Solid dispersion of p2x3 receptor antagonist and preparation process thereof

Abstract

Provided is a solid dispersion containing a P2X3 receptor antagonist compound shown in formula I, which can increase the solubility of the compound shown in formula I, and improve the dissolution rate and bioavailability of the drug, ensuring the therapeutic effect of the drug. Meanwhile, the solid dispersion has good stability. During the storage process, the solid dispersion does not experience crystal form transformation and does not exhibit a significant increase in related substances, which improves the safety of the clinical use of the drug.

Description

A solid dispersion of a P2X3 receptor antagonist and its preparation process

[0001] This application requires the applicant to:

[0002] The priority benefit of the prior application, patent application number 202311872796.5, filed with the State Intellectual Property Office of China on December 29, 2023, entitled “A solid dispersion of a P2X3 receptor antagonist and its preparation process”;

[0003] The priority benefit of the prior application, patent application number 202411907674.X, filed with the State Intellectual Property Office of China on December 23, 2024, entitled “A solid dispersion of a P2X3 receptor antagonist and its preparation process”;

[0004] The entire disclosure of this prior application is hereby incorporated by reference into the present invention. Technical Field

[0005] The present invention belongs to the field of pharmaceutical preparations, and in particular relates to a solid dispersion of a P2X3 receptor antagonist and a preparation process thereof. Background Art

[0006] P2X3 is a subunit of the ATP-gated ion channel and belongs to the purinergic P2X family. It is expressed in the airways and central nervous system endings. Several clinical studies have confirmed that P2X3 receptor antagonists can significantly improve cough frequency, cough urge, and cough severity in patients with refractory chronic cough. The most common adverse reaction is taste loss. The incidence of taste disorders can be reduced by reducing the drug dose and using more selective P2X3 receptor antagonists. Currently, several P2X3 clinical trials are underway, and P2X3 receptor antagonists are expected to become the most promising treatment for refractory chronic cough in the future.

[0007] Gefapixant, the first selective P2X3 receptor antagonist with the same target, was approved for marketing in Japan in January 2022, and plans to submit an NDA to the FDA and EMA in 2023. Its clinical adverse reactions include loss or reduction of taste, dry mouth and nausea. Taste disorders may be related to the effects of Gefapixant on P2X2 / 3 receptors. It is necessary to develop highly selective P2X3 receptor antagonists to reduce adverse reactions of taste loss or disorder. In addition, there are multiple P2X3 selective antagonists under clinical development: Bellus's Camlipixant (Phase III), Bayer's Eliapixant (Phase IIb), Shionogi's Sivopixant (Phase III planned), and four companies in China are in Phase I-II stages, with good target safety. Compared with the already marketed Gefapixant, the P2X3 specific antagonist compound shown in Formula I involved in this application can significantly reduce the occurrence of taste loss and is intended to be used for the treatment of refractory chronic cough.

[0008] However, during research, the inventors discovered that the compound of Formula I has very poor solubility. Its saturated solubility in media with a pH range of 1.0 to 6.8 is less than 0.02 mg / ml, and its solubility in media with pH values ​​of 1.2, 4.5, 6.8, and aqueous media is less than 10%. Furthermore, the drug substance exhibits poor thermodynamic stability, easily crystallizing during storage and exhibiting poor stability. Therefore, a new formulation is needed to address the poor solubility and stability of the compound of Formula I. Summary of the Invention

[0009] In order to improve the above technical problems, the present invention provides a solid dispersion of a P2X3 receptor antagonist (a compound represented by Formula I). ​​The solid dispersion can improve the solubility of the compound represented by Formula I, greatly improving the dissolution rate and bioavailability of the drug; and the solid dispersion has good stability and does not undergo crystal form transformation during storage.

[0010] The present invention provides a solid dispersion (SD) of a P2X3 receptor antagonist, wherein the solid dispersion comprises: a P2X3 receptor antagonist and a pharmaceutically acceptable carrier;

[0011] Wherein, the P2X3 receptor antagonist is selected from the compound represented by the following formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0012] in,

[0013] R 1 Independently selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens;

[0014] X is a halogen;

[0015] m is selected from the integers 1, 2 or 3;

[0016] L is -(CH2) n -, wherein n is selected from an integer of 0, 1 or 2;

[0017] R 2 independently selected from hydrogen, unsubstituted or replaced by R a Substituted C1-C6 alkyl, unsubstituted or replaced by R a Substituted C3-C7 cycloalkyl, unsubstituted or replaced by R a substituted 5-8 membered aryl, unsubstituted or R a substituted 5-10 membered heteroaryl, unsubstituted or replaced by R a substituted 4-7 membered heterocycloalkyl, unsubstituted or replaced by R a substituted 6-12 membered heterobicycloalkyl; said R a Substituted C1-C6 alkyl, the R a Substituted C3-C7 cycloalkyl, the R a substituted 5-8 membered aryl, the R a substituted 5-10 membered heteroaryl, the a substituted 4-7 membered heterocycloalkyl, or the a In the substituted 6-12 membered heterobicycloalkyl group, the R a Substituted with one or more substitutions, the R a Each is independently selected from the following substituents: C1-C4 alkyl, halogen, -OH, -NR, unsubstituted or substituted by 1-5 identical or different halogens. b R c 、-COOR 4 , oxo (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH or deuterated C1-C6 alkyl; when there are multiple substituents, the substituents are the same or different;

[0018] wherein unsubstituted or replaced by R a In the substituted 5-10 membered heteroaryl, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; a In the substituted 4-7 membered heterocycloalkyl, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; a In the substituted 6-12 membered heterobicycloalkyl group, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0019] R 3 independently selected from hydrogen, or C 1- C4 alkyl;

[0020] R 4 are independently selected from hydrogen or C 1- C4 alkyl;

[0021] R b and R c are independently selected from hydrogen or C 1- C4 alkyl;

[0022] A is independently unsubstituted or replaced by R e substituted 5 to 10 membered heteroaryl, said e In the substituted 5- to 10-membered heteroaryl group, the R e Substituted with one or more substitutions, the R e Each is independently selected from the following substituents: halogen, C1-C3 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens, or -O-(C1-C3 alkyl) which is unsubstituted or substituted by 1-5 identical or different halogens; when there are multiple substituents, the substituents are the same or different.

[0023] In an embodiment of the present invention, the solid dispersion is an amorphous solid dispersion.

[0024] In an embodiment of the present invention, the P2X3 receptor antagonist exists in an amorphous form.

[0025] In an embodiment of the present invention, the pharmaceutically acceptable carrier is a pharmaceutically acceptable polymer carrier.

[0026] In an embodiment of the present invention, the pharmaceutically acceptable carrier is selected from any one or more of the following:

[0027] 1) Cellulose derivative carriers; for example, hydroxypropyl methylcellulose E5 (HPMC-E5), hydroxypropyl methylcellulose acetate succinate LF (HPMC-AS-LF), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose phthalate (HPMCP), etc.

[0028] 2) Polyacrylic acid resin carriers; for example, Eudragit L100-55, Eudragit S100, and Eudragit L100;

[0029] 3) Vinyl polymer carriers, such as polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), copovidone VA64, copovidone S630, etc.

[0030] In an embodiment of the present invention, the pharmaceutically acceptable carrier is selected from any one or more of the following:

[0031] Hydroxypropyl methylcellulose HPMC, copovidone PVP, hydroxypropyl methylcellulose acetate succinate HPMC-AS, polymethacrylate (Eudragit), polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus); preferably, selected from any one or more of the following: hydroxypropyl methylcellulose HPMC, hydroxypropyl methylcellulose acetate succinate HPMC-AS, polymethacrylate (Eudragit).

[0032] In an embodiment of the present invention, the pharmaceutically acceptable carrier is selected from any one or more of the following: hydroxypropyl methylcellulose E5 (HPMC-E5), copovidone VA64 (PVP VA64), hydroxypropyl methylcellulose acetate succinate LF (HPMC-AS-LF), Eudragit L100-55 (Eudragit-L100-55), and polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus); preferably, selected from any one or more of the following: hydroxypropyl methylcellulose E5 (HPMC-E5), hydroxypropyl methylcellulose acetate succinate LF (HPMC-AS-LF), and Eudragit L100-55 (Eudragit-L100-55).

[0033] In an embodiment of the present invention, the mass ratio of the P2X3 receptor antagonist to the pharmaceutically acceptable carrier is 1:0.1-10, preferably 1:0.5-5, for example 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5.

[0034] In an embodiment of the present invention, the solid dispersion comprises the following components:

[0035] P2X3 receptor antagonist 10wt%-60wt%

[0036] Pharmaceutically acceptable carrier 40wt%-90wt%.

[0037] In an embodiment of the present invention, the solid dispersion comprises the following components:

[0038] P2X3 receptor antagonist 20wt%-55wt%

[0039] Pharmaceutically acceptable carrier 45wt%-80wt%.

[0040] In an embodiment of the present invention, the solid dispersion comprises the following components:

[0041] P2X3 receptor antagonist 25wt%-50wt% (e.g. 25wt%, 33wt%, 33.3wt%, 50wt%)

[0042] The pharmaceutically acceptable carrier is 50 wt%-75 wt% (eg, 50 wt%, 67 wt%, 66.7 wt%, 75 wt%).

[0043] In an embodiment of the present invention, the solid dispersion comprises the following components:

[0044] A P2X3 receptor antagonist and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is not less than 66.7 wt %;

[0045] In an embodiment of the present invention, the solid dispersion comprises the following components:

[0046] A P2X3 receptor antagonist and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier accounts for no less than 75 wt %;

[0047] In an embodiment of the present invention, the solid dispersion comprises the following components:

[0048] P2X3 receptor antagonist 25wt%, 33.3wt%, 50wt%

[0049] Pharmaceutically acceptable carrier 50wt%, 66.7wt%, 75wt%.

[0050] The pharmaceutically acceptable carrier is selected from hydroxypropyl methylcellulose E5 (HPMC-E5), hydroxypropyl methylcellulose acetate succinate LF (HPMC-AS-LF), and Eudragit L100-55 (Eudragit-L100-55).

[0051] In an embodiment of the present invention, the solid dispersion comprises the following components:

[0052] P2X3 receptor antagonist 25wt%

[0053] Pharmaceutically acceptable carrier 75wt%.

[0054] The pharmaceutically acceptable carrier is selected from hydroxypropyl methylcellulose E5 (HPMC-E5), hydroxypropyl methylcellulose acetate succinate LF (HPMC-AS-LF), and Eudragit L100-55 (Eudragit-L100-55).

[0055] In an embodiment of the present invention, the solid dispersion comprises the following components:

[0056] P2X3 receptor antagonist 33.3wt%

[0057] Pharmaceutically acceptable carrier 66.7wt%.

[0058] The pharmaceutically acceptable carrier is selected from hydroxypropyl methylcellulose E5 (HPMC-E5), hydroxypropyl methylcellulose acetate succinate LF (HPMC-AS-LF), and Eudragit L100-55 (Eudragit-L100-55).

[0059] In an embodiment of the present invention, the solid dispersion comprises the following components:

[0060] A P2X3 receptor antagonist and hypromellose acetate succinate LF, wherein the proportion of hypromellose acetate succinate LF is not less than 75%.

[0061] In an embodiment of the present invention, the solid dispersion comprises the following components:

[0062] P2X3 receptor antagonist 25wt%

[0063] Hydroxypropyl methylcellulose acetate succinate LF 75 wt%.

[0064] In an embodiment of the present invention, the solid dispersion comprises the following components:

[0065] A P2X3 receptor antagonist and hypromellose acetate succinate LF, wherein the proportion of hypromellose acetate succinate LF is not less than 66.7 wt %.

[0066] In an embodiment of the present invention, the solid dispersion comprises the following components:

[0067] P2X3 receptor antagonist 33.3wt%

[0068] Hydroxypropyl methylcellulose acetate succinate LF 66.7 wt%.

[0069] In an embodiment of the present invention, the solid dispersion optionally further comprises a solvent.

[0070] In an embodiment of the present invention, the solvent is a volatile solvent, which evaporates during the process of preparing the solid dispersion.

[0071] In an embodiment of the present invention, the solvent is selected from any one or more of the following: dichloromethane, ethanol, acetone, methanol; preferably acetone, dichloromethane-methanol mixed solvent.

[0072] In an embodiment of the present invention, the solid dispersion optionally further comprises any one or more of the following: sweeteners, flavorings, colorants, surfactants, fillers, lubricants, disintegrants, disintegration promoters, recrystallization inhibitors, defoaming agents, antioxidants and pH regulators.

[0073] In a preferred embodiment of the present invention, the compound represented by Formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are:

[0074] in,

[0075] R 1 Independently selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens;

[0076] X is a halogen;

[0077] m is selected from the integers 1, 2 or 3;

[0078] L is -(CH2) n -, wherein n is selected from an integer of 0, 1 or 2;

[0079] R 2 independently selected from hydrogen, unsubstituted or replaced by R a Substituted C1-C6 alkyl, unsubstituted or replaced by R a Substituted C3-C7 cycloalkyl, unsubstituted or replaced by R a substituted 5-8 membered aryl, unsubstituted or R a substituted 5-10 membered heteroaryl, unsubstituted or replaced by R a substituted 4-7 membered heterocycloalkyl, unsubstituted or replaced by R a substituted 6-12 membered heterobicycloalkyl; said R a Substituted C1-C6 alkyl, the R a Substituted C3-C7 cycloalkyl, the R a substituted 5-8 membered aryl, the R a substituted 5-10 membered heteroaryl, the a substituted 4-7 membered heterocycloalkyl, or the a In the substituted 6-12 membered heterobicycloalkyl, the substitutions are independently one or more of the following substituents: C1-C4 alkyl, halogen, -OH, -NR, which are unsubstituted or substituted with 1-5 identical or different halogens.b R c 、-COOR 4 , oxo (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl) or deuterated C1-C6 alkyl; when there are multiple substituents, the substituents are the same or different;

[0080] wherein unsubstituted or replaced by R a In the substituted 5-10 membered heteroaryl, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; a In the substituted 4-7 membered heterocycloalkyl, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; a In the substituted 6-12 membered heterobicycloalkyl group, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0081] R 3 Independently selected from hydrogen, or C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogen atoms;

[0082] R 4 Independently selected from hydrogen or C1-C4 alkyl;

[0083] R b and R c Independently selected from hydrogen or C1-C4 alkyl;

[0084] A is independently unsubstituted or replaced by R e substituted 5 to 10 membered heteroaryl, said e In the substituted 5- to 10-membered heteroaryl group, the R e Substituted with one or more substitutions, the R e Each is independently selected from the following substituents: halogen, C1-C3 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens, or -O-(C1-C3 alkyl) which is unsubstituted or substituted by 1-5 identical or different halogens; when there are multiple substituents, the substituents are the same or different.

[0085] In a preferred embodiment of the present invention, when R 1 When it is a halogen, the halogen is F, Cl, Br, I, preferably Cl.

[0086] In a preferred embodiment of the present invention, when R 1 When it is an unsubstituted C1-C4 alkyl group, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, preferably methyl or ethyl.

[0087] In a preferred embodiment of the present invention, when R1 When it is a C1-C4 alkyl group substituted by 1-5 identical or different halogen groups, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, preferably methyl or ethyl.

[0088] In a preferred embodiment of the present invention, when R 1 When it is a C1-C4 alkyl group substituted by 1-5 identical or different halogens, the halogen is F, Cl, Br, I, preferably Cl or F.

[0089] In a preferred embodiment of the present invention, when X is halogen, the halogen is one of F or Cl.

[0090] In a preferred embodiment of the present invention, m is selected from integers 1, 2 or 3, preferably 1.

[0091] In a preferred embodiment of the present invention, when L is -(CH2) n -, said n is an integer 0, 1 or 2, preferably n is 0 or 1.

[0092] In a preferred embodiment of the present invention, when R 2 is unsubstituted or replaced by R a When the C1-C6 alkyl group is substituted, the C1-C6 alkyl group is a C1-C4 alkyl group, preferably a sec-butyl group.

[0093] In a preferred embodiment of the present invention, when R 2 is unsubstituted or replaced by R a In the case of a substituted C1-C6 alkyl group, the C1-C6 alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0094] In a preferred embodiment of the present invention, when R 2 is unsubstituted or replaced by R a In the case of a substituted C3-C7 cycloalkyl group, the C3-C7 alkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.

[0095] In a preferred embodiment of the present invention, when R 2 is unsubstituted or replaced by R a When the 4- to 7-membered heterocycloalkyl group is substituted, the 4- to 7-membered heterocycloalkyl group is a 4-, 5- or 6-membered heterocycloalkyl group.

[0096] In a preferred embodiment of the present invention, when R 2 is unsubstituted or replaced by R a In the case of a substituted 4- to 7-membered heterocycloalkyl group, the heteroatom in the 4- to 7-membered heterocycloalkyl group is one or more of N, S, O, and P, preferably one or more of N or O.

[0097] In a preferred embodiment of the present invention, when R 2 is unsubstituted or replaced by R a In the case of a substituted 4- to 7-membered heterocycloalkyl group, the number of heteroatoms in the 4- to 7-membered heterocycloalkyl group is 1 to 3, preferably 1 or 2.

[0098] In a preferred embodiment of the present invention, when R 2 is unsubstituted or replaced by R a When the 4-7 membered heterocycloalkyl group is substituted, the R a 1 to 3, preferably 1.

[0099] In a preferred embodiment of the present invention, R a It is a hydroxyl group.

[0100] In a preferred embodiment of the present invention, when R a When it is a halogen, the halogen is F, Cl, Br, or I, preferably F or Cl.

[0101] In a preferred embodiment of the present invention, when R a When it is a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C3 alkyl group, preferably a methyl group.

[0102] In a preferred embodiment of the present invention, when R a When it is a deuterated C1-C6 alkyl, the C1-C6 alkyl is a C1-C3 deuterated alkyl, preferably

[0103] In a preferred embodiment of the present invention, when R a When it is -(C1-C6 alkylene)-OH, the C1-C6 alkylene is C1-C4 alkylene, preferably methylene, ethylene, n-propylene or isopropylene, more preferably methylene.

[0104] In a preferred embodiment of the present invention, R 3 For hydrogen.

[0105] In a preferred embodiment of the present invention, when R 3 When it is an unsubstituted C1-C4 alkyl group, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, preferably methyl.

[0106] In a preferred embodiment of the present invention, when A is R e In the case of a substituted 5- to 10-membered heteroaryl group, the 5- to 10-membered heteroaryl group is a 6-membered heteroaryl group, preferably pyrimidine or pyridazine.

[0107] In a preferred embodiment of the present invention, when A is R e When the 5- to 10-membered heteroaryl group is substituted, the Re The substitution is mono-substitution.

[0108] In a preferred embodiment of the present invention, when A is R e When the 5- to 10-membered heteroaryl group is substituted, the R e It is a C1-C3 alkyl group substituted by 1-5 identical or different halogen groups, preferably a trifluoromethyl group.

[0109] In a preferred embodiment of the present invention, when A is R e When the 5- to 10-membered heteroaryl group is substituted, the R e is an unsubstituted C1-C3 alkyl group, preferably a methyl group.

[0110] In a preferred embodiment of the present invention, -LR 2 Selected from

[0111] In a preferred embodiment of the present invention, -LR 2 for

[0112] In a preferred embodiment of the present invention, -LR 2 Selected from

[0113] In a preferred embodiment of the present invention, R 1 is methyl, ethyl or Cl.

[0114] In a preferred embodiment of the present invention, -LR 2 Selected from

[0115] In a preferred embodiment of the present invention, -LR 2 Selected from

[0116] In a preferred embodiment of the present invention, R 3 is methyl or hydrogen.

[0117] In a preferred embodiment of the present invention, A is selected from

[0118] In a preferred embodiment of the present invention, the compound of formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are:

[0119] in,

[0120] R 1 Selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens;

[0121] L is -(CH2) n -, wherein n is selected from an integer of 0, 1 or 2;

[0122] R 2 independently selected from hydrogen, unsubstituted or replaced by R a Substituted C1-C6 alkyl, unsubstituted or replaced by R a Substituted C3-C7 cycloalkyl, unsubstituted or replaced by R a substituted 5-8 membered aryl, unsubstituted or R a substituted 5-10 membered heteroaryl, unsubstituted or replaced by R a substituted 4-7 membered heterocycloalkyl, unsubstituted or replaced by R a substituted 6-12 membered heterobicycloalkyl; said R a Substituted C1-C6 alkyl, the R a Substituted C3-C7 cycloalkyl, the R a substituted 5-8 membered aryl, the R a substituted 5-10 membered heteroaryl, the a substituted 4-7 membered heterocycloalkyl, or the a In the substituted 6-12 membered heterobicycloalkyl group, the R a Substituted with one or more substitutions, the R a Each is independently selected from the following substituents: C1-C4 alkyl, halogen, -OH, -NR, unsubstituted or substituted by 1-5 identical or different halogens. b R c 、-COOR 4 , oxo (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH and deuterated C1-C6 alkyl; when there are multiple substituents, the substituents are the same or different;

[0123] wherein unsubstituted or replaced by R a In the substituted 5-10 membered heteroaryl, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; a In the substituted 4-7 membered heterocycloalkyl, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; a In the substituted 6-12 membered heterobicycloalkyl group, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0124] R 4 are independently selected from hydrogen or C 1- C4 alkyl;

[0125] R b and R c are independently selected from hydrogen or C 1- C4 alkyl.

[0126] In a preferred embodiment of the present invention, the compound of formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are:

[0127] in,

[0128] R 1 Selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens;

[0129] L is -(CH2) n -, wherein n is selected from an integer of 0, 1 or 2;

[0130] R 2 independently selected from hydrogen, unsubstituted or replaced by R a Substituted C1-C6 alkyl, unsubstituted or replaced by R a Substituted C3-C7 cycloalkyl, unsubstituted or replaced by R a substituted 5-8 membered aryl, unsubstituted or R a substituted 5-10 membered heteroaryl, unsubstituted or replaced by R a substituted 4-7 membered heterocycloalkyl, unsubstituted or replaced by R a substituted 6-12 membered heterobicycloalkyl; said R a Substituted C1-C6 alkyl, the R a Substituted C3-C7 cycloalkyl, the R a substituted 5-8 membered aryl, the R a substituted 5-10 membered heteroaryl, the a substituted 4-7 membered heterocycloalkyl, or the a In the substituted 6-12 membered heterobicycloalkyl group, the R a Substituted with one or more substitutions, the R a Each is independently selected from the following substituents: C1-C4 alkyl, halogen, -OH, -NR, unsubstituted or substituted by 1-5 identical or different halogens. b R c 、-COOR 4, oxo (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH and deuterated C1-C6 alkyl; when there are multiple substituents, the substituents are the same or different;

[0131] wherein unsubstituted or replaced by R a In the substituted 5-10 membered heteroaryl, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; a In the substituted 4-7 membered heterocycloalkyl, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; a In the substituted 6-12 membered heterobicycloalkyl group, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0132] R 4 Independently selected from hydrogen or C1-C4 alkyl;

[0133] R b and R c Independently selected from hydrogen or C1-C4 alkyl.

[0134] In a preferred embodiment of the present invention, the compound of formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are:

[0135] in,

[0136] R 1 Selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens;

[0137] L is -(CH2) n -, wherein n is selected from an integer of 0, 1 or 2;

[0138] R 2 independently selected from hydrogen, unsubstituted or replaced by R a Substituted C1-C6 alkyl, unsubstituted or replaced by R a Substituted C3-C7 cycloalkyl, unsubstituted or replaced by R a substituted 5-8 membered aryl, unsubstituted or R a substituted 5-10 membered heteroaryl, unsubstituted or replaced by R a substituted 4-7 membered heterocycloalkyl, unsubstituted or replaced by R a substituted 6-12 membered heterobicycloalkyl; said R a Substituted C1-C6 alkyl, the R a Substituted C3-C7 cycloalkyl, the Ra substituted 5-8 membered aryl, the R a substituted 5-10 membered heteroaryl, the a substituted 4-7 membered heterocycloalkyl, or the a In the substituted 6-12 membered heterobicycloalkyl group, the R a Substituted with one or more substitutions, the R a Each is independently selected from the following substituents: C1-C4 alkyl, halogen, -OH, -NR, unsubstituted or substituted by 1-5 identical or different halogens. b R c 、-COOR 4 , oxo (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH and deuterated C1-C6 alkyl; when there are multiple substituents, the substituents are the same or different;

[0139] wherein unsubstituted or replaced by R a In the substituted 5-10 membered heteroaryl, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 4-7 membered heterocycloalkyl which is unsubstituted or substituted by Ra, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; in the 4-7 membered heterocycloalkyl which is unsubstituted or substituted by R a In the substituted 6-12 membered heterobicycloalkyl group, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0140] R 4 Independently selected from hydrogen or C1-C4 alkyl;

[0141] R b and R c Independently selected from hydrogen or C1-C4 alkyl.

[0142] In a preferred embodiment of the present invention, the compound of formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are:

[0143] in,

[0144] R 1 Selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens;

[0145] L is -(CH2) n -, wherein n is selected from an integer of 0, 1 or 2;

[0146] R 2 independently selected from hydrogen, unsubstituted or replaced by Ra Substituted C1-C6 alkyl, unsubstituted or replaced by R a Substituted C3-C7 cycloalkyl, unsubstituted or replaced by R a substituted 5-8 membered aryl, unsubstituted or R a substituted 5-10 membered heteroaryl, unsubstituted or replaced by R a substituted 4-7 membered heterocycloalkyl, unsubstituted or replaced by R a substituted 6-12 membered heterobicycloalkyl; said R a Substituted C1-C6 alkyl, the R a Substituted C3-C7 cycloalkyl, the R a substituted 5-8 membered aryl, the R a substituted 5-10 membered heteroaryl, the a substituted 4-7 membered heterocycloalkyl, or the a In the substituted 6-12 membered heterobicycloalkyl group, the R a Substituted with one or more substitutions, the R a Each is independently selected from the following substituents: C1-C4 alkyl, halogen, -OH, -NR, unsubstituted or substituted by 1-5 identical or different halogens. b R c 、-COOR 4 , oxo (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH and deuterated C1-C6 alkyl; when there are multiple substituents, the substituents are the same or different;

[0147] wherein unsubstituted or replaced by R a In the substituted 5-10 membered heteroaryl, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; a In the substituted 4-7 membered heterocycloalkyl, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; a In the substituted 6-12 membered heterobicycloalkyl group, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0148] R 4 Independently selected from hydrogen or C1-C4 alkyl;

[0149] R b and R c Independently selected from hydrogen or C1-C4 alkyl.

[0150] In a preferred embodiment of the present invention, the compound of formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are:

[0151] in,

[0152] R 1 Independently selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens;

[0153] L is -(CH2) n -, wherein n is selected from an integer of 0, 1 or 2;

[0154] R 2 independently selected from hydrogen, unsubstituted or replaced by R a Substituted C1-C6 alkyl, unsubstituted or replaced by R a Substituted C3-C7 cycloalkyl, unsubstituted or replaced by R a substituted 5-8 membered aryl, unsubstituted or R a substituted 5-10 membered heteroaryl, unsubstituted or replaced by R a substituted 4-7 membered heterocycloalkyl, unsubstituted or replaced by R a substituted 6-12 membered heterobicycloalkyl; said R a Substituted C1-C6 alkyl, the R a Substituted C3-C7 cycloalkyl, the R a substituted 5-8 membered aryl, the R a substituted 5-10 membered heteroaryl, the a substituted 4-7 membered heterocycloalkyl, or the a In the substituted 6-12 membered heterobicycloalkyl group, the R a Substituted with one or more substitutions, the R a Each is independently selected from the following substituents: C1-C4 alkyl, halogen, -OH, -NR, unsubstituted or substituted by 1-5 identical or different halogens. b R c 、-COOR 4 , oxo (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH and deuterated C1-C6 alkyl; when there are multiple substituents, the substituents are the same or different;

[0155] wherein unsubstituted or replaced by R a In the substituted 5-10 membered heteroaryl, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; aIn the substituted 4-7 membered heterocycloalkyl, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; a In the substituted 6-12 membered heterobicycloalkyl group, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0156] R 4 Independently selected from hydrogen or C1-C4 alkyl;

[0157] R b and R c are independently selected from hydrogen or C 1- C4 alkyl.

[0158] In a preferred embodiment of the present invention, the compound of formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are:

[0159] in,

[0160] R 1 Independently selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens;

[0161] L is -(CH2) n -, wherein n is selected from an integer of 0, 1 or 2;

[0162] R 2 independently selected from hydrogen, unsubstituted or replaced by R a Substituted C1-C6 alkyl, unsubstituted or replaced by R a Substituted C3-C7 cycloalkyl, unsubstituted or replaced by R a substituted 5-8 membered aryl, unsubstituted or R a substituted 5-10 membered heteroaryl, unsubstituted or replaced by R a substituted 4-7 membered heterocycloalkyl, unsubstituted or replaced by R a substituted 6-12 membered heterobicycloalkyl; said R a Substituted C1-C6 alkyl, the R a Substituted C3-C7 cycloalkyl, the R a substituted 5-8 membered aryl, the R a substituted 5-10 membered heteroaryl, the a substituted 4-7 membered heterocycloalkyl, or the a In the substituted 6-12 membered heterobicycloalkyl group, the R a Substituted with one or more substitutions, the R aEach is independently selected from the following substituents: C1-C4 alkyl, halogen, -OH, -NR, unsubstituted or substituted by 1-5 identical or different halogens. b R c 、-COOR 4 , oxo (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH and deuterated C1-C6 alkyl; when there are multiple substituents, the substituents are the same or different;

[0163] wherein unsubstituted or replaced by R a In the substituted 5-10 membered heteroaryl, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; a In the substituted 4-7 membered heterocycloalkyl, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; a In the substituted 6-12 membered heterobicycloalkyl group, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0164] R 4 are independently selected from hydrogen or C 1- C4 alkyl;

[0165] R b and R c are independently selected from hydrogen or C 1- C4 alkyl.

[0166] In a preferred embodiment of the present invention, the compound of formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are:

[0167] in,

[0168] R 1 Independently selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens;

[0169] L is -(CH2) n -, wherein n is selected from an integer of 0, 1 or 2;

[0170] R 2 independently selected from hydrogen, unsubstituted or replaced by R a Substituted C1-C6 alkyl, unsubstituted or replaced by R a Substituted C3-C7 cycloalkyl, unsubstituted or replaced by R a substituted 5-8 membered aryl, unsubstituted or R a substituted 5-10 membered heteroaryl, unsubstituted or replaced by Ra substituted 4-7 membered heterocycloalkyl, unsubstituted or replaced by R a substituted 6-12 membered heterobicycloalkyl; said R a Substituted C1-C6 alkyl, the R a Substituted C3-C7 cycloalkyl, the R a substituted 5-8 membered aryl, the R a substituted 5-10 membered heteroaryl, the a substituted 4-7 membered heterocycloalkyl, or the a In the substituted 6-12 membered heterobicycloalkyl group, the R a Substituted with one or more substitutions, the R a Each is independently selected from the following substituents: C1-C4 alkyl, halogen, -OH, -NR, unsubstituted or substituted by 1-5 identical or different halogens. b R c 、-COOR 4 , oxo (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH and deuterated C1-C6 alkyl; when there are multiple substituents, the substituents are the same or different;

[0171] wherein unsubstituted or replaced by R a In the substituted 5-10 membered heteroaryl, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; a In the substituted 4-7 membered heterocycloalkyl, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3; a In the substituted 6-12 membered heterobicycloalkyl group, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1-3;

[0172] R 4 are independently selected from hydrogen or C 1- C4 alkyl;

[0173] R b and R c Independently selected from hydrogen or C1-C4 alkyl.

[0174] In a preferred embodiment of the present invention, the compound represented by formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are selected from any one of the following compounds:

[0175] In a preferred embodiment of the present invention, the compound represented by formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs are selected from any one of the following compounds:

[0176] In an embodiment of the present invention, the P2X3 receptor antagonist is selected from the compound represented by formula A, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0177] The present invention also provides a preparation process of the solid dispersion, which comprises the following steps:

[0178] (1) Add each component to the solvent and stir to dissolve;

[0179] (2) Drying the dissolved solution to obtain the solid dispersion.

[0180] In an embodiment of the present invention, step (1) specifically comprises: first adding a pharmaceutically acceptable carrier to a solvent and stirring to dissolve; then adding a P2X3 receptor antagonist and continuing to stir to dissolve.

[0181] In an embodiment of the present invention, the drying treatment method of step (2) is selected from spray drying.

[0182] In an embodiment of the present invention, step (2) specifically comprises: filtering the dissolved solution into a transfer tank, and then drying the filtered solution to obtain a solid dispersion;

[0183] Preferably, the solution is filtered into a transfer tank through a precision filter press of a certain pore size.

[0184] In an embodiment of the present invention, after the drying treatment in step (2), the solid dispersion after the drying treatment is optionally further dried under reduced pressure.

[0185] In an embodiment of the present invention, in step (1), the stirring time is not less than 60 min (for example, not less than 120 min); preferably 60 to 120 min, 120 to 180 min.

[0186] In an embodiment of the present invention, in step (2), the pore size of the precision filter press is 1 μm-22 μm, preferably 5 μm.

[0187] In an embodiment of the present invention, in step (2), the feed frequency of the spray drying is 5 Hz to 50 Hz, preferably 10 Hz to 20 Hz;

[0188] and / or, the atomization pressure is 0.1 MPa-1.0 MPa, preferably 0.1 MPa-0.2 MPa;

[0189] and / or, the inlet air temperature is 60°C-120°C, preferably 85°C-110°C;

[0190] And / or, the air outlet temperature is 40°C-70°C, preferably 50°C-55°C.

[0191] The present invention also provides a pharmaceutical composition comprising the solid dispersion and a pharmaceutically acceptable carrier, diluent or excipient.

[0192] In an embodiment of the present invention, the dosage form of the pharmaceutical composition is selected from solid preparations, liquid preparations; for example, powders, granules, pills, tablets, sachets, capsules, sugar-coated pills, chewable tablets, effervescent tablets, dispersible tablets, lozenges, melts, solutions, suspensions or emulsions, etc.

[0193] According to a specific embodiment of the present invention, the pharmaceutical composition and a pharmaceutically acceptable pharmaceutical carrier, diluent or excipient are mixed to prepare a pharmaceutical preparation suitable for oral or parenteral administration. The administration method includes, but is not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal and oral routes.

[0194] The present invention also provides a pharmaceutical preparation comprising the solid dispersion and a pharmaceutically acceptable carrier, diluent or excipient.

[0195] In an embodiment of the present invention, the pharmaceutical preparation is selected from a solid preparation, a liquid preparation, such as powder, granules, pills, tablets, sachets, capsules, dragees, chewable tablets, effervescent tablets, dispersible tablets, lozenges, melts, solutions, suspensions or emulsions, etc. It can be prepared according to methods known in the art of manufacturing pharmaceutical preparations.

[0196] The pharmaceutical preparation can be administered by any route, for example, by infusion or bolus, by a route of absorption through the epithelium or mucocutaneous membranes (e.g., oral mucosa or rectum, etc.). Administration can be systemic or local. Examples of oral formulations include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions, etc. The preparation can be prepared by methods known in the art and include carriers, diluents, or excipients conventionally used in the field of pharmaceutical preparations.

[0197] The present invention also provides use of the solid dispersion, pharmaceutical composition, and pharmaceutical preparation in the preparation of drugs for treating and / or preventing P2X3-related diseases.

[0198] In an embodiment of the present invention, the P2X3-related disease is pain, respiratory disease or urogenital disease.

[0199] In an embodiment of the present invention, the pain is chronic pain, acute pain, endometriosis pain, neuropathic pain, back pain, cancer pain, inflammatory pain, surgical pain, migraine or visceral pain;

[0200] and / or the genitourinary system disease is decreased bladder capacity, frequent urination, urge incontinence, stress incontinence, bladder hyperreactivity, benign prostatic hypertrophy, prostatitis, detrusor hyperreflexia, frequent urination, nocturia, urgency, overactive bladder, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatitis, cystitis;

[0201] And / or, the respiratory system disease is chronic obstructive pulmonary disease, pulmonary hypertension, pulmonary fibrosis, asthma and obstructive apnea, chronic cough, refractory chronic cough and acute cough.

[0202] The present invention also provides a method for treating and / or preventing a disease associated with P2X3, comprising administering an effective amount of the above-mentioned solid dispersion, pharmaceutical composition, or pharmaceutical preparation to a patient suffering from the disease associated with P2X3.

[0203] In an embodiment of the present invention, the P2X3-related disease is pain, respiratory disease or urogenital disease.

[0204] In an embodiment of the present invention, the pain is chronic pain, acute pain, endometriosis pain, neuropathic pain, back pain, cancer pain, inflammatory pain, surgical pain, migraine or visceral pain;

[0205] and / or the genitourinary system disease is decreased bladder capacity, frequent urination, urge incontinence, stress incontinence, bladder hyperreactivity, benign prostatic hypertrophy, prostatitis, detrusor hyperreflexia, frequent urination, nocturia, urgency, overactive bladder, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatitis, cystitis;

[0206] And / or, the respiratory system disease is chronic obstructive pulmonary disease, pulmonary hypertension, pulmonary fibrosis, asthma and obstructive apnea, chronic cough, refractory chronic cough and acute cough.

[0207] Terms and Definitions

[0208] Unless otherwise specified, the terms and definitions used in this application, including the specification and claims, are as follows.

[0209] Those skilled in the art will understand that, according to the conventions used in the art, in the structural formula of this application, Used to depict chemical bonds, which are the points where a moiety or substituent is attached to a core or backbone structure.

[0210] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0211] The term "pharmaceutically acceptable salts" refers to salts of pharmaceutically acceptable non-toxic acids or bases, including salts of inorganic acids and bases, and organic acids and bases.

[0212] The term "solvate" refers to a compound of the present invention or a salt thereof including a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, it is a hydrate.

[0213] The term "prodrug" refers to a compound of the present invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the present invention are prepared by modifying functional groups within the compound. These modifications can be removed by conventional procedures or in vivo to yield the parent compound. Prodrugs include compounds in which a hydroxyl group or an amino group within a compound of the present invention is attached to any group. When a prodrug of a compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group or a free amino group, respectively.

[0214] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0215] According to the selection of raw materials and methods, the compounds of the present invention can exist in the form of one of possible isomers or their mixture, for example as pure optical isomers, or as isomer mixtures, such as as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing a compound with optical activity, prefixes D and L or R and S are used to represent the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (-) are symbols for specifying the rotation of plane polarized light caused by the compound, where (-) or L represent that the compound is left-handed. Compounds prefixed with (+) or D are dextrorotatory. With respect to a given chemical structure, except that these stereoisomers are mirror images of each other, these stereoisomers are identical. Specific stereoisomers may also be referred to as enantiomers, and the mixture of the isomers is commonly referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. Numerous geometric isomers of alkenes, C=N double bonds, etc., can also exist in the compounds described herein, and all such stable isomers are contemplated by the present invention. When the compounds described herein contain olefinic double bonds, unless otherwise specified, such double bonds include both E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in either the cis- or trans- configuration.

[0216] When bonds to chiral carbon atoms in formulae of the present invention are depicted as straight lines, it is understood that both the (R) and (S) configurations of the chiral carbon atoms and the enantiomerically pure compounds and mixtures thereof are encompassed within the scope of the formulae. The diagrammatic representations of racemates and enantiomerically pure compounds herein are adapted from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, wedge-shaped bonds and dashed bonds are used to represent the absolute configuration of a stereocenter.

[0217] Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. Compounds of the invention containing asymmetrically substituted carbon atoms can be separated in optically active form or racemic form. Resolution of a racemic mixture of a compound can be carried out by any of a number of methods known in the art. An exemplary method includes fractional recrystallization using a chiral resolving acid that is an optically active, salified organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include α-methyl-benzylamine (e.g., S and R forms or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. The resolution of the racemic mixture can also be carried out by eluting on a column filled with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High performance liquid chromatography (HPLC) can also be used to carry out supercritical fluid chromatography (SFC). The selection of specific methods and elution conditions, chromatographic column selection can be selected by those skilled in the art according to the structure of the compound and test results. Further, optically pure starting materials or reagents of known configuration can also be used to obtain any enantiomer or diastereomer of the compound described in the present invention through stereoorganic synthesis.

[0218] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture with physical and chemical properties consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0219] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0220] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For the oral dosage forms of the present invention, an "effective amount" of an active substance in the composition means the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0221] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0222] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =0), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any chemically feasible basis.

[0223] The term "C1-C6 alkyl" is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. Such alkyl radicals are, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or isomers thereof. In particular, the radical has 1, 2, 3 or 4 carbon atoms ("C1-C4 alkyl"), for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0224] The term "C1-C3 alkoxy" is to be understood as -O-(C1-C3 alkyl), wherein "C1-C3 alkyl" has the above-mentioned definition.

[0225] The term "deuterated C1-C6 alkyl" is understood as a C1-C6 alkyl group in which one or more hydrogen atoms are replaced by deuterium, wherein "C1-C6 alkyl" has the above definition.

[0226] The term "C3-C7 cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 7 carbon atoms, including fused or bridged polycyclic ring systems. Similarly, "C3-C6 cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring as defined above having 3 to 6 carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0227] The term "alkylene" is understood to mean a saturated divalent hydrocarbon radical derived by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon. Unless otherwise specified, an alkylene group contains 1-10 carbon atoms. In some embodiments, an alkylene group contains 1-6 carbon atoms; in other embodiments, an alkylene group contains 1-4 carbon atoms; and in yet other embodiments, an alkylene group contains 1-2 carbon atoms. Examples include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH(CH3)CH2-), and the like.

[0228] The term "heterocycloalkyl" is understood to mean a saturated monovalent monocyclic hydrocarbon ring having the specified number of ring atoms, wherein one, two or three ring atoms of the hydrocarbon ring are replaced by one, two or three heteroatoms or heteroatom-containing groups independently selected from O, S, S(=O), S(=O)2 or N. "4- to 7-membered heterocycloalkyl" is understood to mean a saturated monovalent monocyclic "heterocycloalkyl" ring as defined above containing 4, 5, 6 or 7 ring atoms. Similarly, "4- to 6-membered heterocycloalkyl" is understood to mean a saturated monovalent monocyclic "heterocycloalkyl" ring as defined above containing 4, 5 or 6 ring atoms.

[0229] The term "6- to 12-membered heterobicycloalkyl" is understood to mean a saturated monovalent bicyclic hydrocarbon radical wherein the two rings share one or two common ring atoms, wherein the bicyclic hydrocarbon radical contains 5, 6, 7, 8, 9 or 10 carbon atoms and one, two or three heteroatoms or heteroatom-containing groups independently selected from O, S, S(=O), S(=O)2 or N, provided that the total number of ring atoms is not greater than 12.

[0230] The term "5-8 membered aryl" is understood to mean a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring having 5-8 carbon atoms, particularly a ring having 6 carbon atoms ("C6 aryl"), such as phenyl. When the 5-8 membered aryl is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the position of substitution, and for example, substitution may be in the ortho, para, or meta position.

[0231] The term "5-10 membered heteroaryl" is understood to mean a monovalent monocyclic, bicyclic or tricyclic aromatic ring radical having 5-10 ring atoms, in particular 5 or 6 carbon atoms, and containing 1-5 heteroatoms independently selected from N, O and S. Preference is given to monovalent monocyclic, bicyclic or tricyclic aromatic ring radicals containing 1-3 heteroatoms independently selected from N, O and S, and in each case may be benzo-fused. In particular, the heteroaryl radical is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.

[0232] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0233] Additionally, it should be noted that, unless explicitly stated otherwise, the term "independently" used in the present invention should be broadly interpreted to mean that the individual entities described are independent of each other and can independently represent the same or different specific groups. More specifically, the term "independently" can mean that specific options expressed by the same symbols in different groups do not affect each other, or that specific options expressed by the same symbols in the same group do not affect each other. Beneficial effects

[0234] The present invention provides a solid dispersion comprising a P2X3 receptor antagonist compound represented by Formula I. This solid dispersion significantly improves the solubility of the compound represented by Formula I, greatly enhancing its dissolution rate and bioavailability, thereby ensuring its therapeutic efficacy. Furthermore, the solid dispersion exhibits excellent stability and does not undergo crystal transformation during storage, thereby enhancing the safety of the drug in clinical applications.

[0235] The present invention conducts extensive solid dispersion screening of the compound of formula A, including different types of solid dispersion carriers and drug-carrier ratios, to obtain a solid dispersion with a higher drug-carrier ratio and excellent drug stability. The solid dispersion has good exposure in dogs at a dose of 20 mg / kg, can maintain a supersaturated concentration for a relatively long time, and can maintain stable and sustained in vivo absorption after 4 hours.

[0236] The pharmacokinetic tests in rats, mice and dogs of the present invention show that compounds I-27, I-28, I-29 and I-30 have comparable pharmacokinetic properties. BRIEF DESCRIPTION OF THE DRAWINGS

[0237] Figure 1: XRPD pattern of API compound.

[0238] Figure 2: TGA & DSC graphs of API compounds.

[0239] Figure 3: Dynamic dissolution curves of API and HPMC-AS-LF amorphous films with different ratios.

[0240] Figure 4: Dynamic dissolution profiles of API and Eudragit L100-55 amorphous films at different ratios.

[0241] Figure 5: Dynamic dissolution curves of API and HPMC-E5 amorphous films with different ratios.

[0242] Figure 6: Dynamic dissolution curves of API and PVPVA64 amorphous films with different ratios.

[0243] Figure 7: Dynamic dissolution curves of API and Soluplus amorphous films at different ratios.

[0244] Figure 8: Solid-state XRPD patterns of the physical stability of formulation F25 under various conditions over 7 days.

[0245] Figure 9-1: Solid-state XRPD pattern of Formulation F25 at 40°C and RH 60% for 18 days of physical stability.

[0246] Figure 9-2: Solid-state XRPD pattern of Formulation F25 at 40°C and RH 75% for 18 days of physical stability.

[0247] Figure 9-3: Solid-state XRPD pattern of formulation F25 at 60°C and RH 30% for 18 days.

[0248] Figure 10: Solid-state XRPD patterns of the physical stability of formulation F26 under various conditions over 7 days.

[0249] Figure 11: Solid-state XRPD patterns of the physical stability of formulation F26 under various conditions for 18 days. DETAILED DESCRIPTION

[0250] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0251] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0252] The compounds of the present application and their preparation are described in WO2022068930A1 and WO2023185931A1.

[0253] “Pharmaceutically acceptable” means an excipient that is, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues, does not produce excessive toxicity, irritation, allergic reactions, or other problems or complications, and has a reasonable benefit / risk ratio.

[0254] List of abbreviations

[0255] Table 1-1 Abbreviations and their full names in the present invention

[0256] Instruments and detection methods

[0257] 1. Experimental instruments

[0258] The main instrument models and manufacturers used in this invention are shown in Table 2-1:

[0259] Table 2-1 Main instruments used in the experiment

[0260] 2. X-ray powder diffraction (XRPD)

[0261] The relevant parameters of the X-ray powder diffraction (XRPD) instrument are shown in Table 2-2:

[0262] Table 2-2 XRPD instrument related parameters

[0263] 3. Thermogravimetric analysis (TGA)

[0264] The relevant parameters of the TGA instrument are shown in Table 2-3:

[0265] Table 2-3 TGA instrument related parameters

[0266] 4. Differential Scanning Calorimetry (DSC)

[0267] The relevant parameters of the DSC instrument are shown in Table 2-4:

[0268] Table 2-4 DSC instrument related parameters

[0269] 5. Dynamic Vapor Sorption (DVS)

[0270] The DVS test records the dynamic water absorption curve under the conditions of 25°C, relative humidity 0-90% RH, and dm / dt = 0.002% / min. The relevant parameters of the test instrument are shown in Table 2-5:

[0271] Table 2-5 DVS instrument test methods

[0272] 6. High Performance Liquid Chromatography (HPLC) Analysis Method

[0273] The HPLC test method and related parameters are shown in Table 2-6:

[0274] Table 2-6 HPLC analysis method (physiological medium related dissolution test)

[0275] Reagents, excipients and their manufacturers

[0276] Table 3-1 Reagents, excipients and their manufacturers used in the present invention

[0277] API preparation

[0278] The compound API of formula A (I-27) was prepared according to the methods in WO2022068930A1 and WO2023185931A1. The product was characterized by XRPD (Figure 1), DSC (Figure 2) and TGA (Figure 2), and it was determined to be the free base form A in WO2023185931A1.

[0279] Example 1 Screening of solid dispersion excipients

[0280] 1. Research on screening of amorphous solid dispersion carriers

[0281] Table 4-1 Screening study of amorphous solid dispersion carriers

[0282] The compound represented by Formula A has high solubility in a dichloromethane / methanol system (volume ratio of 1:1). This solvent system was selected to prepare a thin film of an amorphous solid dispersion. The experimental steps are as follows:

[0283] 1) Prepare amorphous solid dispersion films in 96-well plates using the mass ratios listed in Table 4-1. Prepare 10 identical 96-well plates, with each well containing 400 μg of the API (generally 10 times the maximum saturated solubility in physiological solution).

[0284] 2) Using the rapid solvent evaporation method, prepare a total of 10 96-well plates (8 for physiologically relevant dissolution, 1 for physical stability assessment, and 1 for excipient control), as detailed in Table 4-1.

[0285] 3) Perform physiologically relevant dissolution experiments on eight 96-well plates containing amorphous solid dispersion films. Samples were collected (96 channels), filtered (96 channels), and diluted (96 channels) at the following time points: 5 and 10 minutes for simulated gastric fluid (SGF); 15 minutes for concentrated simulated fasting intestinal fluid (FaSSIF); and 20, 30, 45, 60, 90, and 120 minutes for sample exchange.

[0286] 4) The dissolution samples were analyzed by HPLC to reconstruct a 96-channel physiologically relevant dissolution experiment.

[0287] 5) The physical stability evaluation plate and the blank excipient plate were subjected to high-throughput orthogonal polarized light imaging at T0 and 7 days (40°C-75% RH) to evaluate the physical stability of the prescription.

[0288] 6) Compare the differences between different formulations and spray-dry the carriers and sedimentation inhibitors with better dynamic dissolution to prepare solid dispersions (SDDs).

[0289] 2. Dissolution of amorphous films with different carrier types and proportions

[0290] The prepared amorphous solid dispersion films containing different types and proportions of API carriers were subjected to dynamic solubility tests in physiologically relevant media, and the dynamic solubility results were compared with those of the amorphous API films. Dynamic dissolution curves were also prepared. The experimental results are shown in Tables 4-4 to 4-8 and Figures 3 to 7.

[0291] The test method is as follows:

[0292] Table 4-2 Dynamic solubility test methods for physiologically relevant media

[0293] Configuration of physiologically relevant media:

[0294] The preparation method of SGF and concentrated FaSSIF solutions is shown in the table below. The pH value of the concentrated FaSSIF solution is pre-adjusted with a 1.0 mol / L NaOH aqueous solution so that the pH value of SGF and concentrated FaSSIF is 6.5 after being evenly mixed at a volume ratio of 1:2.

[0295] Table 4-3 Preparation methods of SGF and concentrated FaSSIF solutions

[0296] * Adjust as needed based on the pH of the mixed solution.

[0297] Table 4-4 Dynamic dissolution results of API and HPMC-AS-LF amorphous films at different ratios

[0298] In Table 4-4, AS LF-1:1 means API: HPMC-AS-LF = 1:1, and AS LF-1:2 means API: HPMC-AS-

[0299] LF=1:2, AS LF-1:3 means API: HPMC-AS-LF=1:3.

[0300] Table 4-5 Dynamic dissolution results of API and Eudragit L100-55 amorphous film at different ratios

[0301] In Table 4-5, L100-55-1:1 means API:Eudragit-L100-55=1:1, L100-55-1:2 means API:Eudragit-L100-55=1:2, and L100-55-1:3 means API:Eudragit-L100-55=1:3.

[0302] Table 4-6 Dynamic dissolution results of API and HPMC-E5 amorphous films at different ratios

[0303] In Table 4-6, E5-1:1 means API:HPMC E5=1:1, E5-1:2 means API:HPMC E5=1:2, and E5-1:3 means API:HPMC E5=1:3.

[0304] Table 4-7 Dynamic dissolution results of API and PVP VA64 amorphous films at different ratios

[0305] In Table 4-7, VA64-1:1 means API:PVP VA64=1:1, VA64-1:2 means API:PVP VA64=1:2, and VA64-1:3 means API:PVP VA64=1:3.

[0306] Table 4-8 Dynamic dissolution results of API and Soluplus amorphous film at different ratios

[0307] In Table 4-8, Soluplus-1:1 means API:Soluplus=1:1, Soluplus-1:2 means API:Soluplus=1:2, and Soluplus-1:3 means API:Soluplus=1:3.

[0308] 3. Summary of amorphous solid dispersion screening research experiments

[0309] From the above experimental results (Tables 4-4 to 4-8 and Figure 3-7), it can be seen that compared with the API control group, the dissolution of SDD prepared by adding carriers (HPMC-E5, HPMC-AS-LF, Eudragit L100-55, PVP VA64, Soluplus) was improved to varying degrees, among which the dissolution improvement of SDD prepared by HPMC-E5, HPMC-AS-LF, and Eudragit L100-55 was the most obvious.

[0310] Example 2 Preparation of SDD by Spray Drying and Investigation of Dissolution Curve

[0311] Based on the above screening results, the carriers HPMC-E5, HPMC-AS-LF, and Eudragit-L100-55 were spray-dried. Acetone was used as the solvent to prepare the solid dispersions as follows:

[0312] (1) Slowly add the carrier to the solvent and continue stirring for at least 60 minutes until it dissolves into a clear state.

[0313] (2) Slowly add the compound to the above solution and continue stirring for at least 120 min until the solution is dissolved and clear.

[0314] (3) The above solution was filtered through a precision filter with a pore size of 5 μm into a transfer tank of appropriate volume.

[0315] (4) The filtered solution is spray-dried. The feed frequency is 20 Hz; the atomization pressure is 0.2 MPa; the inlet air temperature is controlled at about 85-110°C, and the outlet air temperature range is 40-70°C.

[0316] (5) The spray-dried solid dispersion is transferred to a vacuum box for drying under reduced pressure to obtain a dry solid dispersion.

[0317] Finally, the solid dispersions with different formulations were subjected to physiologically relevant dissolution tests.

[0318] Table 5-1 Summary of prescription information for F21 to F28

[0319] The dissolution results are shown in Table 5-2 and Table 5-3.

[0320] Table 5-2 Dissolution curve study of API:HPMC-E5=1:1, 1:2, 1:3

[0321] Table 5-3 Dissolution study of HPMC-AS-LF and Eudragit as SDD carriers

[0322] The dissolution test results of three different carriers of SDD, HPMC-E5, HPMC-AS-LF and Eudragit, in physiologically relevant media show that:

[0323] For the same carrier type, a higher carrier ratio resulted in higher SDD dissolution rates: API:HPMC-AS-LF = 1:3 (dissolution rate 64.1%) > 1:2 (dissolution rate 36.8%) > 1:1 (dissolution rate 10.4%), API:HPMC-E5 = 1:3 (dissolution rate 23.8%) > 1:2 (dissolution rate 15.1%) > 1:1 (dissolution rate 9.1%), and API:Eudragit L100-55 = 1:3 (dissolution rate 31.3%) > API:Eudragit L100-55 = 1:2 (dissolution rate 28.6%). This indicates that the API:HPMC AS-LF = 1:3 ratio exhibited the best dissolution results, with a dissolution rate of 72% in 60 minutes, followed by API:HPMC-AS-LF = 1:2.

[0324] Example 3 Physical stability study

[0325] Experimental steps for physical stability investigation: weigh about 10.0 mg of sample and put it into a 1.5 mL liquid phase vial. Place the sample under different temperature and humidity conditions. At multiple time points within 3 days, 7 days, and 18 days, take samples and perform XRD detection on the sample.

[0326] The results of the stability study experiments are shown in Tables 6-1, 6-2 and 6-3.

[0327] Table 6-1 Prescription API: HPMC-AS-LF (1:1) Physical stability test results

[0328] Table 6-2 Prescription API: HPMC-AS-LF (1:2) Physical stability test results

[0329] Table 6-3 Physical stability test results of prescription API: HPMC-AS-LF (1:3)

[0330] The stability test results above show that under severe conditions (60°C, RH 75%, 70°C, RH 60%, 75°C, RH 30%), the solid-state properties of prescription F24 changed at the 3-day time point, and the XRD results showed crystal transformation. At the 7-day time point, the appearance color of prescriptions F24, F25, and F26 changed. Prescription F25 (Figure 8) showed crystal transformation at 75°C, RH 30%, and the solid-state properties of prescription F26 (Figure 10) did not change significantly.

[0331] However, the appearance, shape, and solid properties of prescription F25 (Figures 9-1 to 9-3) and prescription F26 (Figure 11) did not change significantly after 18 days under the conditions of 40°C, RH 60%, 40°C, RH 75%, and 60°C, RH 30%. XRD results showed that they were still amorphous solid dispersions. Moreover, prescription F26 (Figure 11) remained basically stable under the extreme conditions of 60°C, RH 75% and 70°C, RH 60% for 18 days, and can be stably produced industrially. This shows that prescription F25 and prescription F26 have good physical stability while achieving a higher drug-carrier ratio.

[0332] Test Example 1: Pharmacokinetics of Compounds in Rats, Mice, and Dogs

[0333] Pharmacokinetic studies were conducted in rats using male Sprague-Dawley rats weighing 180-240 g and fasted overnight. Three rats were orally gavaged at 10 mg / kg, and blood was collected before dosing and 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after dosing. Blood samples were centrifuged at 8,000 rpm for 6 minutes at 4°C, and plasma was collected and stored at -20°C. Plasma was collected at each time point and mixed with 3-5 times the volume of acetonitrile containing the internal standard. The mixture was vortexed for 1 minute and centrifuged at 13,000 rpm for 10 minutes at 4°C. The supernatant was then mixed with 3 times the volume of water, and an appropriate amount of the mixture was analyzed by LC-MS / MS. Key pharmacokinetic parameters were analyzed using a non-compartmental model using WinNonlin 7.0 software.

[0334] Mouse pharmacokinetic studies were conducted using male ICR mice weighing 20-25 g and fasted overnight. Three mice were orally gavaged at 10 mg / kg, and blood was collected before dosing and 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after dosing. Blood samples were centrifuged at 6800 g for 6 minutes at 2-8°C, and plasma was collected and stored at -80°C. Plasma was collected at each time point and mixed with 3-5 times the volume of acetonitrile solution containing the internal standard. The mixture was vortexed for 1 minute and centrifuged at 13,000 rpm at 4°C for 10 minutes. The supernatant was mixed with 3 times the volume of water, and an appropriate amount of the mixture was used for LC-MS / MS analysis. Key pharmacokinetic parameters were analyzed using a non-compartmental model using WinNonlin 7.0 software.

[0335] Canine pharmacokinetic studies were conducted using male beagle dogs weighing 8-10 kg, fasted overnight. Three beagle dogs were administered 5 mg / kg orally by gavage. Blood was collected before dosing and 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after dosing. Three other beagle dogs were administered 1 mg / kg intravenously, and blood was collected before dosing and 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after dosing. Blood samples were centrifuged at 8000 rpm for 6 minutes at 4:00 a.m., and plasma was collected and stored at -20°C. Plasma was collected at each time point and mixed with 3-5 times the volume of acetonitrile containing an internal standard, vortexed for 1 minute, and centrifuged at 13,000 rpm for 4 minutes for 10 minutes. The supernatant was mixed with 3 times the volume of water, and the appropriate amount of the mixture was analyzed by LC-MS / MS. Key pharmacokinetic parameters were analyzed using a non-compartmental model using WinNonlin 7.0 software.

[0336] The results of rat experiments showed that compounds I-27, I-28, I-29 and I-30 of the present invention had excellent and comparable pharmacokinetic properties.

[0337] Table 7-1 Pharmacokinetics of test compounds in mice

[0338] The results of mouse experiments showed that compounds I-27, I-28, I-29 and I-30 of the present invention have excellent and comparable pharmacokinetic properties.

[0339] Table 7-2 Pharmacokinetics of Test Compounds in Dogs

[0340] The test results show that the compounds I-29 and I-30 of the present invention have low clearance rates after intravenous administration, high exposure levels after oral and intravenous administration, long half-lives, similar pharmacokinetic properties, and good drugability.

[0341] Test Example 2: Thermodynamic Solubility Test

[0342] Fasting state simulated gastric fluid FaSSGF at pH 1.6 (1 L solution contains 80 μM sodium taurocholate, 20 μM lecithin, 0.1 g pepsin, 34.2 mM sodium chloride), fasting state simulated intestinal fluid FaSSIF at pH 6.5 (1 L solution contains 3 mM sodium taurocholate, 0.2 mM lecithin, 38.4 mM sodium hydroxide, 68.62 mM sodium chloride, 19.12 mM maleic acid) and pH 7.4 phosphate buffered saline PBS (1 L solution contains 100 mM phosphate buffer, 11 g sodium bicarbonate, 3.5 g sodium dihydrogen phosphate dihydrate) were prepared as assay buffers.

[0343] Accurately weigh the compound and prepare a 4 mg / mL working solution using assay buffers of varying pH values. Shake at 1000 rpm for 1 hour and equilibrate overnight at room temperature. Centrifuge the sample at 12000 rpm for 10 minutes to remove any undissolved particles. Transfer the supernatant to a fresh tube and measure the compound concentration by LCMS / MS.

[0344] The experimental results showed that compounds I-27, I-28, I-29, and I-30 all had good solubility.

[0345] Test Example 3: Pharmacokinetic Study of SDD Prescription Dogs

[0346] Canine pharmacokinetic study using male beagles, 9-11 kg, fasted overnight. 9 beagles were randomly divided into 3 groups, 3 in each group, and the preparations were prepared using the respective prescriptions of this application and administered orally by gavage at a dose of 20 mg / kg. Approximately 0.5 mL of blood was collected before administration and 15 minutes after administration, as well as 1, 2, 4, 8, and 24 hours later, and transferred to an anticoagulant tube containing EDTA-K2. Plasma was collected by centrifugation at 4°C and 1500 g for 10 minutes. After treatment with acetonitrile protein precipitation, an appropriate amount of the mixture was taken for LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed using the non-compartmental model of WinNonlin 7.0 software. The results are shown in Table 7-3.

[0347] Table 7-3 Pharmacokinetic parameters in dogs (oral administration)

[0348] The results of the dog PK experiment show that the SDD prescription API: HMPC-AS-LF 1:3 was administered at a higher dose and had a good exposure, which could maintain supersaturated concentration for a relatively long time and maintain stable and continuous in vivo absorption after 4 hours.

[0349] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A solid dispersion of a P2X3 receptor antagonist, characterized in that, The solid dispersion comprises: a P2X3 receptor antagonist and a pharmaceutically acceptable carrier; Among them, the P2X3 receptor antagonist is selected from the compounds represented by the following formula I, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs: Wherein, R 1 independently selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted with 1-5 identical or different halogen atoms; X is a halogen; m is selected from the integers 1, 2 or 3; L is -(CH2) n -, where n is selected from the integers 0, 1, or 2; R 2 independently selected from hydrogen, unsubstituted or R-substituted C1-C6 alkyl, unsubstituted or R-substituted C3-C7 cycloalkyl, unsubstituted or R-substituted 5-8 membered aryl, unsubstituted or R-substituted 5-10 membered heteroaryl, unsubstituted or R-substituted 4-7 membered heterocycloalkyl, unsubstituted or R-substituted 6-12 membered heterobicycloalkyl; wherein the R-substituted C1-C6 alkyl, the R-substituted C3-C7 cycloalkyl, the R-substituted 5-8 membered aryl, the R-substituted 5-10 membered heteroaryl, the R-substituted 4-7 membered heterocycloalkyl, or the R-substituted 6-12 membered heterobicycloalkyl, the R substitution is one or more substitutions, and the R are each independently selected from the following substituents: C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens, halogen, -OH, -NR a R a 、-COOR a 、 oxo(=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH or deuterated C1-C6 alkyl; when there are multiple substituents, the substituents are identical or different; a a a a a a a a a a a a a a b R c 、-COOR 4 、 oxo(=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH or deuterated C1-C6 alkyl; when there are multiple substituents, the substituents are identical or different; a b R c R 4 4 、 oxo(=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH or deuterated C1-C6 alkyl; when there are multiple substituents, the substituents are identical or different; Among the unsubstituted or R-substituted 5- to 10-membered heteroaryl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; among the unsubstituted or R-substituted a 4- to 7-membered heterocycloalkyl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; among the unsubstituted or R-substituted a 6- to 12-membered heterobicycloalkyl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; a Among the unsubstituted or R-substituted 6- to 12-membered heterobicycloalkyl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; R 3 independently selected from hydrogen, or C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogen atoms; R 4 independently selected from hydrogen or C1-C4 alkyl; R b and R c are independently selected from hydrogen or C1-C4 alkyl; A is independently an unsubstituted or R-substituted 5- to 10-membered heteroaryl group, and in the R-substituted 5- to 10-membered heteroaryl group, e the R substitution is one or more substitutions, and each R is independently selected from the following substituents: halogen, C1-C3 alkyl which is unsubstituted or substituted by 1-5 identical or different halogen atoms, or -O-(C1-C3 alkyl) which is unsubstituted or substituted by 1-5 identical or different halogen atoms; when there are multiple substituents, the substituents are identical or different. e in the R-substituted 5- to 10-membered heteroaryl group, e the R substitution is one or more substitutions, and e each R is independently selected from the following substituents: halogen, C1-C3 alkyl which is unsubstituted or substituted by 1-5 identical or different halogen atoms, or -O-(C1-C3 alkyl) which is unsubstituted or substituted by 1-5 identical or different halogen atoms; when there are multiple substituents, the substituents are identical or different.

2. The solid dispersion according to claim 1, wherein The solid dispersion is an amorphous solid dispersion; Preferably, the P2X3 receptor antagonist exists in an amorphous form; Preferably, the pharmaceutically acceptable carrier is a pharmaceutically acceptable polymeric carrier; Preferably, the pharmaceutically acceptable carrier is selected from any one or more of the following: 1) Cellulose derivative carriers; such as hypromellose E5, hypromellose acetate succinate LF, hydroxypropyl cellulose, hypromellose phthalate; 2) Polyacrylic resin carriers; such as Eudragit L100-55, Eudragit S100, Eudragit L100; 3) Vinyl polymer carriers; such as polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copovidone VA64, copovidone S630; Preferably, the pharmaceutically acceptable carrier is selected from any one or more of the following: hydroxypropyl methylcellulose HPMC, copovidone PVP, hypromellose acetate succinate HPMC-AS, polymethacrylate, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; preferably, selected from any one or more of the following: hydroxypropyl methylcellulose HPMC, hypromellose acetate succinate HPMC-AS, polymethacrylate; Preferably, the pharmaceutically acceptable carrier is selected from any one or more of the following: hypromellose E5, copovidone VA64, hypromellose acetate succinate LF, Eudragit L100-55, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; preferably, selected from any one or more of the following: hypromellose E5, hypromellose acetate succinate LF, Eudragit L100-55.

3. The solid dispersion according to claim 1 or 2, wherein The mass ratio of the P2X3 receptor antagonist to the pharmaceutically acceptable carrier is 1:0.1 - 10, preferably 1:0.5 - 5, such as 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5; Preferably, the solid dispersion comprises the following components: P2X3 receptor antagonist 10wt% - 60wt% Pharmaceutically acceptable carrier 40wt% - 90wt%; Preferably, the solid dispersion comprises the following components: P2X3 receptor antagonist 20wt% - 55wt% Pharmaceutically acceptable carrier 45wt% - 80wt%; Preferably, the solid dispersion comprises the following components: P2X3 receptor antagonist 25wt% - 50wt% (such as 25wt%, 33wt%, 33.3wt%, 50wt%) Pharmaceutically acceptable carrier 50 wt% - 75 wt% (e.g., 50 wt%, 67 wt%, 66.7 wt%, 75 wt%); Preferably, the solid dispersion comprises the following components: A P2X3 receptor antagonist and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is not less than 66.7 wt%; Preferably, the solid dispersion comprises the following components: A P2X3 receptor antagonist and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is not less than 75 wt%; Preferably, the solid dispersion comprises the following components: P2X3 receptor antagonist 25 wt%, 33.3 wt%, 50 wt% Pharmaceutically acceptable carrier 50 wt%, 66.7 wt%, 75 wt% The pharmaceutically acceptable carrier is selected from hypromellose E5, hypromellose acetate succinate LF, and Eudragit L100-55; Preferably, the solid dispersion comprises the following components: P2X3 receptor antagonist 25 wt% Pharmaceutically acceptable carrier 75 wt% The pharmaceutically acceptable carrier is selected from hypromellose E5, hypromellose acetate succinate LF, and Eudragit L100-55; Preferably, the solid dispersion comprises the following components: P2X3 receptor antagonist 33.3 wt% Pharmaceutically acceptable carrier 66.7 wt% The pharmaceutically acceptable carrier is selected from hypromellose E5, hypromellose acetate succinate LF, and Eudragit L100-55; Preferably, the solid dispersion comprises the following components: A P2X3 receptor antagonist and hypromellose acetate succinate LF, wherein the proportion of hypromellose acetate succinate LF is not less than 75 wt%; Preferably, the solid dispersion comprises the following components: P2X3 receptor antagonist 25 wt% Hypromellose acetate succinate LF 75 wt%; Preferably, the solid dispersion comprises the following components: A P2X3 receptor antagonist and hypromellose acetate succinate LF, wherein the proportion of hypromellose acetate succinate LF is not less than 66.7 wt%; Preferably, the solid dispersion comprises the following components: P2X3 receptor antagonist 33.3 wt% Hypromellose acetate succinate LF 66.7 wt%; Preferably, the solid dispersion optionally further comprises a solvent; Preferably, the solvent is a volatile solvent; Preferably, the solvent is selected from any one or more of the following: dichloromethane, ethanol, acetone, methanol; preferably acetone, dichloromethane-methanol mixed solvent; Preferably, the solid dispersion optionally further comprises any one or several of the following: sweeteners, flavoring agents, coloring agents, surfactants, fillers, lubricants, disintegrants, disintegration promoters, recrystallization inhibitors, defoaming agents, antioxidants, and pH regulators.

4. The solid dispersion according to any one of claims 1 to 3, characterized in that The compound shown by Formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is: Wherein, R 1 independently selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted with 1-5 identical or different halogen atoms; X is a halogen; m is selected from the integers 1, 2, or 3; L is -(CH2) n -, where n is selected from the integers 0, 1, or 2; R 2 independently selected from hydrogen, unsubstituted or R-substituted C1-C6 alkyl, unsubstituted or R-substituted C3-C7 cycloalkyl, unsubstituted or R-substituted 5-8 membered aryl, unsubstituted or R-substituted 5-10 membered heteroaryl, unsubstituted or R-substituted 4-7 membered heterocycloalkyl, unsubstituted or R-substituted 6-12 membered heterobicycloalkyl; wherein the R-substituted C1-C6 alkyl, the R-substituted C3-C7 cycloalkyl, the R-substituted 5-8 membered aryl, the R-substituted 5-10 membered heteroaryl, the R-substituted 4-7 membered heterocycloalkyl, or the R-substituted 6-12 membered heterobicycloalkyl, each of the substitutions independently refers to substitution by one or more of the following substituents: C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens, halogen, -OH, -NR a R a 、 -COOR a 、 oxo(=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl) or deuterated C1-C6 alkyl; when there are multiple substituents, the substituents are identical or different; a substituted 5-10 membered heteroaryl, unsubstituted or R-substituted 4-7 membered heterocycloalkyl, unsubstituted or R-substituted 6-12 membered heterobicycloalkyl; the R-substituted C1-C6 alkyl, the R-substituted C3-C7 cycloalkyl, the R-substituted 5-8 membered aryl, the R-substituted 5-10 membered heteroaryl, the R-substituted 4-7 membered heterocycloalkyl, or the R-substituted 6-12 membered heterobicycloalkyl, each of the substitutions independently refers to substitution by one or more of the following substituents: C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens, halogen, -OH, -NR a R a substituted 6-12 membered heterobicycloalkyl; the R-substituted C1-C6 alkyl, the R-substituted C3-C7 cycloalkyl, the R-substituted 5-8 membered aryl, the R-substituted 5-10 membered heteroaryl, the R-substituted 4-7 membered heterocycloalkyl, or the R-substituted 6-12 membered heterobicycloalkyl, each of the substitutions independently refers to substitution by one or more of the following substituents: C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens, halogen, -OH, -NR a R a substituted C3-C7 cycloalkyl, unsubstituted or R-substituted 5-8 membered aryl, unsubstituted or R-substituted 5-10 membered heteroaryl, unsubstituted or R-substituted 4-7 membered heterocycloalkyl, or the R-substituted 6-12 membered heterobicycloalkyl, each of the substitutions independently refers to substitution by one or more of the following substituents: C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens, halogen, -OH, -NR a R a substituted 5-10 membered heteroaryl, unsubstituted or R-substituted 4-7 membered heterocycloalkyl, or the R-substituted 6-12 membered heterobicycloalkyl, each of the substitutions independently refers to substitution by one or more of the following substituents: C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens, halogen, -OH, -NR a R a substituted 4-7 membered heterocycloalkyl, or the R-substituted 6-12 membered heterobicycloalkyl, each of the substitutions independently refers to substitution by one or more of the following substituents: C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens, halogen, -OH, -NR b R c 、 -COOR 4 、 oxo(=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl) or deuterated C1-C6 alkyl; when there are multiple substituents, the substituents are identical or different; wherein the unsubstituted or R-substituted 5- to 10-membered heteroaryl has a heteroatom selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; the unsubstituted or R-substituted 4- to 7-membered heterocycloalkyl has a heteroatom selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; the unsubstituted or Ra-substituted 6- to 12-membered heterobicycloalkyl has a heteroatom selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; a Among the unsubstituted or R-substituted 5- to 10-membered heteroaryls, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; the unsubstituted or R-substituted a Among the 4- to 7-membered heterocycloalkyls, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; among the 6- to 12-membered heterobicycloalkyls which are unsubstituted or substituted by Ra, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; R 3 independently selected from hydrogen, or a C1-C4 alkyl group which is unsubstituted or substituted by 1-5 identical or different halogen atoms; R 4 independently selected from hydrogen or C1-C4 alkyl; R b and R c are independently selected from hydrogen or C1-C4 alkyl; A is independently an unsubstituted or R-substituted 5- to 10-membered heteroaryl group, and in the R-substituted 5- to 10-membered heteroaryl group, e the R substitution is one or more substitutions, and each R is independently selected from the following substituents: halogen, C1-C3 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens, or -O-(C1-C3 alkyl) which is unsubstituted or substituted by 1-5 identical or different halogens; when there are multiple substituents, the substituents are identical or different; e in the R-substituted 5- to 10-membered heteroaryl group, e the R substitution is one or more substitutions, and e each R is independently selected from the following substituents: halogen, C1-C3 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens, or -O-(C1-C3 alkyl) which is unsubstituted or substituted by 1-5 identical or different halogens; when there are multiple substituents, the substituents are identical or different; Preferably, when R 1 is a halogen, the halogen is F, Cl, Br, I, preferably Cl; Preferably, when R 1 is an unsubstituted C1-C4 alkyl group, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, preferably methyl or ethyl; Preferably, when R 1 is a C1-C4 alkyl group substituted by 1-5 identical or different halogen atoms, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, preferably methyl or ethyl; Preferably, when R 1 is a C1-C4 alkyl group substituted by 1-5 identical or different halogens, the halogen is F, Cl, Br, I, preferably Cl or F; Preferably, when X is a halogen, the halogen is one of F or Cl; Preferably, m is selected from the integers 1, 2 or 3, more preferably 1; Preferably, when L is -(CH2) n -, n is an integer of 0, 1 or 2, preferably n is 0 or 1; Preferably, when R 2 is an unsubstituted or R a -substituted C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C4 alkyl group, preferably sec-butyl; Preferably, when R 2 is an unsubstituted or R a -substituted C1-C6 alkyl group, the C1-C6 alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; Preferably, when R 2 is unsubstituted or substituted by R a and is a C3-C7 cycloalkyl group, the C3-C7 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl; Preferably, when R 2 is an unsubstituted or R a -substituted 4- to 7-membered heterocycloalkyl, the 4- to 7-membered heterocycloalkyl is a 4-, 5- or 6-membered heterocycloalkyl; Preferably, when R 2 is an unsubstituted or R a -substituted 4- to 7-membered heterocycloalkyl, the heteroatom in the 4- to 7-membered heterocycloalkyl is one or more of N, S, O, and P, preferably one or more of N or O; Preferably, when R 2 is an unsubstituted or R a -substituted 4- to 7-membered heterocycloalkyl, the number of heteroatoms in the 4- to 7-membered heterocycloalkyl is 1 to 3, preferably 1 or 2; Preferably, when R 2 is an unsubstituted or R a -substituted 4- to 7-membered heterocycloalkyl group, the number of said R a is 1 to 3, preferably 1; Preferably, R a is a hydroxyl group; Preferably, when R a is a halogen, the halogen is F, Cl, Br, I, preferably F or Cl; Preferably, when R a is a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C3 alkyl group, preferably methyl; Preferably, when R a is a deuterated C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C3 deuterated alkyl group, preferably Preferably, when R a is -(C1-C6 alkylene)-OH, the C1-C6 alkylene is a C1-C4 alkylene, preferably methylene, ethylene, n-propylene or isopropylidene, more preferably methylene; Preferably, R 3 is hydrogen; Preferably, when R 3 is an unsubstituted C1-C4 alkyl group, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, preferably methyl; Preferably, when A is a 5- to 10-membered heteroaryl group substituted by R e the 5- to 10-membered heteroaryl group is a 6-membered heteroaryl group, preferably pyrimidine or pyridazine; Preferably, when A is a 5- to 10-membered heteroaryl group substituted by R e , the R e substitution is a single substitution; Preferably, when A is a 5- to 10-membered heteroaryl group substituted by R e , said R e is a C1-C3 alkyl group substituted by 1-5 identical or different halogen atoms, preferably trifluoromethyl; Preferably, when A is a 5- to 10-membered heteroaryl group substituted by R e , said R e is an unsubstituted C1-C3 alkyl group, preferably methyl; Preferably, -L-R 2 selected from Preferably, -L-R 2 is Preferably, -L-R 2 selected from Preferably, R 1 is methyl, ethyl or Cl; Preferably, -L-R 2 selected from Preferably, -L-R 2 selected from Preferably, R 3 is methyl or hydrogen; Preferably, A is selected from Preferably, the compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is: Wherein, R 1 selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted with 1-5 identical or different halogen atoms; L is -(CH2) n -, where n is selected from the integers 0, 1, or 2; R 2 independently selected from hydrogen, unsubstituted or R a -substituted C1-C6 alkyl, unsubstituted or R a -substituted C3-C7 cycloalkyl, unsubstituted or R a -substituted 5-8-membered aryl, unsubstituted or R a -substituted 5-10-membered heteroaryl, unsubstituted or R a -substituted 4-7-membered heterocycloalkyl, unsubstituted or R a -substituted 6-12-membered heterobicycloalkyl; wherein the R a -substituted C1-C6 alkyl, the R a -substituted C3-C7 cycloalkyl, the R a -substituted 5-8-membered aryl, the R a -substituted 5-10-membered heteroaryl, the R a -substituted 4-7-membered heterocycloalkyl, or the R a -substituted 6-12-membered heterobicycloalkyl, wherein the R a substitution is one or more substitutions, and the R a each independently selected from the following substituents: C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens, halogen, -OH, -NR b R c , -COOR 4 , oxo(=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH and deuterated C1-C6 alkyl; when there are multiple substituents, the substituents are identical or different; wherein the unsubstituted or R a -substituted 5- to 10-membered heteroaryl, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; the unsubstituted or R a -substituted 4- to 7-membered heterocycloalkyl, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; the unsubstituted or R a -substituted 6- to 12-membered heterobicycloalkyl, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; R 4 independently selected from hydrogen or C1-C4 alkyl; R b and R c are independently selected from hydrogen or C1-C4 alkyl; Preferably, the compound shown in Formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is: Wherein, R 1 selected from a halogen, a C3-C6 cycloalkyl group, or a C1-C4 alkyl group which is unsubstituted or substituted with 1-5 identical or different halogen atoms; L is -(CH2) n -, where n is selected from the integers 0, 1, or 2; R 2 independently selected from hydrogen, unsubstituted or replaced by R a Substituted C1-C6 alkyl, unsubstituted or replaced by R a Substituted C3-C7 cycloalkyl, unsubstituted or replaced by R a substituted 5-8 membered aryl, unsubstituted or R a substituted 5-10 membered heteroaryl, unsubstituted or R a substituted 4-7 membered heterocycloalkyl, unsubstituted or replaced by R a substituted 6-12 membered heterobicycloalkyl; said R a Substituted C1-C6 alkyl, the R a Substituted C3-C7 cycloalkyl, the R a substituted 5-8 membered aryl, the a substituted 5-10 membered heteroaryl, the a substituted 4-7 membered heterocycloalkyl, or said a In the substituted 6-12 membered heterobicycloalkyl, the R a Substituted with one or more substitutions, the R a Each is independently selected from the following substituents: C1-C4 alkyl, halogen, -OH, -NR, unsubstituted or substituted by 1-5 identical or different halogens. b R c 、-COOR 4 , oxo (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH and deuterated C1-C6 alkyl; when there are multiple substituents, the substituents are the same or different; wherein the unsubstituted or R-substituted 5- to 10-membered heteroaryl has a heteroatom selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; the unsubstituted or R-substituted 4- to 7-membered heterocycloalkyl has a heteroatom selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; the unsubstituted or R-substituted 6- to 12-membered heterobicycloalkyl has a heteroatom selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; a substituted 5-10 membered heteroaryl, the heteroatom is selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3; unsubstituted or R a substituted 4-7 membered heterocycloalkyl, the heteroatom is selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3; unsubstituted or R a substituted 6-12 membered heterobicycloalkyl, the heteroatom is selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3; R 4 independently selected from hydrogen or C1-C4 alkyl; R b and R c are independently selected from hydrogen or C1-C4 alkyl; Preferably, the compound represented by Formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is: Wherein, R 1 selected from a halogen, a C3-C6 cycloalkyl group, or a C1-C4 alkyl group which is unsubstituted or substituted by 1-5 identical or different halogen atoms; L is -(CH2) n -, where n is selected from the integers 0, 1 or 2; R 2 independently selected from hydrogen, unsubstituted or replaced by R a Substituted C1-C6 alkyl, unsubstituted or replaced by R a Substituted C3-C7 cycloalkyl, unsubstituted or replaced by R a substituted 5-8 membered aryl, unsubstituted or R a substituted 5-10 membered heteroaryl, unsubstituted or R a substituted 4-7 membered heterocycloalkyl, unsubstituted or replaced by R a substituted 6-12 membered heterobicycloalkyl; said R a Substituted C1-C6 alkyl, the R a Substituted C3-C7 cycloalkyl, the R a substituted 5-8 membered aryl, the a substituted 5-10 membered heteroaryl, the a substituted 4-7 membered heterocycloalkyl, or said a In the substituted 6-12 membered heterobicycloalkyl, the R a Substituted with one or more substitutions, the R a Each is independently selected from the following substituents: C1-C4 alkyl, halogen, -OH, -NR, unsubstituted or substituted by 1-5 identical or different halogens. b R c 、-COOR 4 , oxo (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH and deuterated C1-C6 alkyl; when there are multiple substituents, the substituents are the same or different; Among them, unsubstituted or substituted by R a In the unsubstituted or R-substituted 5- to 10-membered heteroaryl group, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; unsubstituted or substituted by R a In the unsubstituted or R-substituted 4- to 7-membered heterocycloalkyl group, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; unsubstituted or substituted by R a In the unsubstituted or R-substituted 6- to 12-membered heterobicycloalkyl group, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; R 4 independently selected from hydrogen or C1-C4 alkyl; R b and R c are independently selected from hydrogen or C1-C4 alkyl; Preferably, the compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is: Wherein, R 1 selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted with 1-5 identical or different halogen atoms; L is -(CH2) n -, where n is selected from the integers 0, 1, or 2; R 2 independently selected from hydrogen, unsubstituted or R-substituted C1-C6 alkyl, unsubstituted or R-substituted C3-C7 cycloalkyl, unsubstituted or R-substituted 5-8 membered aryl, unsubstituted or R-substituted 5-10 membered heteroaryl, unsubstituted or R-substituted 4-7 membered heterocycloalkyl, unsubstituted or R-substituted 6-12 membered heterobicycloalkyl; wherein the R-substituted C1-C6 alkyl, the R-substituted C3-C7 cycloalkyl, the R-substituted 5-8 membered aryl, the R-substituted 5-10 membered heteroaryl, the R-substituted 4-7 membered heterocycloalkyl, or the R-substituted 6-12 membered heterobicycloalkyl, the R substitution is one or more substitutions, and the Rs are each independently selected from the following substituents: C1-C4 alkyl which is unsubstituted or substituted with 1-5 identical or different halogens, halogen, -OH, -NR a substituted C1-C6 alkyl, unsubstituted or R a substituted C3-C7 cycloalkyl, unsubstituted or R a substituted 5-8 membered aryl, unsubstituted or R a substituted 5-10 membered heteroaryl, unsubstituted or R a substituted 4-7 membered heterocycloalkyl, unsubstituted or R a substituted 6-12 membered heterobicycloalkyl; the R a substituted C1-C6 alkyl, the R a substituted C3-C7 cycloalkyl, the R a substituted 5-8 membered aryl, the R a substituted 5-10 membered heteroaryl, the R a substituted 4-7 membered heterocycloalkyl, or the R a substituted 6-12 membered heterobicycloalkyl, wherein the R a substitution is one or more substitutions, and the R a s are each independently selected from the following substituents: C1-C4 alkyl which is unsubstituted or substituted with 1-5 identical or different halogens, halogen, -OH, -NR b R c 、-COOR 4 、, oxo (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH, and deuterated C1-C6 alkyl; when there are multiple substituents, the substituents are identical or different; Among the unsubstituted or R-substituted 5- to 10-membered heteroaryl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; the unsubstituted or R-substituted a Among the 4- to 7-membered heterocycloalkyl groups that are unsubstituted or substituted with R, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; the unsubstituted or R-substituted a Among the 6- to 12-membered heterobicycloalkyl groups that are unsubstituted or substituted with R, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; a Among the 6- to 12-membered heterobicycloalkyl groups that are unsubstituted or substituted with R, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; R 4 independently selected from hydrogen or C1-C4 alkyl; R b and R c are independently selected from hydrogen or C1-C4 alkyl; Preferably, the compound shown in Formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is: Wherein, R 1 independently selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted with 1-5 identical or different halogen atoms; L is -(CH2) n -, where n is selected from the integers 0, 1 or 2; R 2 independently selected from hydrogen, unsubstituted or replaced by R a Substituted C1-C6 alkyl, unsubstituted or replaced by R a Substituted C3-C7 cycloalkyl, unsubstituted or replaced by R a substituted 5-8 membered aryl, unsubstituted or R a substituted 5-10 membered heteroaryl, unsubstituted or R a substituted 4-7 membered heterocycloalkyl, unsubstituted or replaced by R a substituted 6-12 membered heterobicycloalkyl; said R a Substituted C1-C6 alkyl, the R a Substituted C3-C7 cycloalkyl, the R a substituted 5-8 membered aryl, the a substituted 5-10 membered heteroaryl, the a substituted 4-7 membered heterocycloalkyl, or said a In the substituted 6-12 membered heterobicycloalkyl, the R a Substituted with one or more substitutions, the R a Each is independently selected from the following substituents: C1-C4 alkyl, halogen, -OH, -NR, unsubstituted or substituted by 1-5 identical or different halogens. b R c 、-COOR 4 , oxo (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH and deuterated C1-C6 alkyl; when there are multiple substituents, the substituents are the same or different; wherein the unsubstituted or R-substituted 5- to 10-membered heteroaryl has a heteroatom selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; the unsubstituted or R-substituted 4- to 7-membered heterocycloalkyl has a heteroatom selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; the unsubstituted or R-substituted 6- to 12-membered heterobicycloalkyl has a heteroatom selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; a substituted 5- to 10-membered heteroaryl, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; the unsubstituted or R a substituted 4- to 7-membered heterocycloalkyl, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; the unsubstituted or R a substituted 6- to 12-membered heterobicycloalkyl, the heteroatom is selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; R 4 independently selected from hydrogen or C1-C4 alkyl; R b and R c are independently selected from hydrogen or C1-C4 alkyl; Preferably, the compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is: Wherein, R 1 independently selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogen atoms; L is -(CH2) n -, where n is selected from the integers 0, 1, or 2; R 2 independently selected from hydrogen, unsubstituted or replaced by R a Substituted C1-C6 alkyl, unsubstituted or replaced by R a Substituted C3-C7 cycloalkyl, unsubstituted or replaced by R a substituted 5-8 membered aryl, unsubstituted or R a substituted 5-10 membered heteroaryl, unsubstituted or R a substituted 4-7 membered heterocycloalkyl, unsubstituted or replaced by R a substituted 6-12 membered heterobicycloalkyl; said R a Substituted C1-C6 alkyl, the R a Substituted C3-C7 cycloalkyl, the R a substituted 5-8 membered aryl, the a substituted 5-10 membered heteroaryl, the a substituted 4-7 membered heterocycloalkyl, or said a In the substituted 6-12 membered heterobicycloalkyl, the R a Substituted with one or more substitutions, the R a Each is independently selected from the following substituents: C1-C4 alkyl, halogen, -OH, -NR, unsubstituted or substituted by 1-5 identical or different halogens. b R c 、-COOR 4 , oxo (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH and deuterated C1-C6 alkyl; when there are multiple substituents, the substituents are the same or different; wherein the unsubstituted or R-substituted 5- to 10-membered heteroaryl has heteroatoms selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; the unsubstituted or R-substituted 4- to 7-membered heterocycloalkyl has heteroatoms selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; the unsubstituted or R-substituted 6- to 12-membered heterobicycloalkyl has heteroatoms selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; a substituted 5- to 10-membered heteroaryl, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; the unsubstituted or R a substituted 4- to 7-membered heterocycloalkyl, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; the unsubstituted or R a substituted 6- to 12-membered heterobicycloalkyl, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; R 4 independently selected from hydrogen or C1-C4 alkyl; Preferably, the compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is: Wherein, R 1 independently selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted with 1-5 identical or different halogen atoms; L is -(CH2) n -, where n is selected from the integers 0, 1 or 2; R 2 independently selected from hydrogen, unsubstituted or replaced by R a Substituted C1-C6 alkyl, unsubstituted or replaced by R a Substituted C3-C7 cycloalkyl, unsubstituted or replaced by R a substituted 5-8 membered aryl, unsubstituted or R a substituted 5-10 membered heteroaryl, unsubstituted or R a substituted 4-7 membered heterocycloalkyl, unsubstituted or replaced by R a substituted 6-12 membered heterobicycloalkyl; said R a Substituted C1-C6 alkyl, the R a Substituted C3-C7 cycloalkyl, the R a substituted 5-8 membered aryl, the a substituted 5-10 membered heteroaryl, the a substituted 4-7 membered heterocycloalkyl, or said a In the substituted 6-12 membered heterobicycloalkyl, the R a Substituted with one or more substitutions, the R a Each is independently selected from the following substituents: C1-C4 alkyl, halogen, -OH, -NR, unsubstituted or substituted by 1-5 identical or different halogens. b R c 、-COOR 4 , oxo (=O), -C(O)O-(C1-C4 alkyl), -C(O)-(C1-C4 alkyl), -(C1-C6 alkylene)-OH and deuterated C1-C6 alkyl; when there are multiple substituents, the substituents are the same or different; Among the unsubstituted or R-substituted 5- to 10-membered heteroaryl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; the unsubstituted or R-substituted a Among the 4- to 7-membered heterocycloalkyl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; the unsubstituted or R-substituted a Among the 6- to 12-membered heterobicycloalkyl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; a Among the unsubstituted or R-substituted 6- to 12-membered heterobicycloalkyl groups, the heteroatoms are selected from one or more of N, S, O, and P, and the number of heteroatoms is 1 to 3; R 4 independently selected from hydrogen or C1-C4 alkyl; R b and R c are independently selected from hydrogen or C1-C4 alkyl.

5. The solid dispersion according to any one of claims 1 to 4, characterized in that, The compound represented by Formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is selected from any of the following compounds:

6. The solid dispersion according to any one of claims 1-4, characterized in that, The compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is selected from any of the following compounds: Preferably, the P2X3 receptor antagonist is selected from the compounds represented by Formula A (Formula I-27), their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

7. The preparation process of the solid dispersion according to any one of claims 1-6, characterized in that, The preparation process comprises the following steps: (1) Add each component into a solvent and stir to dissolve; (2) Dry the dissolved solution to obtain the solid dispersion; Preferably, step (1) is specifically: first add a pharmaceutically acceptable carrier into a solvent and stir to dissolve; then add a P2X3 receptor antagonist and continue to stir to dissolve; Preferably, the drying method in step (2) is selected from spray drying; Preferably, step (2) is specifically: filter the dissolved solution under pressure into a transfer tank, and then dry the filtered solution to obtain the solid dispersion; Preferably, filter under pressure into a transfer tank through a precision filter with a certain pore size; Preferably, after the drying treatment in step (2), optionally further perform reduced-pressure drying on the dried solid dispersion; Preferably, in step (1), the stirring time is not less than 60 min (for example, not less than 120 min); preferably 60 - 120 min, 120 - 180 min; Preferably, in step (2), the pore size of the precision filter is 1 μm - 22 μm, preferably 5 μm; Preferably, in step (2), the feeding frequency of spray drying is 5 Hz - 50 Hz, preferably 10 Hz - 20 Hz; And / or, the atomization pressure is 0.1 Mpa - 1.0 Mpa, preferably 0.1 Mpa - 0.2 Mpa; And / or, the inlet air temperature is 60°C - 120°C, preferably 85°C - 110°C; And / or, the outlet air temperature is 40°C - 70°C, preferably 50°C - 55°C.

8. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the solid dispersion according to any one of claims 1 - 6 and a pharmaceutically acceptable pharmaceutical carrier, diluent or excipient.

9. Use of the solid dispersion according to any one of claims 1 - 6 and the pharmaceutical composition according to claim 8 in the preparation of a drug for treating and / or preventing P2X3-related diseases, characterized in that, Preferably, the P2X3-related diseases are pain, respiratory diseases or urogenital system diseases; Preferably, the pain is chronic pain, acute pain, endometriosis pain, neuropathic pain, back pain, cancer pain, inflammatory pain, surgical pain, migraine or visceral pain; And / or, the urogenital system diseases are reduced bladder capacity, frequent urination, urge incontinence, stress incontinence, overactive bladder, benign prostatic hyperplasia, prostatitis, detrusor hyperreflexia, urinary frequency, nocturia, urgency, overactive bladder, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, cystitis; And / or, the respiratory diseases are chronic obstructive pulmonary disease, pulmonary hypertension, pulmonary fibrosis, asthma and obstructive sleep apnea, chronic cough, refractory chronic cough and acute cough.

10. A method for treating and / or preventing P2X3-related diseases, characterized in that, The method includes administering an effective amount of the solid dispersion according to any one of claims 1-6 and the pharmaceutical composition according to claim 8 to a patient suffering from a P2X3-related disease; Preferably, the P2X3-related disease is pain, a respiratory disease or a urogenital disease; Preferably, the pain is chronic pain, acute pain, endometriosis pain, neuropathic pain, back pain, cancer pain, inflammatory pain, surgical pain, migraine or visceral pain; And / or, the urogenital disease is reduced bladder capacity, frequent urination, urge incontinence, stress incontinence, overactive bladder, benign prostatic hyperplasia, prostatitis, detrusor hyperreflexia, pollakiuria, nocturia, urgency, overactive bladder, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, cystitis; And / or, the respiratory disease is chronic obstructive pulmonary disease, pulmonary hypertension, pulmonary fibrosis, asthma and obstructive apnea, chronic cough, refractory chronic cough and acute cough.

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