Solid dispersion of P2X3 receptor antagonist and preparation process thereof

Abstract

The invention provides the solid dispersion containing the P2X3 receptor antagonist compound shown in the formula I. The solid dispersion can remarkably improve the solubility of the compound shown in the formula I, greatly improve the dissolution rate and bioavailability of the medicine and ensure the treatment effect of the medicine. Meanwhile, the solid dispersion disclosed by the invention is good in stability, does not generate crystal form transformation in a storage process, does not generate obvious growth of related substances, and improves the safety of clinical application of the medicine.

Description

[0001] This application claims the priority benefit of the prior application filed by the applicant:

[0002] on December 29, 2023, with the Patent Application Number 202311872796.5 and the title "A Solid Dispersion of a P2X3 Receptor Antagonist and Its Preparation Process" submitted to the China National Intellectual Property Administration;

[0003] on December 23, 2024, with the Patent Application Number 202411907674.X and the title "A Solid Dispersion of a P2X3 Receptor Antagonist and Its Preparation Process" submitted to the China National Intellectual Property Administration;

[0004] The full text of the prior application is incorporated into the present invention by reference. Technical Field

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

[0006] P2X3 is a subunit of the ATP-gated ion channel and belongs to the purinergic P2X family, which is expressed in both the airway and central nerve endings. Multiple clinical studies have confirmed that P2X3 receptor antagonists can significantly improve the cough frequency, cough impulse, and cough severity of patients with refractory chronic cough. The most common adverse reaction is taste hypogeusia, and the incidence of taste disorders can be reduced by reducing the drug dose and selecting a more selective P2X3 receptor antagonist. Currently, multiple clinical trials of P2X3 are being further carried out, and P2X3 receptor antagonists are expected to become the most promising drugs for the treatment of refractory chronic cough in the future.

[0007] The first selective P2X3 receptor antagonist of the same target, Gefapixant, 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 taste loss or hypogeusia, dry mouth, and nausea, etc. Taste disorders may be related to the effect of Gefapixant on the P2X2 / 3 receptor; it is necessary to develop highly selective P2X3 receptor antagonists to reduce the adverse reactions of taste loss or disorders. In addition, there are multiple clinical P2X3 selective antagonists under research: Bellus's Camlipixant (Phase III), Bayer's Eliapixant (Phase IIb), Shionogi's Sivopixant (planned to carry out Phase III), and there are four in China at the I-II phase stage, and the target safety is good. Compared with the 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 for the treatment of refractory chronic cough.

[0008] However, during the research process, the inventors of the present application found that the compound shown in Formula I has very poor solubility. In the medium with pH 1.0 to pH 6.8, the saturated solubility of the compound shown in Formula I is less than 0.02 mg / ml, and the dissolution rate in the media of pH 1.2, pH 4.5, pH 6.8 and water is less than 10%. Moreover, the raw drug has poor thermokinetic stability and is prone to crystal precipitation during storage, resulting in poor stability. Therefore, it is necessary to provide a new preparation to solve the problems of poor solubility and poor stability of the compound shown in 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 (the compound shown in Formula I), which can improve the solubility of the compound shown in Formula I, greatly improve the dissolution rate and bioavailability of the drug; and the solid dispersion has good stability and no crystal form transformation occurs during storage.

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

[0011] Wherein, the P2X3 receptor antagonist is selected from the compound shown in the following Formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:

[0012]

[0013] Wherein,

[0014] 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;

[0015] X is halogen;

[0016] m is selected from the integer 1, 2 or 3;

[0017] L is -(CH2) n -, and n is selected from the integer 0, 1 or 2;

[0018] R 2 independently selected from hydrogen, C1-C6 alkyl which is unsubstituted or substituted by R a , C3-C7 cycloalkyl which is unsubstituted or substituted by R a , 5-8 membered aryl which is unsubstituted or substituted by R a , 5-10 membered heteroaryl which is unsubstituted or substituted by R a , unsubstituted or substituted by R aSubstituted 4- to 7-membered heterocycloalkyl, unsubstituted or substituted by R a Substituted 6- to 12-membered heterobicycloalkyl; said R a Substituted C1-C6 alkyl, said R a Substituted C3-C7 cycloalkyl, said R a Substituted 5- to 8-membered aryl, said R a Substituted 5- to 10-membered heteroaryl, said R a Substituted 4- to 7-membered heterocycloalkyl, or said R a Substituted 6- to 12-membered heterobicycloalkyl, wherein said R a Substitution is one or more substitutions, said 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 or deuterated C1-C6 alkyl; when there are multiple substituents, said substituents are the same or different;

[0019] Wherein in the unsubstituted or R a Substituted 5- to 10-membered heteroaryl, the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3; in the unsubstituted or R a Substituted 4- to 7-membered heterocycloalkyl, the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3; in the unsubstituted or R a Substituted 6- to 12-membered heterobicycloalkyl, the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3;

[0020] R 3 Independently selected from hydrogen, or, C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogen atoms;

[0021] R 4 Independently selected from hydrogen or C1-C4 alkyl;

[0022] R b And R c Independently selected from hydrogen or C1-C4 alkyl;

[0023] A is independently an unsubstituted or R e Substituted 5- to 10-membered heteroaryl, in the R e Substituted 5- to 10-membered heteroaryl, said R eReplaced by one or more substituents, said R e Each independently selected from the following substituents: halogen, C1-C3 alkyl unsubstituted or substituted with 1-5 identical or different halogens, or, -O-(C1-C3 alkyl) unsubstituted or substituted with 1-5 identical or different halogens; when there are multiple substituents, the substituents are the same or different.

[0024] In an embodiment of the present invention, the solid dispersion is an amorphous solid dispersion.

[0025] In an embodiment of the present invention, the P2X3 receptor antagonist exists in an amorphous form.

[0026] In an embodiment of the present invention, the pharmaceutically acceptable carrier is a pharmaceutically acceptable polymeric carrier.

[0027] In an embodiment of the present invention, the pharmaceutically acceptable carrier is selected from any one or more of the following:

[0028] 1) Cellulose derivative carriers; such as hypromellose E5 (HPMC-E5), hypromellose acetate succinate LF (HPMC-AS-LF), hydroxypropyl cellulose (HPC), hypromellose phthalate (HPMCP), etc.;

[0029] 2) Polyacrylic resin carriers; such as Eudragit L100-55, Eudragit S100, Eudragit L100;

[0030] 3) Vinyl polymer carriers, such as polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), copovidone VA64, copovidone S630, etc.

[0031] In an embodiment of the present invention, the pharmaceutically acceptable carrier is selected from any one or more of the following:

[0032] Hydroxypropyl methyl cellulose HPMC, copovidone PVP, hypromellose acetate succinate HPMC-AS, polymethacrylate (Eudragit); preferably, selected from any one or more of the following: hydroxypropyl methyl cellulose HPMC, hypromellose acetate succinate HPMC-AS, polymethacrylate (Eudragit).

[0033] In an embodiment of the present invention, the pharmaceutically acceptable carrier is selected from any one or more of the following: hypromellose E5 (HPMC-E5), copovidone VA64 (PVP VA64), hypromellose acetate succinate LF (HPMC-AS-LF), Eudragit L100-55 (Eudragit-L100-55), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus); preferably, selected from any one or more of the following: hypromellose E5 (HPMC-E5), hypromellose acetate succinate LF (HPMC-AS-LF), Eudragit L100-55 (Eudragit-L100-55).

[0034] 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, such as 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5.

[0035] In an embodiment of the present invention, the solid dispersion comprises the following components:

[0036] P2X3 receptor antagonist 10wt% - 60wt%

[0037] Pharmaceutically acceptable carrier 40wt% - 90wt%.

[0038] In an embodiment of the present invention, the solid dispersion comprises the following components:

[0039] P2X3 receptor antagonist 20wt% - 55wt%

[0040] Pharmaceutically acceptable carrier 45wt% - 80wt%.

[0041] In an embodiment of the present invention, the solid dispersion comprises the following components:

[0042] P2X3 receptor antagonist 25wt% - 50wt% (such as 25wt%, 33wt%, 33.3wt%, 50wt%)

[0043] Pharmaceutically acceptable carrier 50wt% - 75wt% (such as 50wt%, 67wt%, 66.7wt%, 75wt%).

[0044] In an embodiment of the present invention, the solid dispersion comprises the following components:

[0045] P2X3 receptor antagonist and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is not less than 66.7wt%;

[0046] In an embodiment of the present invention, the solid dispersion comprises the following components:

[0047] A P2X3 receptor antagonist and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is not less than 75 wt%;

[0048] In an embodiment of the present invention, the solid dispersion comprises the following components:

[0049] P2X3 receptor antagonist 25 wt%, 33.3 wt%, 50 wt%

[0050] Pharmaceutically acceptable carrier 50 wt%, 66.7 wt%, 75 wt%.

[0051] The pharmaceutically acceptable carrier is selected from hypromellose E5 (HPMC-E5), hypromellose acetate succinate LF (HPMC-AS-LF), Eudragit L100-55 (Eudragit-L100-55).

[0052] In an embodiment of the present invention, the solid dispersion comprises the following components:

[0053] P2X3 receptor antagonist 25 wt%

[0054] Pharmaceutically acceptable carrier 75 wt%.

[0055] The pharmaceutically acceptable carrier is selected from hypromellose E5 (HPMC-E5), hypromellose acetate succinate LF (HPMC-AS-LF), Eudragit L100-55 (Eudragit-L100-55).

[0056] In an embodiment of the present invention, the solid dispersion comprises the following components:

[0057] P2X3 receptor antagonist 33.3 wt%

[0058] Pharmaceutically acceptable carrier 66.7 wt%.

[0059] The pharmaceutically acceptable carrier is selected from hypromellose E5 (HPMC-E5), hypromellose acetate succinate LF (HPMC-AS-LF), Eudragit L100-55 (Eudragit-L100-55).

[0060] In an embodiment of the present invention, the solid dispersion comprises the following components:

[0061] A P2X3 receptor antagonist and hypromellose acetate succinate LF, wherein the proportion of hypromellose acetate succinate LF is not less than 75%.

[0062] In an embodiment of the present invention, the solid dispersion comprises the following components:

[0063] P2X3 receptor antagonist 25 wt%

[0064] Hydroxypropylmethylcellulose acetate succinate LF 75 wt%.

[0065] In an embodiment of the present invention, the solid dispersion comprises the following components:

[0066] A P2X3 receptor antagonist and hydroxypropylmethylcellulose acetate succinate LF, wherein the proportion of hydroxypropylmethylcellulose acetate succinate LF is not less than 66.7 wt%.

[0067] In an embodiment of the present invention, the solid dispersion comprises the following components:

[0068] P2X3 receptor antagonist 33.3 wt%

[0069] Hydroxypropylmethylcellulose acetate succinate LF 66.7 wt%.

[0070] In an embodiment of the present invention, the solid dispersion optionally further comprises a solvent.

[0071] In an embodiment of the present invention, the solvent is a volatile solvent. The solvent volatilizes during the preparation of the solid dispersion.

[0072] 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 and a dichloromethane-methanol mixed solvent.

[0073] In an embodiment of the present invention, the solid dispersion optionally further comprises any one or several of the following: sweetening agent, flavoring agent, coloring agent, surfactant, filler, lubricant, disintegrant, disintegration promoter, recrystallization inhibitor, defoaming agent, antioxidant and pH regulator.

[0074] In a preferred embodiment of the present invention, the compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:

[0075]

[0076] Wherein,

[0077] 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;

[0078] X is a halogen;

[0079] m is selected from the integers 1, 2 or 3;

[0080] L is -(CH2) n -, where n is selected from the integers 0, 1 or 2;

[0081] R 2 is 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; said R a substituted C1-C6 alkyl, said R a substituted C3-C7 cycloalkyl, said R a substituted 5-8 membered aryl, said R a substituted 5-10 membered heteroaryl, said R a substituted 4-7 membered heterocycloalkyl, or said R a substituted 6-12 membered heterobicycloalkyl, wherein each of said 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, said substituents are identical or different;

[0082] wherein the unsubstituted or R a substituted 5-10 membered heteroaryl, the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3; the unsubstituted or R a substituted 4-7 membered heterocycloalkyl, the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3; the unsubstituted or R a substituted 6-12 membered heterobicycloalkyl, the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3;

[0083] R 3 is independently selected from hydrogen, or, unsubstituted or C1-C4 alkyl substituted by 1-5 identical or different halogen atoms;

[0084] R 4 is independently selected from hydrogen or C1-C4 alkyl;

[0085] R b and R c are independently selected from hydrogen or C1-C4 alkyl;

[0086] A is independently an unsubstituted or R e -substituted 5- to 10-membered heteroaryl, wherein in the R e -substituted 5- to 10-membered heteroaryl, the R e substitution is one or more substitutions, and the R e are each 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.

[0087] In a preferred embodiment of the present invention, when R 1 is halogen, the halogen is F, Cl, Br, I, preferably Cl.

[0088] In a preferred embodiment of the present invention, when R 1 is unsubstituted C1-C4 alkyl, the C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, preferably methyl or ethyl.

[0089] In a preferred embodiment of the present invention, when R 1 is C1-C4 alkyl substituted by 1-5 identical or different halogens, the C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, preferably methyl or ethyl.

[0090] In a preferred embodiment of the present invention, when R 1 is C1-C4 alkyl substituted by 1-5 identical or different halogens, the halogen is F, Cl, Br, I, preferably Cl or F.

[0091] In a preferred embodiment of the present invention, when X is halogen, the halogen is one of F or Cl.

[0092] In a preferred embodiment of the present invention, m is selected from the integers 1, 2 or 3, preferably 1.

[0093] In a preferred embodiment of the present invention, when L is -(CH2) n -, the n is an integer 0, 1 or 2, preferably n is 0 or 1.

[0094] In a preferred embodiment of the present invention, 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 a sec-butyl group.

[0095] In a preferred embodiment of the present invention, 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.

[0096] In a preferred embodiment of the present invention, when R 2 is an unsubstituted or R a -substituted C3-C7 cycloalkyl group, the C3-C7 alkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.

[0097] In a preferred embodiment of the present invention, when R 2 is an unsubstituted or R a -substituted 4-7 membered heterocycloalkyl group, the 4-7 membered heterocycloalkyl group is a 4-membered, 5-membered or 6-membered heterocycloalkyl group.

[0098] In a preferred embodiment of the present invention, when R 2 is an unsubstituted or R a -substituted 4-7 membered heterocycloalkyl group, the heteroatom in the 4-7 membered heterocycloalkyl group is one or more of N, S, O, P, preferably one or more of N or O.

[0099] In a preferred embodiment of the present invention, when R 2 is an unsubstituted or R a -substituted 4-7 membered heterocycloalkyl group, the number of heteroatoms in the 4-7 membered heterocycloalkyl group is 1 to 3, preferably 1 or 2.

[0100] In a preferred embodiment of the present invention, when R 2 is an unsubstituted or R a -substituted 4-7 membered heterocycloalkyl group, the R a is 1 to 3, preferably 1.

[0101] In a preferred embodiment of the present invention, R a is a hydroxyl group.

[0102] In a preferred embodiment of the present invention, when R a is a halogen, the halogen is F, Cl, Br, I, preferably F or Cl.

[0103] In a preferred embodiment of the present invention, when R a is a C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C3 alkyl group, preferably a methyl group.

[0104] In a preferred embodiment of the present invention, when R a is a deuterated C1-C6 alkyl group, the C1-C6 alkyl group is a C1-C3 deuterated alkyl group, preferably

[0105] In a preferred embodiment of the present invention, when R a is -(C1-C6 alkylene)-OH, the C1-C6 alkylene is a C1-C4 alkylene, preferably methylene, ethylene, n-propylene or isopropyl, more preferably methylene.

[0106] In a preferred embodiment of the present invention, R 3 is hydrogen.

[0107] In a preferred embodiment of the present invention, when R 3 is an unsubstituted C1-C4 alkyl group, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, preferably methyl.

[0108] In a preferred embodiment of the present invention, 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.

[0109] In a preferred embodiment of the present invention, when A is a 5- to 10-membered heteroaryl group substituted by R e the R e substitution is a single substitution.

[0110] In a preferred embodiment of the present invention, when A is a 5- to 10-membered heteroaryl group substituted by R e the said R e is a C1-C3 alkyl group substituted by 1-5 identical or different halogen atoms, preferably trifluoromethyl.

[0111] In a preferred embodiment of the present invention, when A is a 5- to 10-membered heteroaryl group substituted by R e the R e is an unsubstituted C1-C3 alkyl group, preferably methyl.

[0112] In a preferred embodiment of the present invention, -L-R 2 is selected from

[0113] In a preferred embodiment of the present invention, -L-R 2 is

[0114] In a preferred embodiment of the present invention, -L-R 2 selected from

[0115] In a preferred embodiment of the present invention, R 1 is methyl, ethyl or Cl.

[0116] In a preferred embodiment of the present invention, -L-R 2 selected from

[0118] In a preferred embodiment of the present invention, -L-R 2 selected from

[0119] In a preferred embodiment of the present invention, R 3 is methyl or hydrogen.

[0120] In a preferred embodiment of the present invention, A is selected from

[0121] In a preferred embodiment of the present invention, the compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:

[0122]

[0123] wherein,

[0124] R 1 is selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens; L is -(CH2) n -, and n is selected from the integers 0, 1 or 2;

[0125] R 2 is independently selected from hydrogen, C1-C6 alkyl which is unsubstituted or substituted by R a substituted C3-C7 cycloalkyl which is unsubstituted or substituted by R a substituted 5-8 membered aryl which is unsubstituted or substituted by R a substituted 5-10 membered heteroaryl which is unsubstituted or substituted by R a substituted 4-7 membered heterocycloalkyl which is unsubstituted or substituted by R a substituted 6-12 membered heterobicycloalkyl; the C1-C6 alkyl substituted by R a substituted by R a substituted C1-C6 alkyl, thea Substituted C3-C7 cycloalkyl, the R-substituted a Substituted 5-8 membered aryl, the R-substituted a Substituted 5-10 membered heteroaryl, the R-substituted a Substituted 4-7 membered heterocycloalkyl, or the R-substituted a Substituted 6-12 membered heterobicycloalkyl, wherein the R a Substitution is one or more substitutions, 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;

[0126] Wherein in the 5-10 membered heteroaryl which is unsubstituted or substituted by R a Substituted, the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3; in the 4-7 membered heterocycloalkyl which is unsubstituted or substituted by R a Substituted, the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3; in the 6-12 membered heterobicycloalkyl which is unsubstituted or substituted by R a Substituted, the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3;

[0127] R 4 Independently selected from hydrogen or C1-C4 alkyl;

[0128] R b And R c Independently selected from hydrogen or C1-C4 alkyl.

[0129] In a preferred embodiment of the present invention, the compound shown in formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:

[0130]

[0131] Wherein,

[0132] R 1 Selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens; L is -(CH2) n -, and the n is selected from the integers 0, 1 or 2;

[0133] 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; 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, 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;

[0134] wherein in the unsubstituted or R a substituted 5-10 membered heteroaryl, the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3; in the unsubstituted or R a substituted 4-7 membered heterocycloalkyl, the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3; in the unsubstituted or R a substituted 6-12 membered heterobicycloalkyl, the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3;

[0135] R 4 independently selected from hydrogen or C1-C4 alkyl;

[0136] R b and R c independently selected from hydrogen or C1-C4 alkyl.

[0137] In a preferred embodiment of the present invention, the compound of formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:

[0138]

[0139] Wherein,

[0140] R 1 is selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens; L is -(CH2) n -, and n is selected from the integers 0, 1 or 2;

[0141] R 2 is independently selected from hydrogen, C1-C6 alkyl which is unsubstituted or substituted by R a , C3-C7 cycloalkyl which is unsubstituted or substituted by R a , 5-8 membered aryl which is unsubstituted or substituted by R a , 5-10 membered heteroaryl which is unsubstituted or substituted by R a , 4-7 membered heterocycloalkyl which is unsubstituted or substituted by R a , 6-12 membered heterobicycloalkyl which is unsubstituted or substituted by R a ; in the C1-C6 alkyl substituted by R a , the C3-C7 cycloalkyl substituted by R a , the 5-8 membered aryl substituted by R a , the 5-10 membered heteroaryl substituted by R a , the 4-7 membered heterocycloalkyl substituted by R a , or the 6-12 membered heterobicycloalkyl substituted by R a , the R a substitution is one or more substitutions, and the R a 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 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;

[0142] Among the 5-10 membered heteroaryl which is unsubstituted or substituted by R a , the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3; the 5-10 membered heteroaryl which is unsubstituted or substituted by R aIn the substituted 4- to 7-membered heterocycloalkyl group, the heteroatom is 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 substituted 6- to 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 to 3;

[0143] R 4 independently selected from hydrogen or C1-C4 alkyl;

[0144] R b and R c independently selected from hydrogen or C1-C4 alkyl.

[0145] In a preferred embodiment of the present invention, the compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug represented by Formula I is:

[0146]

[0147] wherein,

[0148] R 1 is selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted by 1 to 5 identical or different halogens;

[0149] L is -(CH2) n -, and the n is selected from the integers 0, 1 or 2;

[0150] R 2 independently selected from hydrogen, C1-C6 alkyl which is unsubstituted or substituted by R a substituted, C3-C7 cycloalkyl which is unsubstituted or substituted by R a substituted, 5- to 8-membered aryl which is unsubstituted or substituted by R a substituted, 5- to 10-membered heteroaryl which is unsubstituted or substituted by R a substituted, 4- to 7-membered heterocycloalkyl which is unsubstituted or substituted by R a substituted, 6- to 12-membered heterobicycloalkyl which is unsubstituted or substituted by R a substituted; the C1-C6 alkyl substituted by R a substituted, the C3-C7 cycloalkyl substituted by R a substituted, the 5- to 8-membered aryl substituted by R a substituted, the 5- to 10-membered heteroaryl substituted by R a substituted, the 4- to 7-membered heterocycloalkyl substituted by R a substituted, or the 6- to 12-membered heterobicycloalkyl substituted by R a substituted, in the R a substitution is one or more substitutions, and the R aEach 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;

[0151] wherein in the 5-10 membered heteroaryl which is unsubstituted or substituted by R a , the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3; in the 4-7 membered heterocycloalkyl which is unsubstituted or substituted by R a , the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3; in the 6-12 membered heterobicycloalkyl which is unsubstituted or substituted by R a , the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3;

[0152] R 4 independently selected from hydrogen or C1-C4 alkyl;

[0153] R b and R c independently selected from hydrogen or C1-C4 alkyl.

[0154] In a preferred embodiment of the present invention, the compound shown in formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:

[0155]

[0156] wherein,

[0157] 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;

[0158] L is -(CH2) n -, and the n is selected from the integers 0, 1 or 2;

[0159] R 2 independently selected from hydrogen, C1-C6 alkyl which is unsubstituted or substituted by R a , C3-C7 cycloalkyl which is unsubstituted or substituted by R a , 5-8 membered aryl which is unsubstituted or substituted by R a , 5-10 membered heteroaryl which is unsubstituted or substituted by R a substituted 5-10 membered heteroaryl; unsubstituted or substituted by Ra Substituted 4- to 7-membered heterocycloalkyl, unsubstituted or substituted by R a Substituted 6- to 12-membered heterobicycloalkyl; the R-substituted a Substituted C1-C6 alkyl, the R-substituted a Substituted C3-C7 cycloalkyl, the R-substituted a Substituted 5- to 8-membered aryl, the R-substituted a Substituted 5- to 10-membered heteroaryl, the R-substituted a Substituted 4- to 7-membered heterocycloalkyl, or the R-substituted a In the substituted 6- to 12-membered heterobicycloalkyl, the R a Substitution is one or more substitutions, the R a Each independently selected from the following substituents: C1-C4 alkyl unsubstituted or substituted by 1 to 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 the same or different;

[0160] Wherein in the unsubstituted or R-substituted a In the 5- to 10-membered heteroaryl, the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1 to 3; in the unsubstituted or R-substituted a In the 4- to 7-membered heterocycloalkyl, the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1 to 3; in the unsubstituted or R-substituted a In the 6- to 12-membered heterobicycloalkyl, the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1 to 3;

[0161] R 4 Independently selected from hydrogen or C1-C4 alkyl;

[0162] R b and R c Independently selected from hydrogen or C1-C4 alkyl.

[0163] In a preferred embodiment of the present invention, the compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug as shown in formula I is:

[0164]

[0165] Wherein,

[0166] R 1Independently selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens;

[0167] L is -(CH2) n -, and the n is selected from the integers 0, 1 or 2;

[0168] R 2 Independently selected from hydrogen, C1-C6 alkyl which is unsubstituted or substituted by R a substituted, C3-C7 cycloalkyl which is unsubstituted or substituted by R a substituted, 5-8 membered aryl which is unsubstituted or substituted by R a substituted, 5-10 membered heteroaryl which is unsubstituted or substituted by R a substituted, 4-7 membered heterocycloalkyl which is unsubstituted or substituted by R a substituted, 6-12 membered heterobicycloalkyl which is unsubstituted or substituted by R a substituted; in the C1-C6 alkyl substituted by R a substituted, the C3-C7 cycloalkyl substituted by R a substituted, the 5-8 membered aryl substituted by R a substituted, the 5-10 membered heteroaryl substituted by R a substituted, the 4-7 membered heterocycloalkyl substituted by R a substituted, or the 6-12 membered heterobicycloalkyl substituted by R a substituted, the R a substitution is one or more substitutions, and the R a each independently is 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;

[0169] wherein in the 5-10 membered heteroaryl which is unsubstituted or substituted by R a substituted, the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3; in the 4-7 membered heterocycloalkyl which is unsubstituted or substituted by R a substituted, the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3; in the 6-12 membered heterobicycloalkyl which is unsubstituted or substituted by R a substituted, the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3;

[0170] R4 Independently selected from hydrogen or C1-C4 alkyl;

[0171] R b and R c Independently selected from hydrogen or C1-C4 alkyl.

[0172] In a preferred embodiment of the present invention, the compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:

[0173]

[0174] Wherein,

[0175] 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;

[0176] L is -(CH2) n -, and the n is selected from the integers 0, 1 or 2;

[0177] R 2 Independently selected from hydrogen, C1-C6 alkyl which is unsubstituted or substituted by R a substituted, C3-C7 cycloalkyl which is unsubstituted or substituted by R a substituted, 5-8 membered aryl which is unsubstituted or substituted by R a substituted, 5-10 membered heteroaryl which is unsubstituted or substituted by R a substituted, 4-7 membered heterocycloalkyl which is unsubstituted or substituted by R a substituted, 6-12 membered heterobicycloalkyl which is unsubstituted or substituted by R a substituted; the C1-C6 alkyl substituted by R a substituted, the C3-C7 cycloalkyl substituted by R a substituted, the 5-8 membered aryl substituted by R a substituted, the 5-10 membered heteroaryl substituted by R a substituted, the 4-7 membered heterocycloalkyl substituted by R a substituted, or the 6-12 membered heterobicycloalkyl substituted by R a substituted, in 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 the same or different;

[0178] wherein unsubstituted or substituted by R a In the 5-10 membered heteroaryl which is unsubstituted or substituted by R, the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3; unsubstituted or substituted by R a In the 4-7 membered heterocycloalkyl which is unsubstituted or substituted by R, the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3; unsubstituted or substituted by R a In the 6-12 membered heterobicycloalkyl which is unsubstituted or substituted by R, the heteroatoms are selected from one or more of N, S, O, P, and the number of heteroatoms is 1-3;

[0179] R 4 independently selected from hydrogen or C1-C4 alkyl;

[0180] R b and R c independently selected from hydrogen or C1-C4 alkyl.

[0181] In a preferred embodiment of the present invention, the compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is selected from any of the following compounds:

[0182]

[0183]

[0184] In a preferred embodiment of the present invention, the compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is selected from any of the following compounds:

[0185]

[0186]

[0187] In an embodiment of the present invention, the P2X3 receptor antagonist is selected from the compound represented by formula A, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:

[0188]

[0189] The present invention also provides a preparation process for the above solid dispersion, and the preparation process includes the following steps:

[0190] (1) Add each component to a solvent and stir to dissolve;

[0191] (2) Subject the dissolved solution to a drying treatment to obtain the solid dispersion.

[0192] In an embodiment of the present invention, step (1) is specifically: first add a pharmaceutically acceptable carrier to a solvent and stir to dissolve; then add a P2X3 receptor antagonist and continue to stir to dissolve.

[0193] In an embodiment of the present invention, the drying treatment method in step (2) is selected from spray drying.

[0194] In an embodiment of the present invention, step (2) is specifically: filter the dissolved solution by pressure filtration into a transfer tank, and then dry the pressure-filtered solution to obtain the solid dispersion;

[0195] Preferably, filter by pressure through a precision filter with a certain pore size into a transfer tank.

[0196] In an embodiment of the present invention, after the drying treatment in step (2), optionally further subject the dried solid dispersion to vacuum drying.

[0197] 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 - 120 min, 120 - 180 min.

[0198] In an embodiment of the present invention, in step (2), the pore size of the precision filter is 1 μm - 22 μm, preferably 5 μm.

[0199] In an embodiment of the present invention, in step (2), the feeding frequency of spray drying is 5 Hz - 50 Hz, preferably 10 Hz - 20 Hz;

[0200] and / or, the atomization pressure is 0.1 Mpa - 1.0 Mpa, preferably 0.1 Mpa - 0.2 Mpa;

[0201] and / or, the inlet air temperature is 60 °C - 120 °C, preferably 85 °C - 110 °C;

[0202] and / or, the outlet air temperature is 40 °C - 70 °C, preferably 50 °C - 55 °C.

[0203] The present invention also provides a pharmaceutical composition, which includes the above solid dispersion and a pharmaceutically acceptable pharmaceutical carrier, diluent or excipient.

[0204] In an embodiment of the present invention, the dosage form of the pharmaceutical composition is selected from solid preparations and liquid preparations; for example, powders, granules, pills, tablets, sachets, capsules, dragees, chewable tablets, effervescent tablets, dispersible tablets, lozenges, melts, solutions, suspensions or emulsions, etc.

[0205] According to a specific embodiment of the present invention, the pharmaceutical composition, together with a pharmaceutically acceptable pharmaceutical carrier, diluent or excipient, is mixed to prepare a pharmaceutical preparation suitable for oral or parenteral administration. The administration methods include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal and oral routes.

[0206] The present invention also provides a pharmaceutical preparation, which comprises the above solid dispersion and a pharmaceutically acceptable pharmaceutical carrier, diluent or excipient.

[0207] In an embodiment of the present invention, the pharmaceutical preparation is selected from solid preparations and liquid preparations; for example, powders, 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 field of pharmaceutical preparation manufacturing.

[0208] The pharmaceutical preparation can be administered by any route, such as by infusion or bolus injection, and by routes of absorption through the epithelium or skin mucosa (such as oral mucosa or rectum, etc.). The administration can be systemic or local. Examples of orally administered preparations 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 contains carriers, diluents or excipients commonly used in the field of pharmaceutical preparations.

[0209] The present invention also provides the use of the above solid dispersion, pharmaceutical composition and pharmaceutical preparation in the preparation of a drug for treating and / or preventing P2X3-related diseases.

[0210] In an embodiment of the present invention, the P2X3-related diseases are pain, respiratory diseases or urogenital system diseases.

[0211] 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;

[0212] and / or, the urogenital system diseases are 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;

[0213] 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.

[0214] The present invention also provides a method for treating and / or preventing a P2X3-related disease, the method comprising administering an effective amount of the above solid dispersion, pharmaceutical composition, or pharmaceutical preparation to a patient suffering from a P2X3-related disease.

[0215] In an embodiment of the present invention, the P2X3-related disease is a pain, a respiratory system disease, or a urogenital system disease.

[0216] 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;

[0217] and / or, the urogenital system disease is reduced bladder capacity, frequent urination, urge incontinence, stress incontinence, overactive bladder, benign prostatic hyperplasia, prostatitis, detrusor hyperreflexia, pollakiuria, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, or cystitis;

[0218] 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.

[0219] Terms and Definitions

[0220] Unless otherwise specified, the terms and definitions used in this application, including those described in the specification and claims of this application, are as follows.

[0221] Those skilled in the art can understand that, according to the conventions used in the art, in the structural formulas of this application, are used to depict chemical bonds, which are the points where the chemical bonds are connected to the core structure or the backbone structure by a moiety or a substituent.

[0222] 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 contact with human and animal tissues, and without excessive toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0223] The term "pharmaceutically acceptable salt" refers to a non-toxic acid or base salt that is pharmaceutically acceptable, including salts of inorganic acids and bases, organic acids and bases.

[0224] The term "solvate" refers to a stoichiometric or non-stoichiometric solvent in which the compound or its salt of the present invention is combined by intermolecular non-covalent forces, and when the solvent is water, it is a hydrate.

[0225] The term "prodrug" means a compound that can be converted into a biologically active compound of the present invention under physiological conditions or by solvolysis. The prodrugs of the present invention are prepared by modifying the functional groups in the compound, and such modification can be removed by conventional operations or in vivo to obtain the parent compound. Prodrugs include compounds formed by connecting a hydroxyl group or an amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group and a free amino group respectively.

[0226] The term "stereoisomer" refers to isomers generated by different arrangements of atoms in space in a molecule, including cis-trans isomers, enantiomers, diastereoisomers and conformational isomers.

[0227] Depending on the choice of starting materials and methods, the compounds of the present invention may exist in the form of one or a mixture of possible isomers, for example as pure optical isomers, or as a mixture of isomers, such as a racemic and diastereoisomeric mixture, depending on the number of asymmetric carbon atoms. When describing an optically active compound, the 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 chiral centers) in the molecule. The prefixes D and L or (+) and (–) are symbols used to specify the rotation of plane-polarized light caused by the compound, where (–) or L indicates that the compound is levorotatory. A compound with the prefix (+) or D is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that these stereoisomers are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and a mixture of the isomers is usually referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, and such a racemic mixture or racemate may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or method. Many geometric isomers of alkenes, C=N double bonds, etc. may also exist in the compounds described herein, and all such stable isomers are contemplated in the present invention. When the compounds described herein contain an alkene double bond, unless otherwise specified, such a double bond includes E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may be in the cis- or trans- configuration.

[0228] When depicting the bonds to the chiral carbon in the formulas of the present invention as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and both its enantiomerically pure compounds and mixtures resulting therefrom are included within the scope of the general formula. The graphical representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise specified, the absolute configuration of a stereocenter is represented by wedge and dashed bonds.

[0229] The optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral auxiliaries, or resolved using conventional techniques. The compounds of the present invention containing an asymmetrically substituted carbon atom can be isolated in optically active form or in racemic form. The resolution of the racemic mixtures of the compounds can be carried out by any of a number of methods known in the art. Exemplary methods include fractional crystallization using a chiral resolving acid, which is an optically active salt-forming organic acid. Suitable resolving agents for the fractional crystallization method 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 the fractional crystallization method include stereoisomerically pure forms of α-methyl-benzylamine (e.g., the S and R forms or diastereomerically 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 elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoyl-phenylglycine). High performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) can be employed. The choice of the specific method as well as the elution conditions and the selection of the column can be made by those skilled in the art according to the structure of the compound and the test results. Further, any enantiomer or diastereomer of the compounds described in the present invention can be obtained by stereoselective organic synthesis using optically pure starting materials or reagents of known configuration.

[0230] The term "tautomer" refers to functional group isomers resulting from the rapid migration of an atom within a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible species. Prototrophic tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in an equilibrium form, and attempting to isolate a single tautomer usually results in a mixture whose physical and chemical properties are consistent with those of a mixture of compounds. The position of the equilibrium depends on the chemical characteristics 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.

[0231] The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms constituting the compounds. 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 compositions of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0232] For a drug or a pharmacological active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. For the oral dosage forms in the present invention, the "effective amount" of an active substance in the composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. In a specific case, the appropriate effective amount can be determined by those skilled in the art through routine tests.

[0233] The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that can effectively treat a target disorder, disease or condition.

[0234] The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by substituents, including deuterium and variants of hydrogen, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are replaced. Keto substitution does not occur on an aromatic group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary based on what is chemically achievable.

[0235] The term "C1-C6 alkyl" should be understood to represent a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl groups 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, etc. or their isomers. In particular, the group has 1, 2, 3 or 4 carbon atoms ("C1-C4 alkyl"), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0236] The term "C1-C3 alkoxy" is understood to be -O-(C1-C3 alkyl), where "C1-C3 alkyl" has the definition given above.

[0237] The term "deuterated C1-C6 alkyl" is understood to be a C1-C6 alkyl in which one or more hydrogen atoms are replaced by deuterium, where "C1-C6 alkyl" has the definition given above.

[0238] The term "C3-C7 cycloalkyl" is understood to denote a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 7 carbon atoms, including fused or bridged polycyclic systems. Similarly, "C3-C6 cycloalkyl" is understood to be a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms as defined above. Examples of such include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0239] The term "alkylene" is understood to be a saturated divalent hydrocarbon radical obtained by removing two hydrogen atoms from a saturated straight-chain or branched-chain hydrocarbon. Unless otherwise specified in detail, the alkylene radical contains 1-10 carbon atoms. In some embodiments, the alkylene radical contains 1-6 carbon atoms; in other embodiments, the alkylene radical contains 1-4 carbon atoms; in still other embodiments, the alkylene radical contains 1-2 carbon atoms. Examples of such include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylidene (-CH(CH3)CH2-), and the like.

[0240] The term "heterocycloalkyl" is understood to mean a saturated monovalent monocyclic hydrocarbon ring having a 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 containing 4, 5, 6, or 7 ring atoms as defined above. Similarly, "4- to 6-membered heterocycloalkyl" is understood to mean a saturated monovalent monocyclic "heterocycloalkyl" ring containing 4, 5, or 6 ring atoms as defined above.

[0241] The term "6- to 12-membered heterobicycloalkyl" is understood to mean a saturated monovalent bicyclic hydrocarbon radical in which 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 does not exceed 12.

[0242] The term "5-8 aryl" should be understood as a monocyclic, bicyclic or tricyclic hydrocarbon ring that is monovalent, aromatic or partially aromatic and has 5-8 carbon atoms, especially a ring with 6 carbon atoms ("C6 aryl"), such as phenyl; when the 5-8 aryl is substituted, it can be mono-substituted or multi-substituted. Also, there is no restriction on the substitution site, for example, it can be ortho-substituted, para-substituted or meta-substituted.

[0243] The term "5-10 heteroaryl" should be understood as a monovalent monocyclic, bicyclic or tricyclic aromatic ring group having 5-10 ring atoms - especially 5 or 6 carbon atoms - and containing 1-5 heteroatoms independently selected from N, O and S. Preferably 1-3 - monovalent monocyclic, bicyclic or tricyclic aromatic ring groups of heteroatoms independently selected from N, O and S, and can additionally be benzo-fused in each case. In particular, heteroaryl 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.

[0244] The term "halogen" or "halide" is fluorine, chlorine, bromine and iodine.

[0245] In addition, it should be noted that, unless otherwise explicitly stated, the description mode "…… independently" adopted in the present invention should be understood in a broad sense, which means that the described individuals are independent of each other and can independently be the same or different specific groups. More specifically, the description mode "…… independently" can either mean that among different groups, the specific options expressed between the same symbols do not affect each other, or it can also mean that among the same group, the specific options expressed between the same symbols do not affect each other.

[0246] Beneficial effects

[0247] The present invention provides a solid dispersion containing a P2X3 receptor antagonist compound represented by Formula I. The solid dispersion can significantly improve the solubility of the compound represented by Formula I, greatly improve the dissolution rate and bioavailability of the drug, and ensure the therapeutic effect of the drug. Moreover, the solid dispersion of the present invention has good stability, and no crystal form transformation occurs during storage, improving the safety of clinical application of the drug.

[0248] The present invention has conducted extensive screening of solid dispersions of Compound A, including different types of solid dispersion carriers and drug-carrier ratios, and obtained solid dispersions with a high drug-carrier ratio and excellent drug stability. When administered to dogs at a dose of 20 mg / kg, it has good exposure, and can maintain a supersaturated concentration for a relatively long time, and can maintain stable and continuous in vivo absorption after 4 hours.

[0249] In the present invention, pharmacokinetic experiments on rats, mice, dogs, etc. show that Compounds I-27, I-28, I-29, and I-30 have comparable pharmacokinetic properties. Description of the Drawings

[0250] Figure 1 : XRPD pattern of the API compound.

[0251] Figure 2 : TGA&DSC patterns of the API compound.

[0252] Figure 3 : Dynamic dissolution curves of the API with amorphous films of different ratios of HPMC-AS-LF.

[0253] Figure 4 : Dynamic dissolution curves of the API with amorphous films of different ratios of Eudragit L100-55.

[0254] Figure 5 : Dynamic dissolution curves of the API with amorphous films of different ratios of HPMC-E5.

[0255] Figure 6 : Dynamic dissolution curves of the API with amorphous films of different ratios of PVPVA64.

[0256] Figure 7 : Dynamic dissolution curves of the API with amorphous films of different ratios of Soluplus.

[0257] Figure 8 : Solid-state XRPD patterns of the physical stability of Formulation F25 under various conditions for 7 days.

[0258] Figure 9-1 : Solid-state XRPD patterns of the physical stability of Formulation F25 at 40 °C and RH 60% for 18 days.

[0259] Figure 9-2 : Solid-state XRPD patterns of the physical stability of Formulation F25 at 40 °C and RH 75% for 18 days.

[0260] Figure 9-3 : Solid-state XRPD patterns of the physical stability of Formulation F25 at 60 °C and RH 30% for 18 days.

[0261] Figure 10 : Solid state XRPD patterns of the physical stability of Formulation F26 under various conditions for 7 days.

[0262] Figure 11 : Solid state XRPD patterns of the physical stability of Formulation F26 under various conditions for 18 days. Detailed implementation manners

[0263] The technical solutions of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only illustrative explanations of the present invention and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0264] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0265] The compounds of the present application and their preparations refer to WO2022068930A1 and WO2023185931A1.

[0266] "Pharmaceutically acceptable" means an excipient suitable for contact with human and animal tissues within the scope of reasonable medical judgment, which does not produce excessive toxicity, irritation, allergic reactions or other problems or complications, and has a reasonable benefit / risk ratio.

[0267] List of abbreviations

[0268] Table 1-1 Abbreviations and their full names in the present invention

[0269]

[0270]

[0271] Instruments and detection methods

[0272] I. Experimental instruments

[0273] The main instrument models and manufacturers used in the present invention are shown in Table 2-1:

[0274] Table 2-1 Main instruments used in the experiment

[0275]

[0276] II. X-ray powder diffraction (XRPD)

[0277] The relevant parameters of the X-ray powder diffraction (XRPD) instrument are shown in Table 2-2:

[0278] Table 2-2 XRPD instrument relevant parameters

[0279]

[0280]

[0281] III. Thermogravimetric Analysis (TGA)

[0282] The relevant parameters of the TGA instrument are shown in Table 2-3:

[0283] Table 2-3 Relevant Parameters of TGA Instrument

[0284]

[0285] IV. Differential Scanning Calorimeter (DSC)

[0286] The relevant parameters of the DSC instrument are shown in Table 2-4:

[0287] Table 2-4 Relevant Parameters of DSC Instrument

[0288]

[0289] V. Dynamic Vapor Sorption (DVS)

[0290] 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:

[0291] Table 2-5 DVS Instrument Test Method

[0292]

[0293]

[0294] VI. High Performance Liquid Chromatography (HPLC) Analysis Method

[0295] The method and relevant parameters of the HPLC test are shown in Table 2-6:

[0296] Table 2-6 HPLC Analysis Method (Dissolution Determination Related to Physiological Medium)

[0297]

[0298] Reagents, Excipients and Their Manufacturers

[0299] Table 3-1 Reagents, Excipients Used in the Invention and Their Manufacturers

[0300]

[0301] API Preparation

[0302] Prepare the API of the compound of formula A(I-27) 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 crystalline form A in WO2023185931A1.

[0303] Example 1 Screening of Excipients for Solid Dispersions

[0304] 1. Screening Study of Amorphous Solid Dispersion Carriers

[0305] Table 4-1 Screening Study of Amorphous Solid Dispersion Carriers

[0306]

[0307] The compound shown in formula A has a relatively high solubility in the dichloromethane / methanol system (volume ratio 1:1). Select this solvent system to prepare a film of amorphous solid dispersion. The experimental steps are as follows:

[0308] 1) Prepare amorphous solid dispersion films in 96-well plates at the mass ratios shown in Table 4-1. A total of 10 identical 96-well plates were prepared, with each well containing 400 μg of API (generally 10 times the maximum saturation solubility value in physiological solution).

[0309] 2) Use the solvent rapid evaporation method to prepare a total of 10 96-well plates (8 for physiologically relevant dissolution, 1 for physical stability evaluation, and 1 as an excipient control), as detailed in Table 4-1.

[0310] 3) Take 8 96-well plates containing amorphous solid dispersion films and conduct physiologically relevant dissolution experiments. Samples were taken at the following time points (96 channels), filtered (96 channels), and diluted (96 channels): simulated gastric fluid SGF at 5 min and 10

[0311] min; concentrated simulated fasting intestinal fluid FaSSIF, with the fluid changed at 15 min, and samples were taken at 20 min, 30 min, 45 min, 60 min, 90

[0312] min, and 120 min.

[0313] 4) Analyze the samples after dissolution by HPLC to reconstruct the 96-channel physiologically relevant dissolution experiment.

[0314] 5) Perform high-throughput cross-polarized light imaging on the physical stability evaluation plate and the blank excipient plate at T0 and 7 days (40 °C - 75% RH) to evaluate the physical stability of the formulation.

[0315] 6) Compare the differences in different formulations, and spray-dry the carrier with better dynamic dissolution and the sedimentation inhibitor to prepare solid dispersions (SDD).

[0316] 2. Dissolution of amorphous films with different carrier types and ratios

[0317] Perform dynamic solubility tests on the prepared amorphous solid dispersion films containing API with different types and ratios of carriers in physiologically relevant media, compare the results with those of the amorphous API film, and prepare dynamic dissolution curves. The experimental results are shown in Tables 4-4 to 4-8 and Figures 3 to 7 as follows.

[0318] The test method is as follows:

[0319] Table 4-2 Test method for dynamic solubility in physiologically relevant media

[0320] Dissolution Apparatus Fukesi Dissolution Method Paddle Method Rotation Speed 75 rpm Medium SGF Medium for 15 min, SGF + FaSSIF Medium for 105 min Medium Volume 300 mL, 300 mL + 600 mL Medium Temperature 37℃±0.5℃ Sampling Time 5 min, 10 min, 20 min, 30 min, 45 min, 60 min, 90 min, 120 min

[0321] Configuration of physiologically relevant media:

[0322] The preparation methods of SGF and concentrated FaSSIF solutions are shown in the following table. The pH value of the concentrated FaSSIF solution is adjusted with 1.0 mol / L NaOH aqueous solution in advance so that the pH value can be 6.5 after mixing SGF and concentrated FaSSIF evenly in a volume ratio of 1:2.

[0323] Table 4-3 Preparation methods of SGF and concentrated FaSSIF solutions

[0324]

[0325] *Adjust according to the pH requirement of the mixed solution.

[0326] Table 4-4 Dynamic dissolution results of API and amorphous films with different ratios of HPMC-AS-LF

[0327]

[0328] In Table 4-4, AS LF-1:1 means API:HPMC-AS-LF = 1:1, AS LF-1:2 means API:HPMC-AS-LF = 1:2, and AS LF-1:3 means API:HPMC-AS-LF = 1:3.

[0329] Table 4-5 Dynamic dissolution results of API and amorphous films with different ratios of Eudragit L100-55

[0330]

[0331] In Table 4-5, L100-55-1:1 indicates API:Eudragit-L100-55 = 1:1, L100-55-1:2 indicates API:Eudragit-L100-55 = 1:2, and L100-55-1:3 indicates API:Eudragit-L100-55 = 1:3.

[0332] Table 4-6 Dynamic dissolution results of API and amorphous films of different ratios of HPMC-E5

[0333]

[0334] In Table 4-6, E5-1:1 indicates API:HPMC E5 = 1:1, E5-1:2 indicates API:HPMC E5 = 1:2, and E5-1:3 indicates API:HPMC E5 = 1:3.

[0335] Table 4-7 Dynamic dissolution results of API and amorphous films of different ratios of PVP VA64

[0336]

[0337] In Table 4-7, VA64-1:1 indicates API:PVP VA64 = 1:1, VA64-1:2 indicates API:PVP VA64 = 1:2, and VA64-1:3 indicates API:PVP VA64 = 1:3.

[0338] Table 4-8 Dynamic dissolution results of API and amorphous films of different ratios of Soluplus

[0339]

[0340] In Table 4-8, Soluplus-1:1 indicates API:Soluplus = 1:1, Soluplus-1:2 indicates API:Soluplus = 1:2, and Soluplus-1:3 indicates API:Soluplus = 1:3.

[0341] 3. Summary of the experimental study on the screening of amorphous solid dispersions

[0342] 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, and among them, the dissolution improvement of SDD prepared by the three carriers of HPMC-E5, HPMC-AS-LF, and Eudragit L100-55 was the most obvious.

[0343] Example 2 Spray Drying Preparation of SDD and Dissolution Curve Investigation

[0344] According to the above screening results, the prescriptions of carriers HPMC-E5, HPMC-AS-LF, and Eudragit-L100-55 were spray-dried. Acetone was used as the solvent to prepare solid dispersions, and the steps were as follows:

[0345] (1) Slowly add the carrier to the solvent and continuously stir for no less than 60 min until it is dissolved to a clear state.

[0346] (2) Slowly add the compound to the above solution and continuously stir for no less than 120 min until it is dissolved to a clear state.

[0347] (3) Filter the above solution through a precision filter with a pore size of 5 μm into a transfer tank of appropriate volume.

[0348] (4) Spray-dry the filtered solution. The feeding 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.

[0349] (5) Transfer the spray-dried solid dispersion to a vacuum box for vacuum drying to obtain a dried solid dispersion.

[0350] Finally, the solid dispersions with different prescriptions obtained were subjected to physiological relevance dissolution detection.

[0351] Table 5-1 Summary Table of Prescription Information for F21 - F28

[0352]

[0353] The dissolution results are shown in Tables 5-2 and 5-3.

[0354] Table 5-2 Dissolution Curve Study of API:HPMC-E5 = 1:1, 1:2, 1:3

[0355]

[0356] Table 5-3 Dissolution Study of HPMC-AS-LF and Eudragit as SDD Carriers

[0357]

[0358] From the dissolution test results of the three different carriers, namely HPMC-E5, HPMC-AS-LF, and Eudragit SDD in physiologically relevant media, it can be seen that:

[0359] For the same type of carrier, the higher the carrier ratio, the higher the dissolution rate of SDD. 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%); API:Eudragit L100-55 = 1:3 (dissolution rate 31.3%) > API:Eudragit L100-55 = 1:2 (dissolution rate 28.6%). It shows that the dissolution result of API:HPMC AS-LF = 1:3 is the best, with a dissolution rate of up to 72% at 60 minutes, followed by API:HPMC-AS-LF = 1:2.

[0360] Physical stability study of Example 3

[0361] Experimental procedure for physical stability investigation: Weigh approximately 10.0 mg of the sample and place it in a 1.5 mL liquid phase vial. Place the sample under different temperature and humidity conditions, and take samples at multiple time points within 3 days, 7 days, and 18 days for XRD detection of the sample.

[0362] The experimental results of the stability study are shown in Tables 6-1, 6-2, and 6-3.

[0363] Table 6-1 Experimental results of the physical stability of the formulation API:HPMC-AS-LF (1:1)

[0364]

[0365] Table 6-2 Experimental results of the physical stability of the formulation API:HPMC-AS-LF (1:2)

[0366]

[0367] Table 6-3 Experimental results of the physical stability of the formulation API:HPMC-AS-LF (1:3)

[0368]

[0369] From the above stability test results, it can be seen that under severe conditions (60°C, RH 75%, 70°C, RH 60%, 75°C, RH 30%), the solid properties of formulation F24 changed at the 3-day time point, and the XRD results showed crystal transformation; at the 7-day time point, the appearance colors of formulation F24, formulation F25 and formulation F26 changed. Formulation F25 ( Figure 8 ) showed crystal transformation at 75°C, RH 30%, and there was no obvious change in the solid properties of formulation F26 ( Figure 10 ).

[0370] However, for formulation F25 ( Figures 9-1 to 9-3 ) and formulation F26 ( Figure 11 ), after 18 days under the conditions of 40°C, RH 60%, 40°C, RH 75%, and 60°C, RH 30%, there were no obvious changes in the appearance shape and solid properties, and the XRD results showed that they were still amorphous solid dispersions. Moreover, formulation F26 ( Figure 11 ) could still remain basically stable after 18 days under the extreme conditions of 60°C, RH 75% and 70°C, RH 60%, and could be stably produced industrially. This indicates that formulation F25 and formulation F26 have good physical stability when achieving a relatively high drug-carrier ratio.

[0371] Test Example 1: Pharmacokinetic Tests of the Compound in Rats, Mice and Dogs

[0372] For the pharmacokinetic test in rats, male SD rats weighing 180 - 240 g were used and fasted overnight. Three rats were selected and orally administered 10 mg / kg. Blood samples were collected before dosing and at 15, 30 minutes, and 1, 2, 4, 8, 24 hours after dosing. The blood samples were centrifuged at 8000 rpm for 6 minutes at 4°C, the plasma was collected and stored at -20°C. Plasma samples at each time point were mixed with 3 - 5 times the volume of acetonitrile solution containing internal standard, vortexed for 1 minute, centrifuged at 13000 rpm for 10 minutes at 4°C, the supernatant was mixed with 3 times the volume of water, and an appropriate amount of the mixed solution was subjected to LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed using the non-compartmental model with WinNonlin 7.0 software.

[0373] Mouse pharmacokinetic study: Male ICR mice, weighing 20 - 25 g, were fasted overnight. Three mice were orally administered the drug at a dose of 10 mg / kg. Blood samples were collected before dosing and at 15, 30 minutes, and 1, 2, 4, 8, 24 hours after dosing. The blood samples were centrifuged at 6800 g for 6 minutes at 2 - 8 °C, and the plasma was collected and stored at -80 °C. Plasma samples at each time point were mixed with 3 - 5 volumes of acetonitrile solution containing internal standard, vortexed for 1 minute, centrifuged at 13000 rpm for 10 minutes at 4 °C, the supernatant was mixed with 3 volumes of water, and an appropriate amount of the mixture was subjected to LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed using the non-compartmental model with WinNonlin 7.0 software.

[0374] Dog pharmacokinetic study: Male beagle dogs, weighing 8 - 10 kg, were fasted overnight. Three beagle dogs were orally administered the drug at a dose of 5 mg / kg. Blood samples were collected before dosing and at 15, 30 minutes, and 1, 2, 4, 8, 24 hours after dosing; another three beagle dogs were intravenously administered the drug at a dose of 1 mg / kg, and blood samples were collected before dosing and at 15, 30 minutes, and 1, 2, 4, 8, 24 hours after dosing. The blood samples were centrifuged at 8000 rpm for 6 minutes at 4 °C, the plasma was collected and stored at -20 °C. Plasma samples at each time point were mixed with 3 - 5 volumes of acetonitrile solution containing internal standard, vortexed for 1 minute, centrifuged at 13000 rpm for 10 minutes at 4 °C, the supernatant was mixed with 3 volumes of water, and an appropriate amount of the mixture was subjected to LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed using the non-compartmental model with WinNonlin 7.0 software.

[0375] The results of the rat experiments showed that the compounds I-27, I-28, I-29, and I-30 of the present invention have excellent and comparable pharmacokinetic properties.

[0376] Table 7-1 Mouse Pharmacokinetics of Test Compounds

[0377]

[0378] The results of the mouse experiments showed that the compounds I-27, I-28, I-29, and I-30 of the present invention have excellent and comparable pharmacokinetic properties.

[0379] Table 7-2 Dog Pharmacokinetics of Test Compounds

[0380]

[0381]

[0382] The test results showed that 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, and long half-lives. The pharmacokinetic properties of the two are similar, and they have good drug-likeness.

[0383] Test Example 2: Thermodynamic Solubility Test

[0384] Prepare simulated fasting gastric fluid FaSSGF with pH 1.6 (1 L solution contains 80 μM sodium taurocholate, 20 μM lecithin, 0.1 g pepsin, 34.2 mM sodium chloride), simulated fasting intestinal fluid FaSSIF with 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 phosphate buffered saline PBS with pH 7.4 (1 L solution contains 100 mM phosphate buffer, 11 g sodium bicarbonate, 3.5 g sodium dihydrogen phosphate dihydrate) as the assay buffers.

[0385] Accurately weigh the compound, and use the assay buffers with different pH values to prepare a working solution of 4 mg / mL of the compound. Shake at 1000 rpm for 1 hour and equilibrate overnight at room temperature. Place the sample in a centrifuge and centrifuge at 12000 rmp for 10 min to remove undissolved particles. Transfer the supernatant to a new centrifuge tube and detect the compound concentration in the supernatant by LCMS / MS.

[0386] The experimental results show that Compounds I-27, I-28, I-29, and I-30 all have good solubility.

[0387] Test Example 3: SDD Formulation Canine Pharmacokinetics Test

[0388] For the canine pharmacokinetics test, male beagle dogs, 9 - 11 kg, fast overnight. Take 9 beagle dogs and randomly divide them into 3 groups, with 3 dogs in each group. Prepare the formulations with each prescription of this application and administer them by oral gavage at a dose of 20 mg / kg. Collect about 0.5 mL of blood before dosing and at 15 minutes, 1, 2, 4, 8, and 24 hours after dosing and transfer it to an anticoagulation tube containing EDTA-K2. Centrifuge at 4°C and 1500 g for 10 minutes to obtain plasma. After treating with the acetonitrile protein precipitation method, take an appropriate amount of the mixed solution for LC-MS / MS analysis. The main pharmacokinetic parameters are analyzed using the non-compartmental model with WinNonlin 7.0 software. The results are shown in Table 7-3.

[0389] Table 7-3 Canine Pharmacokinetic Parameters (Oral Gavage Administration)

[0390]

[0391] It can be seen from the results of the canine PK experiment that for the SDD formulation API: HMPC-AS-LF 1:3, when administered at a relatively high dose, it has good exposure, can maintain a supersaturated concentration for a relatively long time, and can maintain stable and continuous in vivo absorption after 4 h.

[0392] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope 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; Wherein, the P2X3 receptor antagonist is selected from the compound represented by the following formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug: in, 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; X is a halogen; m is selected from the integers 1, 2 or 3; L is -(CH2) n -, wherein n is selected from an integer of 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 or deuterated C1-C6 alkyl; when there are multiple substituents, the substituents are the same or different; Wherein 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; unsubstituted or replaced by R 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; unsubstituted or replaced 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 the heteroatom is 1-3; 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 Independently selected from hydrogen or C1-C4 alkyl; 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.

2. The solid dispersion according to claim 1, characterized in that 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 polymer carrier; Preferably, the pharmaceutically acceptable carrier is selected from any one or more of the following: 1) Cellulose derivative carriers; for example, hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose acetate succinate LF, hydroxypropyl cellulose, and hydroxypropyl methylcellulose phthalate; 2) Polyacrylic acid resin carriers; for example, Eudragit L100-55, Eudragit S100, Eudragit L100; 3) Vinyl polymer carriers; for example, polyvinyl caprolactam-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, hydroxypropyl methylcellulose acetate succinate HPMC-AS, polymethacrylate, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; preferably, selected from any one or more of the following: hydroxypropyl methylcellulose HPMC, hydroxypropyl methylcellulose acetate succinate HPMC-AS, polymethacrylate; Preferably, the pharmaceutically acceptable carrier is selected from any one or more of the following: hydroxypropyl methylcellulose E5, copovidone VA64, hydroxypropyl methylcellulose acetate succinate LF, Eudragit L100-55, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; preferably, selected from any one or more of the following: hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose acetate succinate LF, Eudragit L100-55.

3. The solid dispersion according to claim 1 or 2, characterized in that 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; Preferably, the solid dispersion comprises the following components: P2X3 receptor antagonist 10wt%-60wt% 40wt%-90wt% of a pharmaceutically acceptable carrier; 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% (e.g. 25wt%, 33wt%, 33.3wt%, 50wt%) A pharmaceutically acceptable carrier 50wt%-75wt% (e.g., 50wt%, 67wt%, 66.7wt%, 75wt%); 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 25wt%, 33.3wt%, 50wt% Pharmaceutically acceptable carrier 50wt%, 66.7wt%, 75wt% The pharmaceutically acceptable carrier is selected from hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose acetate succinate LF, and Eudragit L100-55; Preferably, the solid dispersion comprises the following components: P2X3 receptor antagonist 25wt% Pharmaceutically acceptable carrier 75wt% The pharmaceutically acceptable carrier is selected from hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose acetate succinate LF, and Eudragit L100-55; Preferably, the solid dispersion comprises the following components: P2X3 receptor antagonist 33.3wt% Pharmaceutically acceptable carrier 66.7wt% The pharmaceutically acceptable carrier is selected from hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose acetate succinate LF, and Eudragit L100-55; Preferably, the solid dispersion comprises the following components: A P2X3 receptor antagonist and hydroxypropyl methylcellulose acetate succinate LF, wherein the proportion of hydroxypropyl methylcellulose acetate succinate LF is not less than 75wt%; Preferably, the solid dispersion comprises the following components: P2X3 receptor antagonist 25wt% Hydroxypropyl methylcellulose acetate succinate LF 75wt%; Preferably, the solid dispersion comprises the following components: A P2X3 receptor antagonist and hydroxypropyl methylcellulose acetate succinate LF, wherein the proportion of hydroxypropyl methylcellulose acetate succinate LF is not less than 66.7wt%; Preferably, the solid dispersion comprises the following components: P2X3 receptor antagonist 33.3wt% Hydroxypropyl methylcellulose acetate succinate LF 66.7wt%; 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 more of the following: a sweetener, a flavoring agent, a colorant, a surfactant, a filler, a lubricant, a disintegrant, a disintegration accelerator, a recrystallization inhibitor, a defoaming agent, an antioxidant and a pH adjuster.

4. The solid dispersion according to any one of claims 1 to 3, characterized in that The compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is: in, 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; X is a halogen; m is selected from the integers 1, 2 or 3; L is -(CH2) n -, wherein n is selected from an integer of 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 substitutions are independently one or more of the following substituents: unsubstituted or substituted with 1-5 identical or different halogens, C1-C4 alkyl, 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 the same or different; Wherein 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; unsubstituted or replaced by R 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; unsubstituted or replaced 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 the heteroatom is 1-3; 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 Independently selected from hydrogen or C1-C4 alkyl; A is independently unsubstituted or substituted 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; Preferably, when R 1 When it is a halogen, the halogen is F, Cl, Br, I, preferably Cl; Preferably, 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; Preferably, when R 1 When it is a C1-C4 alkyl group substituted by 1-5 identical or different halogens, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, preferably methyl or ethyl; Preferably, when R 1 When it is a C1-C4 alkyl 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 integers 1, 2 or 3, preferably 1; Preferably, when L is -(CH2) n -, said n is an integer of 0, 1 or 2, preferably n is 0 or 1; Preferably, 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; Preferably, when R 2 is unsubstituted or replaced by R a When the C1-C6 alkyl group is substituted, 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 replaced by R a When the C3-C7 cycloalkyl is substituted, the C3-C7 alkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl; Preferably, when R 2 is unsubstituted or replaced by R a When the 4-7 membered heterocycloalkyl is substituted, the 4-7 membered heterocycloalkyl is a 4-membered, 5-membered or 6-membered heterocycloalkyl; Preferably, when R 2 is unsubstituted or replaced by R a When the 4-7 membered heterocycloalkyl is substituted, the heteroatom in the 4-7 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 unsubstituted or replaced by R a In the case of a substituted 4-7 membered heterocycloalkyl group, the number of heteroatoms in the 4-7 membered heterocycloalkyl group is 1 to 3, preferably 1 or 2; Preferably, when R 2 is unsubstituted or replaced by R a When the 4-7 membered heterocycloalkyl is substituted, the R a 1 to 3, preferably 1; Preferably, R a is hydroxyl group; Preferably, when R a When it is a halogen, the halogen is F, Cl, Br, I, preferably F or Cl; Preferably, 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; Preferably, when R a When it is a deuterated C1-C6 alkyl, the C1-C6 alkyl is a C1-C3 deuterated alkyl, preferably Preferably, 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; Preferably, R 3 is hydrogen; Preferably, 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; Preferably, when A is R e When the 5- to 10-membered heteroaryl is substituted, the 5- to 10-membered heteroaryl is a 6-membered heteroaryl, preferably pyrimidine or pyridazine; Preferably, when A is R e When the 5- to 10-membered heteroaryl group is substituted, the R e The substitution is single substitution; Preferably, when A is R e When the 5- to 10-membered heteroaryl group is substituted, the R e is a C1-C3 alkyl group substituted by 1 to 5 identical or different halogen groups, preferably a trifluoromethyl group; Preferably, 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; Preferably, -LR 2 Selected from Preferably, -LR 2 for Preferably, -LR 2 Selected from Preferably, R 1 is methyl, ethyl or Cl; Preferably, -LR 2 Selected from Preferably, -LR 2 Selected from Preferably, R 3 is methyl or hydrogen; Preferably, A is selected from Preferably, the compound as shown in Formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is: in, R 1 Selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens; L is -(CH2) n -, wherein n is selected from an integer of 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 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; unsubstituted or replaced by R 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; unsubstituted or replaced 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 the heteroatom is 1-3; R 4 Independently selected from hydrogen or C1-C4 alkyl; R b and R c Independently selected from hydrogen or C1-C4 alkyl; Preferably, the compound as shown in Formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is: in, R 1 Selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens; L is -(CH2) n -, wherein n is selected from an integer of 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 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; unsubstituted or replaced by R 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; unsubstituted or replaced 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 the heteroatom is 1-3; R 4 Independently selected from hydrogen or C1-C4 alkyl; R b and R c Independently selected from hydrogen or C1-C4 alkyl; Preferably, the compound as shown in Formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is: in, R 1 Selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens; L is -(CH2) n -, wherein n is selected from an integer of 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 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; unsubstituted or replaced by R 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; unsubstituted or replaced 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 the heteroatom is 1-3; R 4 Independently selected from hydrogen or C1-C4 alkyl; R b and R c Independently selected from hydrogen or C1-C4 alkyl; Preferably, the compound as shown in Formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is: in, R 1 Selected from halogen, C3-C6 cycloalkyl, or C1-C4 alkyl which is unsubstituted or substituted by 1-5 identical or different halogens; L is -(CH2) n -, wherein n is selected from an integer of 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 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; unsubstituted or replaced by R 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; unsubstituted or replaced 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 the heteroatom is 1-3; R 4 Independently selected from hydrogen or C1-C4 alkyl; R b and R c Independently selected from hydrogen or C1-C4 alkyl; Preferably, the compound as shown in Formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is: in, 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; L is -(CH2) n -, wherein n is selected from an integer of 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 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; unsubstituted or replaced by R 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; unsubstituted or replaced 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 the heteroatom is 1-3; R 4 Independently selected from hydrogen or C1-C4 alkyl; R b and R c Independently selected from hydrogen or C1-C4 alkyl; Preferably, the compound as shown in Formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is: in, 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; L is -(CH2) n -, wherein n is selected from an integer of 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 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; unsubstituted or replaced by R 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; unsubstituted or replaced 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 the heteroatom is 1-3; R 4 Independently selected from hydrogen or C1-C4 alkyl; Preferably, the compound as shown in Formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is: in, 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; L is -(CH2) n -, wherein n is selected from an integer of 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 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; unsubstituted or replaced by R 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; unsubstituted or replaced 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 the heteroatom is 1-3; R 4 Independently selected from hydrogen or C1-C4 alkyl; R b and R c 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 as shown in formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is selected from any one of the following compounds:

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

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

9. Use of the solid dispersion according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 8 in the preparation of a drug for treating and / or preventing a disease related to P2X3, characterized in that: Preferably, the P2X3-related disease is pain, respiratory disease or 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 system disease is reduced bladder capacity, frequent urination, urge incontinence, stress incontinence, bladder hyperresponsiveness, benign prostatic hypertrophy, prostatitis, detrusor hyperreflexia, frequent urination, nocturia, urgency, overactive bladder, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatitis, 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.

10. A method for treating and / or preventing a disease related to P2X3, characterized in that: The method comprises administering an effective amount of the solid dispersion according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 8 to a patient with a P2X3-related disease; Preferably, the P2X3-related disease is pain, respiratory disease or 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 system disease is reduced bladder capacity, frequent urination, urge incontinence, stress incontinence, bladder hyperresponsiveness, benign prostatic hypertrophy, prostatitis, detrusor hyperreflexia, frequent urination, nocturia, urgency, overactive bladder, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatitis, 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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