compound or a pharma- ceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof. FIELD OF THEINVENTION

[0002] Cough is a common respiratory symptom caused by inflammation, foreign bodies, physical or chemical irritation to the tracheal and bronchial mucosa or pleura. Coughing is initially manifested as closure of the glottis, contraction of the respiratory muscles, and increased intrapulmonary pressure, followed by glottic opening and air expulsion from the lungs, usually accompanied by a sound. Coughing plays a protective role in clearing the airway of foreign bodies and secretions. If the cough persists and becomes acute to chronic, it may cause the patient to have more severe pain, such as chest distress, pharyngeal itching, and / or gasping.

[0003] The cause of cough and recurrent attacks are usually due to the combined effect of various complex factors. The factors that cause cough typically include inhaled materials, infection, food, climate change, etc. At present, there is still no effective drug to treat cough caused by various factors. Summary of the Invention

[0004] In one aspect, the present invention provides a method of treating, suppressing or alleviating cough or the urge to cough, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof: [ka] [In the formula, L is selected from the group consisting of C(=O), CRR', NR, O, S, S=O and S(=O)2; V 1 is N, [ka] and NR; V 2 CR 6 and C(=O), [ka] represents a single bond or a double bond, provided that [ka] When is a single bond, V 1 is NR and V 2 is C(=O), R and R' are H, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 aralkyl, wherein at most two ring members in the cyclic hydrocarbyl and heterocyclyl are C(=O); R 1 , R 2 , R 3 and R 6 are H, halogen, -CN, -NO2, -NH2, -OH, -SH, -Se-R, -Si(R)3, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, C 1~6 Haloalkyl, -C(=O)Ra , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR a R b , -S(=O)(=NR)R a , -NR a R b , -C(=O)NR a R b , -C(=S)NR a R b , -C(=NR)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O)2-R b , -NR a -C(=O)-NR a R b , -C 1~6 Alkylene-NR a R b , -C 1~6 Alkylene-OR a , -C 1~6 Alkylene -C(=O)R, -C 1~6 Alkenylene-OR a , -OC 1~6 Alkylene-NR a R b and -P(=O)R a R b are each independently selected from the group consisting of: R 4 and R 5 H, -C(=O)OR a , -NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -C 1~6 Alkylene-NR a R b , -C1~6 Alkylene-OR a , -C 1~6 Alkylene-OC 1~6 Alkylene-OR a , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 aralkyl; Or, R 1 and R 4 together, -NH-(C 1~6 alkylene)-L-(C 1~6 alkylene)-, preferably -NHCH2CH2-O-CH2CH2-, The above alkyl, alkylene, alkenyl, alkynyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl each independently represent halogen, hydroxyl, oxo, amino, cyano, nitro, -Si(R)3, C 1~6 Alkyl, saturated or partially unsaturated C 3~6 Cyclic hydrocarbyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)ORb , -NR a -S(=O)2-R b , -NR a -C(=O)-NR a R b , -C 1~6 Alkylene-NR a R b , -C 1~6 Alkylene-OR a , -C 1~6 Alkenylene-OR a and -OC 1~6 Alkylene-NR a R b and wherein alkyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, oxo, amino, cyano, nitro, -NR a R b , C 1~6 Alkyl, -OC 1~6 Alkyl, saturated or partially unsaturated C 3~6 Cyclic hydrocarbyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 and optionally further substituted with one or more substituents independently selected from the group consisting of: aralkyl; R a and R b In each occurrence, H, -OH, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 aralkyl, or R a and R b together with the atoms to which they are attached form a 3- to 12-membered heterocyclic or heteroaromatic ring, the above groups being halogen, hydroxyl, oxo, amino, cyano, nitro, C 1~6Alkyl, -OC 1~6 Alkyl, saturated or partially unsaturated C 3~6 Cyclic hydrocarbyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 and optionally further substituted with one or more substituents independently selected from the group consisting of: aryl, arylalkyl, arylsulfonyl ...

[0005] In another aspect, the present invention provides the use of a compound of formula (I) as defined above or a pharma- ceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labelled compound, metabolite or prodrug thereof in the manufacture of a medicament for treating, suppressing or relieving cough or the urge to cough.

[0006] In another aspect, the present invention provides a compound of formula (I) as defined above or a pharma- ceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labelled compound, metabolite or prodrug thereof for use in treating, suppressing or relieving cough or the urge to cough. [Brief description of the drawings]

[0007] [Figure 1] FIG. 1 shows the antitussive effect of Compound 2 at doses of 23 mg / kg and 92 mg / kg. [Diagram 2] FIG. 1 shows the antitussive effect of compound 66 at doses of 46 mg / kg and 92 mg / kg. [Diagram 3] FIG. 1 shows the antitussive effect of compound 66 at doses of 5.1 mg / kg, 15.3 mg / kg and 46 mg / kg. [Figure 4] FIG. 1 shows the effect of compound 66 on P2X3-mediated currents in 1321N1 cells stably transfected with P2X3. [Diagram 5] FIG. 1 shows the concentration-inhibition curve of compound 66 on P2X3-mediated currents in 1321N1 cells stably transfected with P2X3. [Figure 6]FIG. 1 shows the effect of compound 66 on P2X3-mediated currents in rat dorsal root ganglion cells. [Figure 7] FIG. 1 shows the concentration-inhibition curve of compound 66 against P2X3-mediated current in rat dorsal root ganglion cells. Detailed Description of the Invention

[0008] definition Unless otherwise defined in the context, all scientific and technical terms used herein are intended to have the same meaning as commonly understood by those skilled in the art. References to techniques utilized herein are intended to refer to techniques commonly understood in the art, including variations of such techniques or equivalent alternatives that would be obvious to those skilled in the art. Although the following terms are believed to be readily understood by those skilled in the art, the following definitions are nevertheless presented to better explain the present invention.

[0009] As used herein, the terms "contain," "include," "comprise," "have," or "relate to," and other variations, are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0010] As used herein, the term "alkylene" refers to a divalent saturated hydrocarbyl, preferably a divalent saturated hydrocarbyl having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.

[0011] As used herein, the term "alkyl" is defined as a straight or branched chain saturated aliphatic hydrocarbon. In some embodiments, an alkyl has 1 to 12, e.g., 1 to 6, carbon atoms. For example, as used herein, the term "C 1~6"Alkyl" refers to a straight or branched chain group having 1 to 6 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl), optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as a halogen (in which case the group can be referred to as a "haloalkyl") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). The term "C 1~4 "Alkyl" refers to a straight or branched aliphatic hydrocarbon chain having 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0012] As used herein, the term "alkenyl" refers to a monovalent linear or branched hydrocarbyl radical having a double bond and 2 to 6 carbon atoms ("C 2~6 Alkenyl refers to the alkyl group represented by the formula (I) and (II). Alkenyl is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the present invention contain an alkenylene group, they can exist as the pure E (entgegen) form, the pure Z (zusammen) form, or any mixture thereof.

[0013] As used herein, the term "alkynyl" refers to a monovalent hydrocarbyl containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.

[0014] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or cyclononyl, or bicyclic, including spiro, fused, or bridged ring systems (e.g., bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, or bicyclo[5.2.0]nonyl, or decahydronaphthalene, etc.)) optionally substituted with one or more (e.g., 1 to 3) suitable substituents. A cycloalkyl has 3 to 15 carbon atoms. For example, the term "C 3~6 "Cycloalkyl" refers to a saturated mono- or polycyclic (e.g., bicyclic) hydrocarbon ring having 3 to 6 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) optionally substituted with one or more (e.g., 1 to 3) suitable substituents, for example, methyl-substituted cyclopropyl.

[0015] As used herein, the terms "cyclic hydrocarbylene", "cyclic hydrocarbyl" and "hydrocarbon ring" refer to a saturated (i.e., "cycloalkylene" and "cycloalkyl") or unsaturated (i.e., having one or more double and / or triple bonds in the ring) monocyclic or polycyclic hydrocarbon ring having, for example, 3 to 10 (preferably 3 to 8, more preferably 3 to 6) ring carbon atoms, including, but not limited to, cyclopropyl(ene)(ring), cyclobutyl(ene)(ring), cyclopentyl(ene)(ring), cyclohexyl(ene)(ring), cycloheptyl(ene)(ring), cyclooctyl(ene)(ring), cyclononyl(ene)(ring), cyclohexenyl(ene)(ring), and the like.

[0016] As used herein, the terms "heterocyclyl", "heterocyclylene" and "heterocycle" refer to a saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double and / or triple bonds in the ring) cyclic group having, for example, 3 to 10 (preferably 3 to 8, more preferably 3 to 6) ring atoms, in which at least one ring atom is a heteroatom selected from the group consisting of N, O and S, and the remaining ring atoms are C. For example, the "3-10 membered heterocyclyl(ene)" of a "3-10 membered heterocycle" refers to a saturated or partially unsaturated heterocyclyl(ene) or heterocycle having 2 to 9 (e.g., 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from the group consisting of N, O and S. Examples of heterocyclylene, heterocyclyl and heterocycle include, but are not limited to, oxiranyl(ene), aziridinyl(ene), azetidinyl(ene), oxetanyl(ene), tetrahydrofuranyl(ene), dioxolinyl(ene), pyrrolidinyl(ene), pyrrolidonyl(ene), imidazolidinyl(ene), pyrazolidinyl(ene), pyrrolinyl(ene), tetrahydropyranyl(ene), piperidinyl(ene), morpholinyl(ene), dithianyl(ene), thiomorpholinyl(ene), piperazinyl(ene) or trithianyl(ene). The above groups also include bicyclic systems, including spiro, fused or bridged systems (e.g., 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azabicyclo[2.2.2]octane, etc.). The heterocyclylene, heterocyclyl, and heterocycle can be optionally substituted with one or more (eg, 1, 2, 3 or 4) suitable substituents.

[0017] As used herein, the terms "aryl(ene)" and "aromatic ring" refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system. For example, as used herein, the term "C 6~10 Aryl(ene) and C 6~10"Aromatic ring" refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl(ene) (benzene ring) or naphthyl(ene) (naphthalene ring). The aryl(ene) or aromatic ring may have one or more (such as 1 to 3) suitable substituents, such as halogen, -OH, -CN, -NO2, and -C. 1~6 and optionally substituted with alkyl.

[0018] As used herein, the terms "heteroaryl(ene)" and "heteroaromatic ring" refer to monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and containing at least one heteroatom (such as O, N or S), which may be the same or different. Furthermore, in any case, they may be benzo-fused. In particular, the "heteroaryl(ene)" or "heteroaromatic ring" is selected from the group consisting of thienyl(ene), furyl(ene), pyrrolyl(ene), oxazolyl(ene), thiazolyl(ene), imidazolyl(ene), pyrazolyl(ene), isoxazolyl(ene), isothiazolyl(ene), oxadiazolyl(ene), triazolyl(ene), thiadiazolyl(ene), and the like, and benzo derivatives thereof; or pyridinyl(ene), pyridazinyl(ene), pyrimidinyl(ene), pyrazinyl(ene), triazinyl(ene), and the like, and benzo derivatives thereof.

[0019] As used herein, the term "aralkyl" refers to an alkyl group substituted with, preferably, an aryl or heteroaryl, where aryl, heteroaryl, and alkyl are as defined herein. Typically, an aryl group can have 6 to 14 carbon atoms, a heteroaryl group can have 5 to 14 ring atoms, and an alkyl group can have 1 to 6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0020] As used herein, the term “halo” or “halogen” is defined to include F, Cl, Br, or I.

[0021] As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and at least one nitrogen atom in the ring, which may optionally further include one or more (e.g., 1, 2, 3 or 4) ring members selected from the group consisting of N, O, C=O, S, S=O and S(=O)2. The nitrogen-containing heterocycle is bonded to the rest of the molecule through the nitrogen atom of the nitrogen-containing heterocycle and any other ring atom. The nitrogen-containing heterocycle is optionally benzo-fused, and is preferably bonded to the rest of the molecule through the nitrogen atom of the nitrogen-containing heterocycle and any carbon atom of the fused benzene ring.

[0022] The term "substituted" means that one or more (e.g., 1, 2, 3, or 4) hydrogens on a specified atom are replaced with one selected from the indicated group, provided that the normal valence of the specified atom is not exceeded under the present circumstances and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0023] When a substituent is described as being "optionally substituted," the substituent can be (1) unsubstituted or (2) substituted. When a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the carbon (to the extent that hydrogens are present) can be replaced separately and / or together with an independently selected optional substituent. When a nitrogen of a substituent is described as being optionally substituted with one or more from a list of substituents, one or more of the hydrogens on the nitrogen (to the extent that hydrogens are present) can each be replaced with an independently selected optional substituent.

[0024] When substituents are described as "independently selected" from a group, each substituent is selected without regard to the other substituent(s). Thus, each substituent can be the same or different from the other substituent(s).

[0025] As used herein, the term "one or more" means one or more than one (e.g., 2, 3, 4, 5 or 10), reasonably.

[0026] In this specification, unless specified otherwise, the point of attachment of a substituent may be through any suitable position of the substituent.

[0027] When a bond to a substituent is shown to cross a bond connecting two atoms of a ring, then such substituent may be bonded to any of the substitutable ring-forming atoms of that ring.

[0028] The present invention also includes all pharma- ceutically acceptable isotopically labeled compounds that are identical to the compounds of the present invention except that one or more atoms have been replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include: 2 H, 3 Isotopes of hydrogen, such as H; 11 C. 13 C, and 14 isotopes of carbon, such as C; 36 isotopes of chlorine such as Cl; 18 isotopes of fluorine such as F; 123 I and 125 isotopes of iodine such as I; 13 N and 15 isotopes of nitrogen such as N; 15 O. 17 O, and 18 isotopes of oxygen such as O; 32 Isotopes of phosphorus, such as P; 35Some isotope-labeled compounds of the present invention, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies (e.g., assays). 3 H, and carbon-14, i.e. 14 C are particularly useful for this purpose in view of their ease of incorporation and convenient means of detection. 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes such as N may be useful in positron emission tomography (PET) studies to investigate substrate receptor occupancy. Isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying schemes and / or examples and preparations, by substituting the appropriate isotopically labeled reagent for the previously utilized non-labeled reagent. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent of crystallization is isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0029] The term "stereoisomer" refers to an isomer that contains at least one asymmetric center. Compounds with one or more (e.g., one, two, three, or four) asymmetric centers can give rise to racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Some individual molecules can exist as geometric isomers (cis / trans). Similarly, compounds of the present invention can exist as mixtures of two or more structurally distinct forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It should be understood that all such isomers and mixtures thereof, in any percentage (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, and 99%), are encompassed within the scope of the present invention.

[0030] Chemical bonds in the compounds of the present invention are shown herein as solid lines ( [ka] ), solid wedge ( [ka] ), or a dotted wedge ( [ka] ) can be used to depict the bond to an asymmetric carbon atom. The use of a solid line to depict a bond to an asymmetric carbon atom is meant to indicate that all possible stereoisomers at that carbon atom (e.g., a specific enantiomer, a racemic mixture, etc.) are included. The use of a solid or dashed wedge to depict a bond to an asymmetric carbon atom is meant to indicate that the depicted stereoisomer exists. The solid and dashed wedges are used to define relative stereochemistry when present in a racemic compound, rather than absolute stereochemistry. Unless otherwise indicated, it is intended that the compounds of the present invention can exist as stereoisomers, including cis and trans isomers, optical isomers, e.g., R and S enantiomers, diastereomers, geometric isomers, rotamers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention exhibit more than one isomeric type and consist of mixtures thereof, such as racemates and diastereomeric pairs.

[0031] The present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, in any ratio, either as a single polymorph or as a mixture of more than one polymorph.

[0032] It should also be understood that some compounds of the present invention can be used in treatment in free form or, if necessary, in the form of a pharmaceutically acceptable derivative.In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs that can directly or indirectly produce the compound of the present invention or its metabolites or residues after administration to a patient in need of the compound.Therefore, the "compound of the present invention" described herein is also meant to include various derivative forms of the above-mentioned compounds.

[0033] Pharmaceutically acceptable salts of the compounds of the present invention include the acid addition and base salts thereof.

[0034] Suitable acid addition salts are formed from acids which form pharma- ceutically acceptable salts, such as acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, hydrogensulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethione, etc. Salts include, but are not limited to, acetic acid salts, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthenate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate.

[0035] Suitable base addition salts are formed from bases which form pharma- ceutically acceptable salts, examples of which include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

[0036] For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth, Wiley-VCH, 2002. Methods for preparing pharma- ceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

[0037] As used herein, the term "ester" refers to compounds of various formulas in this application, and includes physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the invention in the free acid or alcohol form). The compounds of the invention may themselves be esters.

[0038] The compounds of the invention can exist as solvates (preferably hydrates), in which the compounds of the invention contain a polar solvent, in particular water, methanol or ethanol, for example as a structural element of the crystal lattice of the compound. The amount of polar solvent, in particular water, can be present in a stoichiometric or non-stoichiometric ratio.

[0039] As one skilled in the art can understand, not all nitrogen-containing heterocycles can form N-oxides, since nitrogen requires an available lone pair of electrons for oxidation to an oxide. One skilled in the art will recognize nitrogen-containing heterocycles that can form N-oxides. One skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for the preparation of N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include the oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for the preparation of N-oxides have been extensively described and reviewed in the literature. See, for example, TL Gilchrist, Comprehensive Organic Synthesis, Vol. 7, pp. 748-750; AR Katritzky and AJ Boulton, eds., Academic Press; and GWH Cheeseman and ESG Werstiuk, Advances in Heterocyclic Chemistry, Vol. 22, pp. 390-392, AR Katritzky and AJ Boulton, eds., Academic Press.

[0040] Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances formed in vivo upon administration of a compound of the invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic degradation, etc. of the administered compound. In view of the above, the invention encompasses metabolites of compounds of the invention, including compounds produced by a process comprising contacting a compound of the invention with a mammal for a period of time sufficient to yield a metabolic product thereof.

[0041] Prodrugs of the compounds of the present invention are also within the scope of the present invention, which are certain derivatives of the compounds of the present invention that have little or no pharmacological activity themselves, but can be converted into the compounds of the present invention having the desired activity when administered into or onto the body, for example, by hydrolytic cleavage. In general, such prodrugs are functional derivatives of compounds that are easily converted in vivo into compounds having the desired therapeutic activity. Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). Prodrugs according to the present invention can be produced, for example, by replacing suitable functional groups present in the compounds of the present invention with some moieties known to those skilled in the art as "promoieties", for example, as described in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985).

[0042] The present invention further includes the compounds of the present invention having protective groups. In any of the processes for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups in any of the molecules, thereby producing chemically protected forms of the compounds of the present invention. This is achieved by conventional protective groups, such as those described in TW Greene & PGM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., 1991, which is incorporated herein by reference. The protective groups can be removed at a convenient subsequent stage using methods known in the art.

[0043] The term "about" refers to a range within ±10%, preferably within ±5%, and more preferably within ±2% of the specified value.

[0044] As used herein, the term "effective amount" refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated.

[0045] Unless otherwise indicated, as used herein, the terms "treat" or "treatment" mean to reverse, alleviate, inhibit the progression of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition, or to prevent such disorder or condition, or one or more symptoms thereof.

[0046] As used herein, "treatment of cough" or "treating a cough" refers to any treatment that reduces the number and / or severity of coughs. Preferably, it refers to a reduction in the number of coughs, i.e., a direct antitussive effect that reduces the body's urge to cough. In a preferred embodiment, when compared to a control, the method of the present invention reduces the number of coughs by 40% to 95%, preferably 50% to 90%, over the same time period.

[0047] As used herein, the term "subject" includes humans and non-human mammals. Exemplary human subjects include human subjects (referred to as patients) having a disease (such as those described herein) or healthy subjects. As used herein, the term "non-human animals" includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles), as well as mammals, such as non-human primates, farm animals and / or domesticated animals (sheep, dog, cat, cow, pig, etc.). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0048] In some embodiments, the present invention provides a method of treating, suppressing, or alleviating cough or the urge to cough, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof: [ka] [In the formula, L is selected from the group consisting of C(=O), CRR', NR, O, S, S=O and S(=O)2; V 1 is N, [ka] and NR; V 2 CR 6 and C(=O), [ka] represents a single bond or a double bond, provided that [ka] When is a single bond, V 1 is NR and V 2 is C(=O), R and R' are H, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 aralkyl, wherein at most two ring members in the cyclic hydrocarbyl and heterocyclyl are C(=O); R 1 , R 2 , R 3 and R 6 are H, halogen, -CN, -NO2, -NH2, -OH, -SH, -Se-R, -Si(R)3, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12Aralkyl, C 1~6 Haloalkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR a R b , -S(=O)(=NR)R a , -NR a R b , -C(=O)NR a R b , -C(=S)NR a R b , -C(=NR)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O)2-R b , -NR a -C(=O)-NR a R b , -C 1~6 Alkylene-NR a R b , -C 1~6 Alkylene-OR a , -C 1~6 Alkylene -C(=O)R, -C 1~6 Alkenylene-OR a , -OC 1~6 Alkylene-NR a R b and -P(=O)R a R b are each independently selected from the group consisting of: R 4 and R 5 H, -C(=O)OR a , -NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -C 1~6 Alkylene-NRa R b , -C 1~6 Alkylene-OR a , -C 1~6 Alkylene-OC 1~6 Alkylene-OR a , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 aralkyl; Or, R 1 and R 4 together, -NH-(C 1~6 alkylene)-L-(C 1~6 alkylene)-, preferably -NHCH2CH2-O-CH2CH2-, The above alkyl, alkylene, alkenyl, alkynyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl each independently represent halogen, hydroxyl, oxo, amino, cyano, nitro, -Si(R)3, C 1~6 Alkyl, saturated or partially unsaturated C 3~6 Cyclic hydrocarbyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b, -NR a -C(=O)OR b , -NR a -S(=O)2-R b , -NR a -C(=O)-NR a R b , -C 1~6 Alkylene-NR a R b , -C 1~6 Alkylene-OR a , -C 1~6 Alkenylene-OR a and -OC 1~6 Alkylene-NR a R b and wherein alkyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, oxo, amino, cyano, nitro, -NR a R b , C 1~6 Alkyl, -OC 1~6 Alkyl, saturated or partially unsaturated C 3~6 Cyclic hydrocarbyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 and optionally further substituted with one or more substituents independently selected from the group consisting of: aralkyl; R a and R b In each occurrence, H, -OH, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 aralkyl, or R a and R btogether with the atoms to which they are attached form a 3- to 12-membered heterocyclic or heteroaromatic ring, the above groups being halogen, hydroxyl, oxo, amino, cyano, nitro, C 1~6 Alkyl, -OC 1~6 Alkyl, saturated or partially unsaturated C 3~6 Cyclic hydrocarbyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 and optionally further substituted with one or more substituents independently selected from the group consisting of: aryl, arylalkyl, arylsulfonyl ...

[0049] In another embodiment, the present invention provides the use of a compound of formula (I) as defined above or a pharma- ceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labelled compound, metabolite or prodrug thereof in the manufacture of a medicament for treating, suppressing or relieving cough or the urge to cough.

[0050] In another embodiment, the present invention provides a compound of formula (I) above or a pharma- ceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof for use in treating, suppressing or relieving cough or the urge to cough.

[0051] In preferred embodiments, L is selected from the group consisting of CH2, O, S, and NH.

[0052] In a preferred embodiment, V 1 is N, [ka] and NCH3.

[0053] In a preferred embodiment, V 2 is selected from the group consisting of CH, C-NHCH3, C-OCH3, CF and C(=O).

[0054] In a preferred embodiment, R a and R b is independently selected at each occurrence from the group consisting of H, -OH, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, benzyl, methoxy, and ethoxy; or R a and R b together with the atoms to which they are attached form a 5- to 8-membered heterocyclic or heteroaromatic ring.

[0055] In a preferred embodiment, R 1 , R 2 , R 3 and R 6 are H, F, Cl, Br, I, -CN, -NH2, -OH, -SH, -Se-CH3, -Si(CH3)3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, vinyl, propenyl, allyl, ethynyl, propynyl, trifluoromethyl, acetyl, -C(=O)OH, -C(=O)NH2, -C(=S)NH2, -C(=NH)NH2, -NHCH3, -NHCH2CH3, -NHCH2CF3, -N(CH3) 2, -N(CH3)(C2H5), -N(C2H5)2, -NHCH2CH2OH, -NH-C(=O)CH3, -NH-C(=O)CH=CH2, methoxy, ethoxy, propoxy, phenyl, -NH-C(=O)-NH2, -NH-C(=O)OCH3, -SCH3, -SCH2CH3, -S C(CH3)3, -SBn, -S(=O)CH3, -S(=O)Bn, -S(=O)2CH3, -S(=O)2Bn, -S(=O)2NH2, -S( =O)2NHCH3, -S(=O)2N(CH3)2, -S(=O)(=NH)CH3, -P(=O)(CH3)2, -P(=O)(C2H5)2, [ka] are each independently selected from the group consisting of:

[0056] In a preferred embodiment, R 4 and R 5 are H, -C(=O)OC(CH3)3, -NH2, -NHCH3, -NHPh, -NHC(=O)CH3, -NHBoc, methyl, ethyl, -CH2CF3, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, [ka] are each independently selected from the group consisting of:

[0057] In a preferred embodiment, the compound of formula (I) has the following formula: [ka] and preferably has the following formula: [ka] and more preferably, the compound of formula (I) has the structure of any of the following formulas: [ka] [In the formula, R 1 are F, Cl, Br, I and C 2~6 alkynyl, preferably Br or ethynyl; R 3 is C 1~6 alkyl, preferably isopropyl].

[0058] The technical solution obtained by any combination of the various embodiments is encompassed by the present invention.

[0059] In a preferred embodiment, the compound of formula (I) has the following structure: [ka] TIFF0007665529000019.tif226149 TIFF0007665529000020.tif226149 TIFF0007665529000021.tif220149 TIFF0007665529000022.tif226149 TIFF0007665529000023.tif226149 TIFF0007665529000024.tif226149 TIFF0007665529000025.tif221149 TIFF0007665529000026.tif174149 has.

[0060] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof is administered in an amount of about 0.005 mg / day to about 5000 mg / day, e.g., about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 mg / day.

[0061] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof is administered in an amount of about 1 ng / kg body weight to about 200 mg / kg body weight, about 1 μg / kg body weight to about 100 mg / kg, or about 1 mg / kg body weight to about 50 mg / kg per day, e.g., about 1 μg / kg body weight, about 10 μg / kg body weight, about 25 μg / kg body weight, about 50 μg / kg body weight, about 75 ... 0μg / kg body weight, approx. 125μg / kg body weight, approx. 150μg / kg body weight, approx. 175μg / kg body weight, approx. 200μg / kg body weight, approx. 225μg / kg body weight, approx. 250μg / kg body weight, approx. 275μg / kg body weight, approx. 300μg / kg body weight, approx. 325μg / kg body weight, approx. 350μg / kg body weight, approx. 375μg / kg body weight, approx. 400μg / kg body weight, approx. 425μg / kg body weight, approx. 450μg / kg body weight, approx. 475μg / kg body weight, approx. 500μg / kg body weight, approx. 525μg / kg body weight, approx. 550μg / kg body weight 1kg body weight, 575μg / kg body weight, 600μg / kg body weight, 625μg / kg body weight, 650μg / kg body weight, 675μg / kg body weight, 700μg / kg body weight, 725μg / kg body weight, 750μg / kg body weight, 775μg / kg body weight, 800μg / kg body weight, 825μg / kg body weight, 850μg / kg body weight, 875μg / kg body weight, 900μg / kg body weight, 925μg / kg body weight, 950μg / kg body weight, 975μg / kg body weight, 1mg / kg body weight, The amount of the compound administered is about 5 mg / kg body weight, about 10 mg / kg body weight, about 15 mg / kg body weight, about 20 mg / kg body weight, about 25 mg / kg body weight, about 30 mg / kg body weight, about 35 mg / kg body weight, about 40 mg / kg body weight, about 45 mg / kg body weight, about 50 mg / kg body weight, about 60 mg / kg body weight, about 70 mg / kg body weight, about 80 mg / kg body weight, about 90 mg / kg body weight, about 100 mg / kg body weight, about 125 mg / kg body weight, about 150 mg / kg body weight, about 175 mg / kg body weight, or about 200 mg / kg body weight.

[0062] In some embodiments, the daily dose of a compound of formula (I) or a pharma- ceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof is administered once, or in two, three, or four administrations.

[0063] In some embodiments, the compound of Formula (I) or a pharma- ceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof is administered continuously for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, at least 50 days, at least half a year, at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years, or more years.

[0064] In some embodiments, the compound of Formula (I) or a pharma- ceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof is administered in one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) treatment courses, each treatment course lasting at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least It lasts for 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days or at least 50 days, and the interval between every two treatment courses is 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 2 weeks, 3 weeks or 4 weeks.

[0065] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof is administered by injection (e.g., intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including drops), or transdermally, or via oral, buccal, nasal, transmucosal, or topical routes, in an ophthalmic formulation, or via inhalation.

[0066] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof is administered in a dosage form selected from the group consisting of a tablet, a capsule, a troche, a hard candy, a powder, a spray, an emulsion, a cream, an ointment, a suppository, a gel, a paste, a lotion, an injectable, a nanoformulation, a patch, an aqueous suspension, an injectable solution, an elixir, and a syrup.

[0067] In some embodiments, the "cough" is selected from the group consisting of acute cough, subacute cough, chronic cough, treatment-resistant cough, treatment-resistant chronic cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, cough associated with postnasal drip, cough associated with the common cold, cough associated with upper respiratory tract infections, asthma, lung cancer and / or chronic obstructive pulmonary disease (COPD), cough associated with interstitial disease, cough associated with pulmonary fibrosis, cough associated with gastroesophageal reflux disease (GERD), cough associated with smoking or forms of bronchitis, and neuronal hypersensitivity underlying acute, subacute or chronic cough, preferably the cough is selected from the group consisting of chronic cough, treatment-resistant cough, treatment-resistant chronic cough, and cough associated with pulmonary fibrosis.

[0068] The method of the present invention can also be applied to various diseases accompanied by cough, such as various respiratory diseases such as the common cold (common cold syndrome), acute bronchitis, chronic bronchitis, bronchiectasis, pneumonia, pulmonary tuberculosis, silicosis and silicotuberculosis, lung cancer, upper respiratory tract infections (pharyngitis, laryngitis and catarrhal rhinitis), asthmatic bronchitis, bronchial asthma, childhood asthma, (chronic) emphysema, pneumoconiosis, pulmonary fibrosis, pulmonary abscess, pleuritis, tonsillitis, cough urticaria, whooping cough; cough during bronchography or bronchoscopy, etc. EXAMPLES

[0069] In order to make the object and technical solution of the present invention clearer, the present invention will be further described below with reference to specific examples. It should be understood that the following examples are only for illustrating the present invention and should not be understood as limiting the scope of the present invention. In addition, the specific experimental methods not described in the following examples are carried out according to the conventional experimental methods.

[0070] Unless otherwise stated, reagents utilized in the following examples were purchased from companies such as Sigma.

[0071] Compound 2 and compound 66 of the present application were prepared according to the methods described in International Application PCT / CN2018 / 112829, which is incorporated herein by reference in its entirety.

[0072] Example 1 Effect on guinea pig cough model In this study, dextromethorphan (purchased from Shanghai Send Pharmaceutical Technology Co., Ltd.) was used as a positive control compound. The clinical control compound with the following structure was used and prepared according to the method described in WO2008 / 040652A1: [ka]

[0073] The test animals were Dunkin-Hartley guinea pigs (purchased from Shanghai Jiagan Biotechnology Co., Ltd) weighing 300-350 g. After purchasing and feeding adaptively for 1 week, the animals were randomly divided into groups based on body weight, and each test group contained 10-15 test animals. Vehicle (0.5% CMCNa solution), test compound, positive control compound (dextromethorphan) or clinical control compound were orally administered (test doses of compounds were added to 0.5% CMCNa solution, respectively, and uniformly dispersed by thorough sonication. The solutions were mixed again by vortexing and then administered to each animal, and the test doses were 1 mg / kg-100 mg / kg). Administration was performed 30 min-1 h before inducing cough.

[0074] Method of inducing cough: The test animal was placed in a body pneumotachograph (Buxco) and left for several minutes. After the animal was stabilized, 250 μM ATP was sprayed for 2 minutes or 0.6 mM histamine was sprayed for 2 minutes. After 3 minutes, 0.5 M citric acid was sprayed for 5 minutes. Using a small animal lung function detector (Buxco), the number of coughs of the animal was recorded for 10 minutes, starting from the spray of citric acid.

[0075] The data in Figures 1 to 3 are based on the compound of the present application. 2 and compound 66 exerted significant antitussive effects, which were better than those of the clinical control compound.

[0076] Example 2. Inhibition of P2X3-mediated currents in 1321N1 cell lines stably transfected with P2X3 Membrane currents were recorded by utilizing a HEKA EPC-10 patch clamp amplifier and a PATCHMASTER acquisition system. 1321N1 P2X3 stable transfected cells were transferred to a bath of about 1 ml embedded in an inverted microscope platform and perfused with extracellular solution (2 mM CaCl2, 1 mM MgCl2, 5 mM KCl, 155 mM NaCl, 12 mM glucose and 10 mM HEPES (pH=7.4)) by using a gravity perfusion system. P2X3-mediated currents of single cells were recorded in whole-cell recording mode. After gigaseal formation and membrane rapture, the clamp potential was set to -60 mV. 10 μM Na2ATP was perfused for 5 seconds, and the P2X3-mediated current induced at this time was the control current. Then, cells were treated with a specific concentration of Compound 66 solution (prepared in extracellular solution) for 5 minutes. This concentration of Compound 66 solution and 10 μM Na 2 ATP were applied together to induce cell currents (see FIG. 4 for the effect of compounds on currents) and the percentage inhibition relative to the control current was calculated according to the following formula: Percentage of inhibition relative to control current = (1-I2 / I1)*100% [where I1 represents the control current and I2 represents the current following application of compound 66. Test compound 66 concentrations included 4, 12, 37, 110 and 330 nM, with at least three cells (n≧3) tested at each concentration].

[0077] The concentration of compound 66 (horizontal axis) was plotted against the percentage inhibition of the control current (vertical axis) (see FIG. 5 ), and the data was fitted to the Hill equation to determine the concentration of compound 66 required to inhibit 50% of the P2X3-mediated current induced by 10 μM Na2ATP (IC 50 ) was found to be 26.16 nM.

[0078] Example 3. Inhibition of P2X3-mediated currents in ex vivo cultured rat dorsal root ganglia (DRG) Membrane currents were recorded by utilizing a HEKA EPC-10 patch clamp amplifier and a PATCHMASTER acquisition system. Primary rat DRG cells were transferred to a bath of approximately 1 ml embedded in an inverted microscope platform and perfused with extracellular solution (2 mM CaCl2, 1 mM MgCl2, 5 mM KCl, 155 mM NaCl, 12 mM glucose and 10 mM HEPES (pH=7.4)) by using a gravity perfusion system. P2X3-mediated currents of single cells were recorded in whole-cell recording mode. After gigaseal formation and membrane rapture, the clamp potential was set to -60 mV. 30 μM a,b-Me ATP (also known as "α,β-meATP") was perfused for 5 seconds, and the P2X3-mediated current induced at this time was the control current. The cells were then treated with a specific concentration of Compound 66 solution (prepared in the extracellular solution) for 5 minutes. This concentration of compound 66 solution and 30 μM a,b-Me ATP were applied together to induce cell currents (see FIG. 6 for the effects of compounds on currents) and the percentage inhibition relative to the control current was calculated according to the following formula: Percentage of inhibition relative to control current = (1-I2 / I1)*100% [where I1 represents the control current and I2 represents the current following application of compound 66. Test compound 66 concentrations included 4, 12, 37, 110 and 330 nM, with at least three cells (n≧3) tested at each concentration].

[0079] The concentration of compound 66 (horizontal axis) was plotted against the percentage inhibition of the control current (vertical axis) (see FIG. 7 ), and the data was fitted to the Hill equation to determine the concentration of compound 66 required to inhibit 50% of the P2X3-mediated current induced by 30 μM a,b-Me ATP (IC 50 ) was found to be 28.30 nM.

[0080] In addition to the modifications described herein, various modifications to the present invention will become apparent to those skilled in the art from the above description. Such modifications are intended to fall within the scope of the appended claims. Each reference cited herein, including all patents, applications, journal articles, books, and any other disclosures, is hereby incorporated by reference in its entirety.

Claims

1. A pharmaceutical composition for treating, suppressing, or relieving cough or the urge to cough comprising a therapeutically effective amount of compound 2 or 66, or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof. 【Chemistry 1】

2. The pharmaceutical composition of claim 1, wherein the compound or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof is administered in an amount of 0.005 mg / day to 5000 mg / day.

3. The pharmaceutical composition of claim 2, wherein the compound or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof is for administration in an amount of 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 mg / day.

4. The pharmaceutical composition of claim 1, wherein the compound or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof is for administration in an amount of 1 ng / kg to 200 mg / kg of body weight, 1 μg / kg to 100 mg / kg of body weight, or 1 mg / kg to 50 mg / kg of body weight per day.

5. The compound or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, or isotope-labeled compound thereof is administered at a dose of 1 μg / kg body weight, 10 μg / kg body weight, 25 μg / kg body weight, 50 μg / kg body weight, 75 μg / kg body weight, 100 μg / kg body weight, 125 μg / kg body weight, 150 μg / kg body weight, 175 μg / kg body weight, 200 μg / kg body weight, 225 μg / kg body weight, 250 μg / kg body weight, 275μg / kg body weight, 300μg / kg body weight, 325μg / kg body weight, 350μg / kg body weight, 375μg / kg body weight, 400μg / kg body weight, 425μg / kg body weight, 450μg / kg body weight, 475μg / kg body weight, 500μg / kg body weight, 525μg / kg body weight, 550μg / kg body weight, 575μg / kg body weight, 600μg / kg body weight, 625μg / kg body weight, 650μg / kg body weight, 675μg / kg body weight kg, 700μg / kg body weight, 725μg / kg body weight, 750μg / kg body weight, 775μg / kg body weight, 800μg / kg body weight, 825μg / kg body weight, 850μg / kg body weight, 875μg / kg body weight, 900μg / kg body weight, 925μg / kg body weight, 950μg / kg body weight, 975μg / kg body weight, 1mg / kg body weight, 5mg / kg body weight, 10mg / kg body weight, 15mg / kg body weight, 20mg / kg body weight, 2 5. The pharmaceutical composition of claim 4, which is for administration in an amount of 5 mg / kg body weight, 30 mg / kg body weight, 35 mg / kg body weight, 40 mg / kg body weight, 45 mg / kg body weight, 50 mg / kg body weight, 60 mg / kg body weight, 70 mg / kg body weight, 80 mg / kg body weight, 90 mg / kg body weight, 100 mg / kg body weight, 125 mg / kg body weight, 150 mg / kg body weight, 175 mg / kg body weight, or 200 mg / kg body weight.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the daily dose of the compound or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof is to be administered once, or in two, three, or four doses.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the compound or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof is for continuous administration for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, at least 50 days, at least half a year, at least 1 year, at least 2 years, at least 3 years, at least 4 years, or at least 5 years. [0010] Claim 8: The compound or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof is for administration in one or more treatment courses, each treatment course lasting at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, or at least The pharmaceutical composition according to any one of claims 1 to 6, wherein each treatment course lasts for at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days or at least 50 days, and the interval between every two treatment courses is 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 2 weeks, 3 weeks or 4 weeks.

9. The pharmaceutical composition of claim 8, wherein the compound or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof is for administration in 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 treatment courses.

10. The pharmaceutical composition of any one of claims 1 to 9, wherein the compound or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof is for administration by injection, or for administration transdermally, or via oral, buccal, nasal, mucosal, or topical routes, as an ophthalmic formulation, or via inhalation.

11. The pharmaceutical composition of claim 10, wherein the compound or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof is for administration by intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection.

12. The pharmaceutical composition of claim 11, wherein the compound or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof is for administration by dropwise injection.

13. The pharmaceutical composition of any one of claims 1 to 12, wherein the compound or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof is for administration in a dosage form selected from the group consisting of tablets, capsules, troches, hard candies, powders, sprays, emulsions, creams, ointments, suppositories, gels, pastes, lotions, injectables, nanoformulations, patches, aqueous suspensions, solutions, elixirs, and syrups.

14. 14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the cough is selected from the group consisting of acute cough, subacute cough, chronic cough, treatment-resistant cough, treatment-resistant chronic cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, cough associated with postnasal drip, cough associated with the common cold, cough associated with upper respiratory tract infections, asthma, lung cancer and / or chronic obstructive pulmonary disease (COPD), cough associated with interstitial diseases, cough associated with pulmonary fibrosis, cough associated with gastroesophageal reflux disease (GERD), cough associated with smoking or forms of bronchitis, and neuronal hypersensitivity underlying acute, subacute or chronic cough.

15. 15. The pharmaceutical composition of claim 14, wherein the cough is selected from the group consisting of chronic cough, treatment-resistant cough, treatment-resistant chronic cough, and cough associated with pulmonary fibrosis.

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