Oral formulation comprising pyridine phenyl compound, preparation method therefor, and use thereof

Abstract

An oral formulation, comprising a chemical component pyridine phenyl compound and a pharmaceutical excipient. The active component pyridine phenyl compound comprises a compound of formula (II), a crystal form thereof, or a pharmaceutically acceptable salt thereof. The oral formulation can be used for treating chronic cough, asthma, and alcoholic liver disease. The oral formulation exhibits rapid dissolution, has good stability and a simple preparation process, and is suitable for industrial mass production.

Description

An oral preparation containing a pyridinephenyl compound, and its preparation method and application Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, relates to an oral preparation of a pyridinephenyl compound and a preparation method thereof, and also includes the application of the preparation in treating chronic cough, asthma and alcoholic liver disease. Background Art

[0002] Chronic cough (CC) is categorized as unexplained chronic cough and refractory chronic cough. Cough is typically the sole or primary symptom, with a duration of >8 weeks and no significant chest abnormalities (>4 weeks for children). A key pathophysiological characteristic of chronic cough is cough hypersensitivity, which is associated with dysregulation of channels and receptors in peripheral and central nervous systems. Various stimuli in peripheral nerves activate cough receptors, transmitting signals along nerve fibers. Inflammatory mediators can sensitize cough receptors, increasing their excitability, thereby lowering the cough threshold and increasing peripheral impulse input to the cough center, inducing cough.

[0003] Asthma is a chronic, heterogeneous airway disease with a high prevalence worldwide. Its clinical manifestations primarily include recurrent episodes of wheezing, shortness of breath, chest tightness, or cough. Airway pathology manifests as airway hyperresponsiveness, variable airflow limitation, and airway remodeling. The pathogenesis of asthma is complex, driven by both genetic and environmental factors and involving multiple systems, including the nervous, endocrine, and immune systems. Asthma is broadly categorized into allergic and non-allergic asthma. Allergic asthma is a subtype of allergen-induced asthma characterized by eosinophilic airway inflammation, bronchial hyperresponsiveness, and elevated immunoglobulin E (IgE) levels. Allergic asthma is characterized by the synthesis of specific immunoglobulin antibodies following initial exposure to the allergen. Subsequent exposure to the allergen leads to crosslinking of high-affinity IgA receptors on tissue mast cells, resulting in degranulation of mast cells and basophils, leading to bronchoconstriction, and subsequent eosinophil recruitment and inflammatory responses. Asthma episodes are often accompanied by significant behavioral changes, such as nasal scratching and coughing and wheezing. Existing therapeutic drugs include maintenance anti-inflammatory drugs, including inhaled corticosteroids (ICS), systemic hormones, leukotriene modifiers, long-acting inhale bete2-agonist (LABA), sustained-release theophylline, supelalast tolyl, sodium cromoglycate, etc. In addition, there are drugs that can quickly relieve bronchospasm and thus relieve asthma symptoms, including fast-acting inhaled and short-acting oral beta2 receptor agonists, inhaled anticholinergics, short-acting theophylline and systemic hormones, etc. There are additional therapeutic drugs for severe asthma: mainly biological targeted drugs, such as anti-IgE monoclonal antibodies, anti-IL-5 monoclonal antibodies, anti-IL-5 receptor monoclonal antibodies and anti-IL-4 receptor monoclonal antibodies, etc., and others include macrolide drugs, etc. However, inhaled and oral steroids have numerous adverse reactions and are not suitable for long-term use. Leukotriene modifiers can also cause psychiatric symptoms. Theophylline-based medications have significant individual variability and are only used as supplemental maintenance therapy. Other medications also have limitations in efficacy and safety. Therefore, there is a significant unmet clinical need for asthma treatments.

[0004] Alcoholic liver disease (ALD) is a chronic liver disease caused by long-term, heavy drinking. It typically presents initially with hepatocyte fatty degeneration, which can progress to alcoholic hepatitis and further to alcoholic liver fibrosis and cirrhosis. The liver is one of the most complex organs in the human body, with functions such as detoxification, digestion, and regulation of glucose and lipid levels. Under normal circumstances, hepatocytes possess a robust capacity for repair and regeneration. However, chronic alcohol abuse can lead to persistent damage to hepatocytes, reducing their regenerative capacity and potentially causing severe liver impairment, ultimately leading to the development of ALD. Alcoholic hepatitis (AH) is a severe inflammatory response syndrome of alcohol-related liver disease. It often occurs in patients with persistent, heavy drinking. Its main clinical features are nausea, vomiting, jaundice, and hepatomegaly and tenderness, which can be complicated by liver failure and upper gastrointestinal bleeding. Severe alcohol abuse can induce hepatocellular necrosis and even lead to liver failure. The pathogenesis of AH is complex, involving both direct and indirect effects of alcohol and its metabolites on the liver. Oxidative stress is a hallmark mechanism of alcoholic hepatitis. Oxidative stress can trigger numerous cascading injury responses and, in concert with other factors, accelerate liver damage. Furthermore, alcohol-induced Kupffer cell activation, resulting in the massive release of inflammatory factors and inhibition of autophagy, is another key factor in the development of alcoholic fatty liver disease. Currently, there is no definitive treatment for alcoholic fatty liver disease and alcoholic hepatitis; alcohol abstinence, psychological counseling, and infection prevention remain the cornerstones of treatment. When patients have a good appetite and normal serum creatinine levels, corticosteroids remain the mainstay of treatment, while early liver transplantation is the only option for patients unresponsive to steroids. While there is currently no cure for alcoholic liver fibrosis and alcoholic cirrhosis, controlling and reversing the progression of alcoholic fatty liver disease and alcoholic hepatitis can delay the development of severe alcoholic fibrosis and cirrhosis. Therefore, the search for safe and effective antioxidant and anti-inflammatory agents is of great clinical significance in addressing the development of alcoholic liver disease.

[0005] Because tissues and organs in the body produce some toxic aldehydes through metabolic mechanisms, such as malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4HNE), these aldehydes are highly reactive with proteins, carbohydrates, fats and DNA, leading to chemical modification of biological molecules and activation of inflammatory molecule regulators such as NF-kappaB, thereby causing damage to different organs.

[0006] WO2020125659 discloses a series of compounds satisfying the general formula (II) of a pyridinephenyl RASP inhibitor compound or a pharmaceutically acceptable salt thereof:

[0007] WO / 2022 / 063325 discloses a crystal form of a pyridinephenyl compound and a preparation method thereof, and also includes the use of the crystal form in the preparation and treatment of related diseases.

[0008] However, the oral formulations and their therapeutic effects on chronic cough, asthma, or alcoholic liver disease have not yet been disclosed. Therefore, further research is needed to explore the efficacy and safety of oral formulations of the above-mentioned small molecule compounds for chronic cough, asthma, or alcoholic liver disease, and to develop preparation processes and oral formulations with stable quality. Summary of the Invention

[0009] The purpose of the present invention is to provide an oral preparation with rapid dissolution and good stability, and the preparation process of the oral preparation is simple, the quality is stable, and it is suitable for large-scale industrial production.

[0010] The present invention provides an oral preparation comprising a RASP inhibitor pyridinylphenyl compound and a pharmaceutical excipient, wherein the RASP inhibitor pyridinylphenyl compound comprises a compound of formula (II) or a pharmaceutically acceptable salt or a crystalline form thereof:

[0011] in,

[0012] described is selected from single bonds and double bonds;

[0013] T1, T2, T3 or T4 are each independently selected from N, C or CR1;

[0014] T5 is selected from C, CR5 or C=O;

[0015] T6 is selected from C, CR6 or N;

[0016] T7 is selected from N or CR7;

[0017] When T5 is selected from C=O and T6 is selected from N, is selected from single bonds;

[0018] L is selected from a single bond, -O-, -S-, -NR2- or -(CR3R4) n -;

[0019] R1 is selected from H, F, Cl, Br, I, OH or NH2;

[0020] R2 is selected from H or optionally substituted by 1, 2 or 3 R a Substituted C 1-3 alkyl;

[0021] R3 or R4 are independently selected from H, F, Cl, Br, I, OH, NH2, CN or optionally 1, 2 or 3 R bSubstituted C 1-3 alkyl;

[0022] R 5、 R6 or R7 are independently selected from H, F, Cl, Br or I;

[0023] n is selected from 1, 2 or 3;

[0024] R a or R b Each is independently selected from H, F, Cl, Br, I, OH, NH2, CN or CH3.

[0025] In some embodiments of the present invention, R2 in the compound of formula (II) is selected from H, CH3 or CH2CH3, and the CH3 or CH2CH3 is optionally replaced by 1, 2 or 3 R a Substitution, other variables are as defined in the present invention.

[0026] In some embodiments of the present invention, in the compound of formula (II), R2 is selected from H, CH3 or CH2CH3, and other variables are as defined in the present invention.

[0027] In some embodiments of the present invention, R3 and R4 in the compound of formula (II) are independently selected from H, F, Cl, Br, I, OH, NH2, CN, CH3 or CH2CH3, and the CH3 or CH2CH3 is optionally replaced by 1, 2 or 3 R b Substitution, other variables are as defined in the present invention.

[0028] In some embodiments of the present invention, R3 and R4 in the compound of formula (II) are independently selected from H, F, Cl, Br, I, OH, NH2, CN, CH3 or CH2CH3, and other variables are as defined in the present invention.

[0029] In some embodiments of the present invention, L in the compound of formula (II) is selected from a single bond, -O-, -S-, -NH-, -(CH2)2- or -CH2-, and other variables are as defined in the present invention.

[0030] Some other solutions of the present invention are obtained by arbitrarily combining the above variables.

[0031] In the present invention, as one of the embodiments, the alcoholic liver disease includes alcoholic fatty liver, alcoholic hepatitis, alcoholic liver fibrosis or cirrhosis.

[0032] In the present invention, as one of the embodiments, it is characterized in that the application is the application of the compound of formula (II) or a pharmaceutically acceptable salt thereof in the preparation of a method for treating alcoholic fatty liver.

[0033] In the present invention, as one of the embodiments, it is characterized in that the application is the application of the compound of formula (II) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating alcoholic hepatitis.

[0034] In the present invention, as one of the embodiments, it is characterized in that the application is the application of the compound of formula (II) or a pharmaceutically acceptable salt thereof in the preparation of a method for treating alcoholic liver fibrosis.

[0035] In the present invention, as one of the embodiments, it is characterized in that the application is the application of the compound of formula (II) or a pharmaceutically acceptable salt thereof in the preparation of a method for treating liver cirrhosis.

[0036] In some embodiments of the present invention, the above-mentioned compound, its pharmaceutically acceptable salt or its crystalline form is selected from

[0037] in,

[0038] T3 or T4 are each independently selected from N or CR1;

[0039] R1 or L is as defined in the present invention.

[0040] In some embodiments of the present invention, the above-mentioned compound, its pharmaceutically acceptable salt or its crystalline form is selected from

[0041] in,

[0042] R1 or L is as defined in the present invention.

[0043] The present invention also provides a compound represented by the following formula, a pharmaceutically acceptable salt thereof, or a crystalline form thereof, selected from:

[0044] The present invention provides an oral formulation comprising a RASP inhibitor pyridinylphenyl compound as an active ingredient, one or more fillers, one or more disintegrants, one or more binders, one or more lubricants, and one or more surfactants, wherein the pyridinylphenyl compound comprises a compound of formula (III), formula (IV), formula (V), formula (VI), formula (VII), or formula (VIII), or a pharmaceutically acceptable salt thereof, or a crystalline form thereof:

[0045] In the present invention, as one embodiment, the active ingredient also includes the B form of the compound of formula (III) (the B form is described in patent application WO / 2022 / 063325), which is also referred to as the compound of formula (IX) in the present invention:

[0046] In the present invention, as one embodiment, the active ingredient further comprises a salt form of a compound of formula (III), preferably a hydrochloride:

[0047] In the present invention, as one of the embodiments, the active ingredient is the hydrochloride of the compound of formula (III), preferably its G crystal form.

[0048] In some technical solutions of the present invention, the salt of the compound of formula (III) is selected from hydrochloride, and the molar ratio of the compound of formula (III) to hydrochloric acid is preferably 1:0-3.1, more preferably 1:0.5-2.5, more preferably 1:1.0-2.1, and most preferably 1:1.0 or 1:2.0.

[0049] The present invention provides a G crystal form of the hydrochloride salt of a compound represented by formula (III), characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2θ angles: 18.82±0.20°, 25.45±0.20° and 28.17±0.20°.

[0050] The present invention provides a G crystal form of the hydrochloride salt of the compound represented by formula (III), characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2θ angles: 14.08±0.20°, 16.84±0.20°, 18.82±0.20°, 25.45±0.20°, 27.41±0.20°, 28.17±0.20°, 28.40±0.20° and 35.79±0.20°.

[0051] The present invention provides a G crystal form of the hydrochloride of the compound of formula (III), characterized in that, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystal form has characteristic diffraction peaks at the following 2θ angles: 7.41±0.20°, 8.64±0.20°, 14.08±0.20°, 15.32±0.20°, 16.84±0.20°, 17.30±0.20°, 18.82±0 .20°, 20.61±0.20°, 20.88±0.20°, 22.82±0.20°, 24.59±0.20°, 25.45±0.20°, 25.74±0.20°, 27.41±0.20°, 28.17±0.20°, 28.40±0.20°, 29.80±0.20°, 30.07±0.20° and 35.79±0.20°.

[0052] In some embodiments of the present invention, the XRPD pattern of the hydrochloride form G of the compound of formula (III) is shown in Figure 1.

[0053] In some embodiments of the present invention, the XRPD pattern analysis data of the G crystal form of the hydrochloride salt of the compound of formula (III) are shown in Table 1.

[0054] Table 1: XRPD pattern analysis data of Form G of hydrochloride salt of compound of formula (III)

[0055] In some embodiments of the present invention, Form G of the hydrochloride salt of the compound of formula (III) exhibited a 0.9% weight loss during heating to 90°C, with possible decomposition occurring after 100°C. DSC results revealed endothermic signals at 144.8°C and 148.5°C. The TGA / DSC spectrum is shown in FIG2 .

[0056] The G-form of the hydrochloride salt of the compound of formula (III) described herein has advantages such as good solid-state stability, high solubility in water and biological media, and no significant hygroscopicity. Its good solubility enables the design of higher dosage specifications. Furthermore, the G-form of the hydrochloride salt of the compound of formula (III) exhibits excellent compressibility, making it suitable for the development of oral formulations.

[0057] In the present invention, as one embodiment, the oral preparation comprises one or more fillers.

[0058] In the present invention, as one embodiment, the oral preparation includes one or more disintegrants.

[0059] In the present invention, as one embodiment, the oral preparation includes one or more binders.

[0060] In the present invention, as one of the embodiments, the oral preparation further comprises one or more lubricants.

[0061] In the present invention, as one of the embodiments, the oral preparation further comprises one or more surfactants.

[0062] In the present invention, as one embodiment, the oral preparation comprises one or more fillers and one or more disintegrants.

[0063] In the present invention, as one embodiment, the oral preparation comprises one or more fillers, one or more disintegrants and one or more binders.

[0064] In the present invention, as one embodiment, the oral preparation includes one or more fillers, one or more disintegrants, one or more binders and one or more lubricants.

[0065] In the present invention, as one embodiment, the oral preparation includes one or more fillers, one or more disintegrants, one or more binders, one or more lubricants and one or more surfactants.

[0066] In the present invention, as one of the embodiments, the filler is selected from microcrystalline cellulose, mannitol, lactose, or a combination of two or more thereof.

[0067] In the present invention, as one of the embodiments, the disintegrant is selected from cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, cross-linked polyvinylpyrrolidone or calcium carboxymethyl cellulose, or a combination of two or more thereof.

[0068] In the present invention, as one of the embodiments, the binder is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone or methylcellulose, or a combination of two or more thereof.

[0069] In the present invention, as one embodiment, the lubricant is selected from magnesium stearate or colloidal silicon dioxide, or a combination of two or more thereof.

[0070] In the present invention, as one of the embodiments, the surfactant is selected from sodium lauryl sulfate.

[0071] As one embodiment, in the oral preparation provided by the present invention, the active ingredient RASP inhibitor pyridine phenyl compound can be selected from the compound of formula (III) and the crystalline form B of compound of formula (III), and the content of the active ingredient (on anhydrous basis) is 1% to 75% of the total weight of the composition, preferably 10% to 60%, further preferably 20% to 50%, more preferably 30% to 40%, and most preferably 32.68%.

[0072] As one embodiment, in the oral preparation provided by the present invention, the active ingredient, a RASP inhibitor pyridinephenyl compound, can be selected from the hydrochloride of the compound of formula (III) or the G crystal form of the hydrochloride of the compound of formula (III), and the content of the active ingredient (calculated as anhydrous free state) is 1% to 75% of the total weight of the composition, preferably 10% to 60%, further preferably 20% to 50%, more preferably 30% to 40%, and most preferably 33.33%.

[0073] The oral preparation provided in the present invention may further include one or more of a filler, a disintegrant, a binder, a lubricant and a surfactant.

[0074] In the oral preparation provided by the present invention, the filler may include but is not limited to lactose, microcrystalline cellulose, mannitol, pregelatinized starch, anhydrous calcium hydrogen phosphate, calcium sulfate, calcium carbonate, dextrin, maltose, sorbitol, trehalose or xylitol.

[0075] In a preferred embodiment of the present invention, the filler is selected from one or more of lactose, microcrystalline cellulose, and mannitol. In a more preferred embodiment, the filler is a mixture of mannitol and microcrystalline cellulose.

[0076] In the oral preparation provided by the present invention, the content of the filler can be 0.1% to 75% of the total weight of the pharmaceutical composition, preferably 5% to 70%, more preferably 10% to 65%, and more preferably 20% to 63%. As an example, it can be 60.95%, 60.94%, 58.98%, 57.02%, 54.08%, 53.59%, 47.90%, 30.47%, 29.49%, 28.51%, 27.04%, 27.12%, 26.47%, or 23.95%. The weight ratio of microcrystalline cellulose to mannitol is 0:1, 5:3, 3:1, 1:1, or 1:0, preferably 1:1 or 1:0; the weight ratio of microcrystalline cellulose to lactose is 1.02:1, 5:3, 3:1, 1:1, or 1:0, preferably 1:1, 1:0, or 1.02:1.

[0077] In the oral formulations provided herein, disintegrants may include, but are not limited to, cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, cross-linked polyvinylpyrrolidone, carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose alginate, chitosan, and corn starch. In a preferred embodiment of the present invention, the disintegrant in the composition may include, but is not limited to, one or more of cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, cross-linked polyvinylpyrrolidone, and carboxymethyl cellulose calcium. In a preferred embodiment of the present invention, the disintegrant is cross-linked sodium carboxymethyl cellulose.

[0078] In the oral preparation provided by the present invention, the content of the disintegrant can be 0.1% to 20% of the total weight of the pharmaceutical composition, preferably 0.5% to 15%, more preferably 1% to 10%, and most preferably 1.00%, 1.96%, 2.00%, 3.92%, 5.88% or 7.84%.

[0079] In the oral preparation provided by the present invention, the binder may include, but is not limited to, one or more of hydroxypropyl methylcellulose, methylcellulose, polyvinyl pyrrolidone, pregelatinized starch, hydroxypropyl cellulose, sodium carboxymethyl cellulose, and ethyl cellulose.

[0080] In the oral preparation provided by the present invention, the content of the binder is about 0.1% to 5%, preferably 0.5% to 4%, more preferably 1% to 3%, and most preferably 1.47% or 1.50%, based on the total weight of the composition.

[0081] The oral preparation provided in the present invention may further contain one or more lubricants, such as magnesium stearate, micropowdered silica, colloidal silicon dioxide, talc, hydrogenated vegetable oil, polyethylene glycol, and the content of the lubricant is 0.1% to 5% of the total weight of the composition, preferably 0.3% to 3%, more preferably 0.4% to 2%, and most preferably 0.49%, 0.98% or 1.00%.

[0082] The oral formulations provided herein may also be surfactant-free or contain a surfactant, such as sodium lauryl sulfate (SDS), in an amount of about 0.1% to 5%, preferably 0.3% to 3%, more preferably 0.5% to 2%, and most preferably 0.98%, based on the total weight of the composition.

[0083] In a preferred embodiment of the present invention, a pharmaceutical composition is provided, comprising the following ingredients by weight (active ingredients are calculated as anhydrous):

[0084] 1) 1% to 75% of 2-(2-amino-4-(5-amino-6-(2-hydroxypropan-2-yl)pyridin-3-yl)phenyl)propan-2-ol or its crystalline form B (monohydrate);

[0085] 2) 0.1% to 75% of a filler selected from one or both of lactose, microcrystalline cellulose, and mannitol;

[0086] 3) 0.1% to 20% of a disintegrant selected from one or more of croscarmellose sodium, sodium starch glycolate, cross-linked polyvinylpyrrolidone, or carboxymethylcellulose calcium;

[0087] 4) 0.1% to 5% of a binder selected from one or more of hypromellose, methylcellulose, or polyvinylpyrrolidone;

[0088] 5) 0.1% to 5% of a lubricant selected from magnesium stearate or colloidal silicon dioxide;

[0089] 6) 0.1% to 5% of a surfactant selected from sodium dodecyl sulfate (SDS).

[0090] In a further preferred embodiment of the present invention, there is also provided a pharmaceutical composition comprising the following ingredients by weight (active ingredients are calculated as anhydrous):

[0091] 1) 30% to 40% of 2-(2-amino-4-(5-amino-6-(2-hydroxypropan-2-yl)pyridin-3-yl)phenyl)propan-2-ol or its crystalline form B (monohydrate);

[0092] 2) 20% to 65% of a filler selected from microcrystalline cellulose and lactose, wherein the weight ratio of microcrystalline cellulose to lactose is preferably 1:1 or 1.02:1;

[0093] 3) 1% to 8% of a disintegrant selected from one or more of croscarmellose sodium, sodium starch glycolate, cross-linked polyvinylpyrrolidone, or carboxymethylcellulose calcium;

[0094] 4) 1% to 3% of a binder selected from hypromellose;

[0095] 5) 0.5% to 1% of a lubricant selected from magnesium stearate or colloidal silicon dioxide;

[0096] 6) 0.5% to 1% of a surfactant selected from sodium dodecyl sulfate (SDS).

[0097] In a more preferred embodiment of the present invention, there is also provided a pharmaceutical composition comprising the following ingredients by weight (active ingredients are calculated as anhydrous):

[0098] 1) 30% to 40% of 2-(2-amino-4-(5-amino-6-(2-hydroxypropan-2-yl)pyridin-3-yl)phenyl)propan-2-ol or its crystalline form B (monohydrate);

[0099] 2) 30% to 65% of a filler selected from microcrystalline cellulose and mannitol, wherein the weight ratio of microcrystalline cellulose to mannitol is preferably 1:1 or 1:0;

[0100] 3) 1% to 2% of a disintegrant selected from croscarmellose sodium;

[0101] 4) 1% to 2% of a binder selected from one or more of hypromellose, methylcellulose, or polyvinylpyrrolidone;

[0102] 5) 0.5% to 1% of a lubricant selected from magnesium stearate.

[0103] In the most preferred embodiment of the present invention, there is also provided a pharmaceutical composition comprising the following ingredients by weight (active ingredients are calculated as anhydrous):

[0104] 1) 32.68% of 2-(2-amino-4-(5-amino-6-(2-hydroxypropan-2-yl)pyridin-3-yl)phenyl)propan-2-ol or its crystalline form B (monohydrate);

[0105] 2) 60.94% of a filler selected from mannitol and microcrystalline cellulose, wherein the weight ratio of mannitol to microcrystalline cellulose is preferably 1:1;

[0106] 3) 1.96% of a disintegrant selected from croscarmellose sodium;

[0107] 4) 1.47% binder selected from hypromellose;

[0108] 5) 0.98% of a lubricant selected from magnesium stearate.

[0109] In a preferred embodiment of the present invention, a pharmaceutical composition is provided, comprising the following ingredients by weight (active ingredients are calculated in anhydrous free form):

[0110] 1) 1% to 75% of 2-(2-amino-4-(5-amino-6-(2-hydroxypropan-2-yl)pyridin-3-yl)phenyl)propan-2-ol hydrochloride or its G crystalline form hydrochloride, preferably 10% to 60%, more preferably 20% to 50%, more preferably 30% to 40%, and most preferably 33.33%;

[0111] 2) 0.1% to 75% of a filler selected from one or both of microcrystalline cellulose and mannitol, preferably 5% to 70%, more preferably 10% to 65%, more preferably 20% to 63%, and most preferably 23.95% or 47.90%, wherein the weight ratio of microcrystalline cellulose to mannitol is 1:1 or 1:0;

[0112] 3) 0.1% to 20% of a disintegrant selected from one or more of croscarmellose sodium, sodium starch glycolate, and cross-linked polyvinylpyrrolidone, preferably 0.5% to 15%, more preferably 1% to 10%, and most preferably 1.00% or 2.00%;

[0113] 4) 0.1% to 5% of a binder selected from one or more of hypromellose, methylcellulose, or hydroxypropylcellulose, preferably 0.5% to 4%, more preferably 1% to 3%, and most preferably 1.50%;

[0114] 5) 0.1% to 5% of a lubricant selected from magnesium stearate, preferably 0.4% to 2%, most preferably 1.00%.

[0115] In the most preferred embodiment of the present invention, there is provided a pharmaceutical composition comprising the following ingredients by weight (active ingredients are calculated in anhydrous free form):

[0116] 1) 33.33% of 2-(2-amino-4-(5-amino-6-(2-hydroxypropan-2-yl)pyridin-3-yl)phenyl)propan-2-ol hydrochloride or its hydrochloride Form G;

[0117] 2) 47.90% of a filler selected from microcrystalline cellulose;

[0118] 3) 2.00% of a disintegrant selected from croscarmellose sodium;

[0119] 4) 1.50% binder selected from hypromellose;

[0120] 5) 1.00% of a lubricant selected from magnesium stearate.

[0121] Technical Effects

[0122] The present invention discloses an oral preparation containing a pyridinephenyl compound, which exhibits good stability in influencing factor tests and accelerated tests, dissolves quickly in an in vitro dissolution medium, and has the advantage of easy process scale-up. In addition, in efficacy tests on citric acid-induced chronic cough in guinea pigs, efficacy tests on a Gao-binge diet-induced alcoholic hepatitis model in mice, and efficacy tests on an OVA-induced asthma model in mice, the oral preparation demonstrates efficacy in treating chronic cough, asthma, and alcoholic liver disease.

[0123] Definition and Description

[0124] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered as undefined or unclear in the absence of a specific definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0125] The "pharmaceutical composition" of the present invention is generally intended for oral administration. Pharmaceutical compositions for oral administration may further comprise sweeteners, flavorings, coloring agents, coating agents, and / or preservatives to provide a palatable formulation. In one embodiment, the pharmaceutical composition is in the form of a tablet. Tablets can be prepared by compression or molding. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, or preservative. Molded tablets can be prepared by molding a mixture of powdered active ingredients moistened with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored.

[0126] As used herein, "pharmaceutical formulation" refers to a process in which different chemical substances (including active drugs) are combined to produce a final pharmaceutical product. Pharmaceutical formulations include enteral formulations (tablets, capsules), parenteral formulations (liquids, lyophilized powders), or topical formulations (dermal, inhalable).

[0127] The "pharmaceutically acceptable excipients, carriers or diluents" of the present invention include, but are not limited to, any adjuvant, carrier, excipient, retention aid, extender, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by relevant government regulatory authorities as acceptable for use by humans or livestock.

[0128] The term "filler" refers to substances that improve the compression moldability of a drug and enhance content uniformity. Fillers include starch, sucrose, dextrin, lactose, pregelatinized starch, microcrystalline cellulose, corn starch, dextrose, ethyl cellulose, fructose, maltodextrin, maltose, medium-chain triglycerides, anhydrous calcium hydrogen phosphate, calcium sulfate, calcium carbonate, and the sugar alcohols erythritol, isomalt, lactitol, mannitol, sorbitol, trehalose, and xylitol.

[0129] The term "disintegrant" refers to an excipient that helps tablets break down into fine particles quickly in gastrointestinal fluids. It primarily serves to eliminate the binding forces created by adhesion and / or high compression, thereby causing the tablet to disintegrate in water. Disintegrants include dry starch, sodium starch glycolate, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, microcrystalline cellulose, alginic acid, and sodium alginate.

[0130] The term "binder" refers to an excipient that possesses inherent viscosity and can impart appropriate viscosity to a non-viscous or insufficiently viscous material. This helps solid powders bind together into larger particles, thus contributing to the creation of a more robust dosage form. Binders include starch slurry, cellulose derivatives, methylcellulose, hydroxypropyl cellulose, hypromellose, sodium carboxymethylcellulose, povidone, gelatin, 50%-70% sucrose solution, and sodium alginate solution.

[0131] The term "lubricant" refers to a material that prevents material from agglomerating and adhering to the punch tip or the punch tip surface, or to the material in the capsule filling machine. Lubricants can improve the surface properties of particles, such as improving electrostatic distribution and surface roughness, reducing friction, enhancing the selective adsorption of gases, and weakening the van der Waals forces between particles. Lubricants include magnesium stearate, micronized silica gel, talc, hydrogenated vegetable oils, polyethylene glycols, hydrogenated castor oil, cottonseed oil, glyceryl behenate, glyceryl monostearate, glyceryl palmitate, medium-chain triglycerides, mineral oil, light mineral oil, octyldodecanol, poloxamer, polyethylene glycol, polyoxyethylene stearate, and polyvinyl alcohol.

[0132] The term "surfactant" refers to a class of excipients that can significantly reduce the surface tension of a solution. It not only has the common properties of surfactants such as solubilization, emulsification, wetting, foaming, dispersion, and surface tension reduction, but can also be used as a wetting agent, binder, disintegrant, and lubricant in oral solid preparations. Surfactants include sodium lauryl sulfate, sodium lauryl sulfate, sodium dioctyl succinyl sulfonate, polyoxyethylene (40) stearate, polyoxyethylene fatty alcohol ether, polyoxyethylene alkylphenol ether, Tween-type, Span-type, amino acid type and betaine type, polyethylene glycol caprylic acid glyceryl ester, polyethylene glycol lauric acid glyceride, polyethylene glycol stearic acid glyceride, etc.

[0133] The solvents used in the present invention can be obtained commercially. Software naming, commercially available compounds use supplier catalog names.

[0134] Specific methods of XRPD, DSC, TGA, and DVS (including equipment models and parameters)

[0135] X-ray powder diffraction (XRPD) of the present invention

[0136] Samples were analyzed using a Bruker D8 Advance X-ray powder diffractometer (Bruker, Germany). The 2θ scan angle ranged from 3° to 45°, with a scan step size of 0.02° and an exposure time of 0.08 seconds. The test method used Cu target Kα1 radiation, a voltage of 40 kV, a current of 40 mA, and a zero-background sample pan.

[0137] Thermogravimetric analysis (TGA) of the present invention

[0138] The thermogravimetric analyzer (TA Discovery 55, TA, US) was used. A 2-5 mg sample was placed in a equilibrated open aluminum sample pan and automatically weighed in the TGA furnace. The sample was heated to the final temperature at a rate of 10°C / min. A nitrogen purge rate of 60 mL / min was maintained at the sample and 40 mL / min at the balance.

[0139] Differential scanning calorimetry (DSC)

[0140] The differential scanning calorimeter was a TA Discovery 2500 (TA, US). 1-2 mg of sample was accurately weighed and placed in a perforated DSC Tzero sample pan. The sample was heated to the final temperature at a rate of 10°C / min, with nitrogen purge rate of 50 mL / min.

[0141] Dynamic moisture sorption / desorption analysis (DVS)

[0142] Dynamic moisture sorption / desorption analysis was performed using a DVS Intrinsic (SMS, UK). The test used a gradient mode with humidity changes from 0% to 95% to 0%, with each gradient increasing by 10% within the 0% to 90% range. The gradient endpoint was determined using the dm / dt method, with a dm / dt of less than 0.002% maintained for 10 minutes, or a maximum of 180 minutes per gradient. After the test, the sample was analyzed by XRPD to confirm any changes in the solid form. BRIEF DESCRIPTION OF THE DRAWINGS

[0143] Figure 1: XRPD pattern of the hydrochloride form G of the compound of formula (III);

[0144] Figure 2: DSC and TGA spectra of the hydrochloride form G of the compound of formula (III);

[0145] Figure 3 shows the dissolution curves of the tablets of Examples 1 to 7 in pH 4.5 acetate buffer solution;

[0146] Figure 4 shows the dissolution profile of the tablet of Example 8 in pH 4.5 acetate buffer solution;

[0147] FIG5 shows the dissolution curves of the capsules of Examples 9-10 in acetate buffer solution at pH 4.5;

[0148] Figure 6 shows the dissolution profiles of the tablets of Examples 11 to 14 in acetate buffer solution at pH 4.5;

[0149] Figure 7a: DVS curve of the hydrochloride form G of the compound of formula (III);

[0150] Figure 7b: XRPD patterns of Form G hydrochloride of the compound of formula (III) before and after DVS testing;

[0151] Figure 8: XRPD pattern of the stability study of the hydrochloride form G of the compound of formula (III);

[0152] Figure 9 shows the dissolution profiles of the tablets of Examples 16-17 in acetate buffer solution at pH 4.5;

[0153] Figure 10 shows the dissolution curves of the tablets of Examples 16 and 18 to 21 in acetate buffer solution at pH 4.5;

[0154] Figure 11: Number of coughs in each group on day 8 ***p < 0.001 vs Model;

[0155] Figure 12: Cough counts of guinea pigs on day 12, *p<0.05 vs Model, **p<0.01 vs Model, ***p<0.001 vs Model;

[0156] Figure 13: Cough counts of guinea pigs on day 15, *p<0.05 vs Model, **p<0.01 vs Model, ***p<0.001 vs Model;

[0157] Figure 14: Mouse righting reflex. (A) Latency of righting reflex loss. (B) Recovery period of righting reflex loss. **p < 0.01 vs. Model, ***p < 0.001 vs. Model;

[0158] Figure 15: Mouse liver index. ***p<0.001 vs Control;

[0159] Figure 16: Serum alanine aminotransferase (ALT) levels in mice. *p<0.05 vs Model, ##p<0.01 vs Control;

[0160] Figure 17: Pathological changes of mouse liver tissue (H&E staining, Oil Red O staining, ×200);

[0161] Figure 18: Number of times mice scratched their noses on day 28;

[0162] Figure 19: Cough and wheeze frequency of mice on day 28, *p<0.05 vs Model, ***p<0.001 vs Model;

[0163] Figure 20: Cough and asthma latency in mice on day 28, ***p < 0.001 vs Model;

[0164] Figure 21: Behavioral scores of panting in mice on day 28, **p<0.01 vs Model, ***p<0.001 vs Model;

[0165] Figure 22: Total cell number in mouse BALF on day 28, *p<0.05 vs Model, **p<0.01 vs Model;

[0166] Figure 23: Eosinophil counts in BALF of mice on day 28, *p<0.05 vs Model, **p<0.01 vs Model, ***p<0.001 vs Model;

[0167] Figure 24: The number of basophils in BALF of mice on day 28, **p<0.01 vs Model. DETAILED DESCRIPTION

[0168] The present invention is further described in detail by the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0169] Examples 1 to 7

[0170] The compound of formula (IX) (crystal form B of the compound of formula (III), for the preparation and crystal form data of the crystal form B, see patent application No. WO / 2022 / 063325), lactose, microcrystalline cellulose, cross-linked carboxymethyl cellulose sodium, sodium starch glycolate, cross-linked polyvinylpyrrolidone, carboxymethyl cellulose calcium, and sodium lauryl sulfate are wet granulated in the proportions of Table 2 using a high-efficiency wet mixing granulator. A 3.4% aqueous solution of hydropropyl methylcellulose is used as the granulating liquid. After granulation, wet granulation and drying are performed. The dried granules (moisture content <3%) are granulated, and additional cross-linked carboxymethyl cellulose sodium or sodium starch glycolate, cross-linked polyvinylpyrrolidone, carboxymethyl cellulose calcium and magnesium stearate are added, mixed evenly and tableted.

[0171] Table 2

[0172] Experimental Example 1 Dissolution Test

[0173] According to the second method (slurry method) of Part 4 of the 2020 edition of the Chinese Pharmacopoeia, 0931, the dissolution rate of the tablets in Examples 1 to 7 was determined. The dissolution test was carried out using 900 ml of pH 4.5 acetate buffer solution as the dissolution medium at a slurry speed of 50 rpm at 37°C ± 0.5°C. The results showed that the compound of formula (IX) in Example 7 dissolved slowly and failed to dissolve completely in 45 minutes. The compounds of formula (IX) in the remaining examples were all completely dissolved. Based on the results of the above examples, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch and cross-linked polyvinylpyrrolidone are preferred as disintegrants. Considering that cross-linked sodium carboxymethyl cellulose has relatively low hygroscopicity, cross-linked sodium carboxymethyl cellulose is most preferred as a disintegrant. Since increasing the amount of disintegrant and adding a surfactant does not significantly improve the dissolution behavior, the amount of disintegrant is preferably 2.0%. The dissolution data are shown in Table 3, and the dissolution curve is shown in Figure 3.

[0174] Table 3

[0175] Experimental Example 2 Stability Study

[0176] (1) Influencing factor test

[0177] The tablets of Example 1 were placed in a watch glass and subjected to a stability study under conditions of high temperature (60°C), high humidity (relative humidity 75%±1%, 25°C) and illumination (illuminance 4500lx±500lx). Samples were taken at 15 days and 30 days, and the changes in related substances were determined by HPLC. The results showed that the properties of the tablets of Example 1 were stable. When the results at 15 days and 30 days were compared with those at day 0, there was no significant increase in the related substances. The data are shown in Table 4.

[0178] (2) Accelerated test

[0179] The tablets of Example 1 were placed in an environment with a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% for stability study. After being placed for 1 month, the changes in the content of related substances and dissolution rates were determined by HPLC. The results showed that the tablets of Example 1 were stable. When the results of accelerated treatment for 1 month were compared with those at 0 days, there was no significant increase in related substances. The data are shown in Table 4.

[0180] Table 4

[0181] Example 8

[0182] The compound of formula (IX), lactose, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, hypromellose, magnesium stearate, and colloidal silicon dioxide were uniformly mixed according to the proportions shown in Table 5, and tablets were compressed by direct powder compression.

[0183] Table 5

[0184] Experimental Example 3 Dissolution Test

[0185] According to the second method (slurry method) of Part IV of the 2020 edition of the Chinese Pharmacopoeia, 0931, the dissolution rate of the tablets in Example 8 was determined. 900 ml of pH 4.5 acetate buffer solution was used as the dissolution medium at a slurry speed of 50 rpm at 37°C ± 0.5°C. The dissolution data are shown in Table 6 below, and the dissolution curve is shown in Figure 4. The results show that in Example 8, the compound of formula (IX) dissolves slowly and fails to dissolve completely. Based on the results of the above examples, the wet granulation process is preferred.

[0186] Table 6

[0187] Examples 9-10

[0188] The compound of formula (IX), lactose, microcrystalline cellulose, and croscarmellose sodium were wet granulated according to the proportions shown in Table 7, using a 3.4% aqueous solution of hypromellose and a 2.3% aqueous solution of sodium lauryl sulfate as the granulating liquid. After granulation, wet granulation and drying were performed. The dried granules (moisture content <3%) were granulated, and additional croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate were added. After uniform mixing, the mixture was filled into size 0 hypromellose capsules.

[0189] Table 7

[0190] Experimental Example 4 Dissolution Test

[0191] According to the general rules of the fourth part of the 2020 edition of the Chinese Pharmacopoeia 0931, the dissolution rate of the capsules in Examples 9 and 10 was determined by the first method (basket method). The tablets were tested for dissolution using 900 ml of pH 4.5 acetate buffer solution as the dissolution medium at a slurry speed of 50 rpm at 37°C ± 0.5°C, and the capsules were tested for dissolution using 900 ml of pH 4.5 acetate buffer solution as the dissolution medium at a speed of 100 rpm at 37°C ± 0.5°C. The dissolution data are shown in Table 8 below, and the dissolution curves are shown in Figure 5. The results show that the compound of formula (IX) in Examples 10 and 11 dissolved slowly and failed to dissolve completely. Based on the results of the above examples, the preferred dosage form is tablets.

[0192] Table 8

[0193] Examples 11 to 14

[0194] The compound of formula (IX), microcrystalline cellulose, mannitol, and croscarmellose sodium were wet granulated according to the ratios in Table 9, using a 3.4% aqueous solution of hydropropyl methylcellulose, methylcellulose, or polyvinyl pyrrolidone as the granulating liquid. After granulation, wet granulation and drying were performed. The dried granules (moisture content <3%) were granulated, and additional croscarmellose sodium and magnesium stearate were added. The mixture was mixed evenly and then tableted.

[0195] Table 9

[0196] Experimental Example 5 Dissolution Test

[0197] According to the second method (slurry method) of Part IV of the 2020 edition of the Chinese Pharmacopoeia, 0931, the dissolution rate of the tablets in Examples 11 to 14 was determined. The dissolution test was carried out at a slurry speed of 50 rpm at 37°C ± 0.5°C using 900 ml of pH 4.5 acetate buffer solution as the dissolution medium. The dissolution data are shown in Table 10 below, and the dissolution curve is shown in Figure 6. The results show that in Examples 11 to 13, different binders have no significant effect on the dissolution rate, and the main drug is not completely dissolved when the proportion of microcrystalline cellulose in the prescription is too large. The dissolution of Example 14, which reduces the proportion of microcrystalline cellulose, is more complete. In addition, considering that lactose is a reducing excipient, it may potentially interact with the main drug during long-term storage, thereby affecting the quality of the preparation. Based on the results of the above examples, mannitol and microcrystalline cellulose are preferably used as fillers.

[0198] Table 10

[0199] Example 15 Preparation of the hydrochloride salt of the compound of formula (III) and its crystal form

[0200] 63.8 mg (0.2 mmol) of the compound of formula (IX) (on anhydrous basis) and 2 equivalents of a 1 M ethanolic hydrochloric acid solution were weighed, 2.0 ml of cyclohexane was added, and the mixture was stirred at room temperature for 3 days. The suspension was centrifuged, and the solid was dried under vacuum at room temperature. The resulting solid was characterized to obtain Form G of the hydrochloride salt of the compound of formula (III) (see Figure 1 for its XRPD pattern, and Figure 2 for its DSC and TGA patterns).

[0201] Experimental Example 6: Hygroscopicity of the hydrochloride G crystal form of the compound of formula (III):

[0202] The DVS results (as shown in FIG7a ) show that the hydrochloride G crystal form of the compound of formula (III) gained about 0.88% weight at 95% RH, gained about 0.50% weight by adsorption at 80% RH, gained about 0.47% weight by desorption, and lost 0.16% weight by desorption at 0% RH, indicating that the hydrochloride G crystal form of the compound of formula (III) is slightly hygroscopic; the XRPD results (as shown in FIG7b ) show that the sample did not undergo any change in crystal form after the DVS test.

[0203] Experimental Example 7: Study on the stability of the hydrochloride G crystal form of the compound of formula (III)

[0204] The stability of the hydrochloride form G of the compound of formula (III) was studied under high temperature (60°C), high humidity (25°C / 92.5% RH), light (25°C / 4500 Lux), and accelerated conditions (40°C / 75% RH). Samples were taken for XRPD characterization and HPLC testing at 7 days and 15 days, respectively. The results are shown below. The XRPD results (as shown in Figure 8) show that the hydrochloride form G of the compound of formula (III) was stable under high temperature, high humidity, light, and accelerated conditions for 15 days, and no crystal form transformation occurred. The HPLC results show that the chemical purity of the hydrochloride form G of the compound of formula (III) did not change significantly after being placed under high humidity and accelerated conditions for 15 days; the chemical purity decreased slightly after being placed under high temperature and light conditions for 15 days.

[0205] Table 11 Stability study results

[0206] Experimental Example 8: Solubility test of the hydrochloride G crystal form of the compound of formula (III) in biological media and water

[0207] Equilibrium solubility measurements were performed on Form G hydrochloride of the compound of formula (III) in three biological media (FaSSIF, FeSSIF, and FaSSGF) and water. The results showed that the 24-hour equilibrium solubility of Form G hydrochloride of the compound of formula (III) in biological media and water was, from highest to lowest, FaSSIF > water > FaSSGF > FeSSIF.

[0208] Table 12 Solubility test in biological media and water *Solubility values ​​are for the free form, calculated using a standard curve for the free form. (Note: FaSSIF: fasting state simulated intestinal fluid; FeSSIF: fed state simulated intestinal fluid; FaSSGF: fasting state simulated gastric fluid)

[0209] Examples 16-17

[0210] Form G of the hydrochloride of the compound of formula (III), microcrystalline cellulose, mannitol, and croscarmellose sodium were wet granulated according to the ratios in Table 13. A 3.4% aqueous solution of hypromellose was used as the granulating liquid. After granulation, wet granulation and drying were performed. The dried granules (moisture content <3%) were granulated, and additional croscarmellose sodium and magnesium stearate were added. The mixture was mixed evenly and then tableted.

[0211] Table 13

[0212] Experimental Example 9: Dissolution Test

[0213] According to the second method (slurry method) of Part 4 of the 2020 edition of the Chinese Pharmacopoeia, 0931, the dissolution rate of the tablets in Examples 16 to 17 was determined. 900 ml of pH 4.5 acetate buffer solution was used as the dissolution medium at a slurry speed of 50 rpm at 37 ± 0.5 ° C. The dissolution data are shown in Table 14 below, and the dissolution curves are shown in Figure 9. The results show that in Examples 16 to 17, different fillers have a greater effect on the dissolution rate. Based on the results of the above examples, microcrystalline cellulose is preferably used as the filler.

[0214] Table 14

[0215] Examples 18 to 21

[0216] The compound of formula (IX) (also known as the B crystal form of the compound of formula (III)) or the G crystal form of the hydrochloride of the compound of formula (III), microcrystalline cellulose, croscarmellose sodium, sodium starch glycolate, and cross-linked polyvinylpyrrolidone are wet granulated according to the proportions in Table 15. A 3.4% aqueous solution of hydroxypropyl methylcellulose, methylcellulose, or hydroxypropyl cellulose is used as the granulating liquid. After granulation, wet granulation and drying are performed. The dried granules (moisture content <3%) are granulated, and additional croscarmellose sodium, sodium starch glycolate, or cross-linked polyvinylpyrrolidone and magnesium stearate are added. The mixture is mixed evenly and then tableted.

[0217] Table 15

[0218] Experimental Example 10: Dissolution Test

[0219] According to the second method (slurry method) of Part 4 of the 2020 edition of the Chinese Pharmacopoeia, 0931, the dissolution rate of the tablets in Example 16 and Examples 18 to 21 was determined. The dissolution test was carried out at a slurry speed of 50 rpm at 37 ± 0.5 ° C using 900 ml of pH 4.5 acetate buffer solution as the dissolution medium. The dissolution data are shown in Table 16 below, and the dissolution curve is shown in Figure 10. The results show that in Examples 18 to 19, the cumulative dissolution amount of the prescription containing sodium carboxymethyl starch and cross-linked polyvinylpyrrolidone is lower than that of the cross-linked sodium carboxymethylcellulose prescription, and cross-linked sodium carboxymethylcellulose is preferably used as a disintegrant. In Examples 20 to 21, the dissolution rate of the prescription prepared with methylcellulose or hydroxypropyl cellulose as a binder is slower than that of the hypromellose prescription. Therefore, hypromellose is preferably used as a binder.

[0220] Table 16

[0221] Experimental Example 11: Study on the efficacy of the compound in the citric acid-induced chronic cough model in guinea pigs

[0222] In this study, a chronic cough model was established in guinea pigs by repeated inhalation of aerosol citric acid, and the pharmacological effects of the compounds in the citric acid-induced chronic cough model in guinea pigs were evaluated.

[0223] Experimental process:

[0224] 1) Modeling and Grouping: A total of 38 male guinea pigs were used in this study. Modeling was induced with 0.4 M citric acid.

[0225] 2) Administration of Test Substances: All subjects were administered orally. The normal control group (G1) and the model group (G2) were administered 0.9% saline. Group 3 (G3) was administered benproperine at a dose of 10 mg / kg via intraperitoneal injection once daily. The treatment groups (G4 and G5) were administered a suspension of Form B of the compound of formula (III) by oral gavage at doses of 25 mg / kg (G4) and 50 mg / kg (G5), respectively, twice daily. Dosing began 8 days after citric acid induction. The dosing cycle was 7 days.

[0226] 3) Detection index: number of guinea pig coughs in 5 minutes.

[0227] Table 17 Modeling, grouping and drug administration

[0228] 4) Index detection: On the 8th, 12th and 15th days, the guinea pigs were induced to cough for 3 minutes using 0.4M citric acid, and the number of coughs over 5 minutes (including the 3 minutes of cough induction and the 2 minutes after cough induction) was recorded.

[0229] 5) Statistical Analysis: Data are presented as mean ± standard error. Statistical significance was analyzed using t-test, one-way ANOVA, and post-hoc Dunnett's test. When the number of participants within a group was small or did not conform to a normal distribution, the Mann-Whitney nonparametric test was used. P < 0.05 was considered significant.

[0230] Experimental results:

[0231] 1. Detection of Coughing Number of Guinea Pigs on Day 8

[0232] On the 8th day after citric acid modeling, the number of coughs of the animals was recorded. The test results are shown in Figure 11. The number of coughs of the animals in the modeling group was significantly increased compared with the control group (***p<0.001, Figure 11, Table 18). Based on the number of coughs of the animals, the animals in the modeling group were randomly divided into four groups (Groups 2 to 5; G2-G5), and drug administration began on the ninth day.

[0233] Table 18 Statistics of guinea pig coughing on day 8 Note: Mean ± standard error; ***p < 0.001 vs G2; One-way ANOVA

[0234] 2. Detection of Coughing Number of Guinea Pigs on Day 12

[0235] On day 12 of the study, the number of coughs in the model group was significantly increased compared to the control group (***p<0.001; Figure 12; Table 19). Compared to the model group (Group 2) (G2), the number of coughs in the positive drug group was significantly reduced (**p<0.01; Figure 12; Table 19). Compared to the model group (Group 2) (G2), the number of coughs in the guinea pigs in the treatment group at a dose of 25 mg / kg (G4) was significantly reduced when administered orally twice daily (*p<0.01; Figure 12; Table 19). There was no significant change in the number of coughs in the treatment group at a dose of 50 mg / kg (G5) when administered orally twice daily (Figure 12; Table 19).

[0236] Table 19 Statistics of guinea pig coughing on day 12 Note: Mean ± standard error; *p < 0.05 vs G2; **p < 0.01 vs G2; ***p < 0.001 vs G2; One-way ANOVA

[0237] 3. End point of the experiment: Detection of the number of guinea pig coughs

[0238] At the study endpoint, the number of coughs in the model group was significantly increased compared to the control group (***p<0.001; Figure 13; Table 20). Compared to the model group (Group 2) (G2), the number of coughs in the positive drug group was significantly reduced (***p<0.001; Figure 13; Table 20). Compared to the model group (Group 2) (G2), the number of coughs in the guinea pigs in the drug group (25 mg / kg (G4)) was significantly reduced by gavage twice daily (***p<0.001; Figure 13; Table 20). The number of coughs in the guinea pigs in the drug group (50 mg / kg (G5)) was significantly reduced by gavage twice daily (**p<0.01; Figure 13; Table 20).

[0239] Table 20 Statistics of guinea pig coughing on day 15 Note: Mean ± standard error; *p < 0.05 vs G2; **p < 0.01 vs G2; ***p < 0.001 vs G2; One-way ANOVA

[0240] Experimental conclusion:

[0241] Compared with the normal control group, the number of coughs in the guinea pigs in the chronic cough model group increased significantly, indicating that the model was successfully established.

[0242] Compared with the model group, the number of coughs was significantly reduced on the 12th and 15th days of the study when benproperine was administered orally at a dose of 10 mg / kg once a day, indicating that the positive drug benproperine can significantly suppress coughs.

[0243] Compared with the model group, the drug group with a dose of 25 mg / kg (G4) was administered orally twice a day, which significantly reduced the number of coughs in the model animals on the 12th day and at the end of the study.

[0244] Compared with the model group, the dose of 50 mg / kg (G5) in the treatment group was administered orally twice daily. The number of coughs in the model animals on the 12th day after modeling (the 4th day of administration) showed a trend of decrease, but there was no statistical difference. The number of coughs in the model animals at the end of the study was significantly reduced.

[0245] In summary, the suspension of Form B of the compound of Formula (III) demonstrated significant efficacy in treating coughing behavior in a guinea pig model of chronic cough. It significantly reduced the number of coughs in the model animals, and the 25 mg / kg (G4) dose group exhibited significant cough suppression effects as early as four days after treatment. This suggests that the suspension of Form B of the compound of Formula (III) can reduce the number of coughs in cough model mice and has the potential to treat chronic cough.

[0246] Experimental Example 12: Study on the efficacy of compounds in a mouse alcoholic hepatitis model

[0247] In this study, the Gao-binge model of mice was established to evaluate the pharmacological effects of the compounds in alcoholic hepatitis.

[0248] Experimental process:

[0249] 1) Modeling and Grouping: A total of 59 female C57BL / 6 mice were randomly divided into groups. The modeling method used was an alcoholic hepatitis model induced by a short-term alcohol liquid diet (Gao-binge model).

[0250] 2) Administration of Test Articles: All test articles were administered orally. The normal control group (G1) and the model group (G2) were gavaged with 0.9% saline twice daily. The treatment groups (G3-G5) were gavaged with a suspension of Form B of the compound of formula (III) at doses of 45 mg / kg (G3), 90 mg / kg (G4), and 180 mg / kg (G5), respectively, twice daily. The modeling and administration cycle was 21 days, with samples collected at the experimental endpoint on the 22nd day.

[0251] Table 21 Modeling, grouping and drug administration

[0252] 3) Detection indicators: latency period of righting reflex disappearance, recovery period of righting reflex disappearance

[0253] 4) Detection indicators: Liver index

[0254] 5) Detection indicators: serum alanine aminotransferase (ALT)

[0255] 6) Detection indicators: liver tissue pathological analysis (H&E staining, Oil Red O staining)

[0256] 7) Statistical Analysis: Data are presented as mean ± SEM. Statistical significance was analyzed using t-test, one-way ANOVA, and post-hoc Dunnett's test. When the number of participants within a group was small or did not conform to a normal distribution, the Mann-Whitney nonparametric test was used. P < 0.05 was considered significant.

[0257] Experimental results:

[0258] 1. Latency period of righting reflex disappearance and recovery period of righting reflex disappearance

[0259] On day 22, the experiment reached its endpoint, mice were gavaged with 20 μL / g body weight of alcohol and then tested for righting reflex. The control group was gavaged with 9 g / kg of maltodextrin, while the model and treatment groups were gavaged with 5 g / kg of 31.5% alcohol. The righting reflex was recorded, and blood and liver samples were collected. The experimental results showed that compared with the model group (G2), when the dose of the drug group was 45 mg / kg (G3), there was no significant difference in the latency of loss of righting reflex and the recovery period of loss of righting reflex in mice (Figure 14A, B; Table 22); when the dose of the drug group was 90 mg / kg (G4), there was no significant difference in the latency of loss of righting reflex in mice (Figure 14A; Table 22), and the recovery period of loss of righting reflex was significantly reduced (**p<0.01; Figure 14B; Table 22); when the dose of the drug group was 180 mg / kg (G5), the latency of loss of righting reflex in mice was significantly increased (***p<0.001; Figure 14A; Table 22), and the recovery period of loss of righting reflex was significantly reduced (***p<0.001; Figure 14B, Table 22).

[0260] Table 22 Statistics of righting reflex in mice Note: Mean ± standard error; **p < 0.01 vs Model; ***p < 0.001 vs Model; One-way ANOVA

[0261] 2. Liver index

[0262] On day 22, the experiment reached its endpoint, the body weight and liver weight of the mice were recorded. The experimental results showed that compared with the normal control group (G1), the liver index of mice in the model group (G2) and the treatment groups (G3-G5) administered with a suspension of Form B of the compound of Formula (III) by oral gavage at doses of 45 mg / kg (G3), 90 mg / kg (G4), and 180 mg / kg (G5), respectively, was significantly increased (###p<0.001; Figure 15; Table 23).

[0263] Table 23 Mouse liver index statistics Note: Mean ± standard error; ###p<0.001 vs Control; One-way ANOVA

[0264] 3. Serum alanine aminotransferase (ALT)

[0265] The experimental results showed that compared with the control group (G1), the serum ALT levels of mice in the model group (G2) were significantly increased (##p<0.01; Figure 16; Table 24); there were no significant differences in serum ALT levels among the three dose groups (G3-G5) (Figure 16; Table 24). Compared with the model group (G2), the serum ALT levels of mice in the 45 mg / kg dose group (G3) were significantly decreased (*p<0.05; Figure 16; Table 24); the serum ALT levels of mice in the 90 mg / kg dose group (G4) were significantly decreased (*p<0.05; Figure 16; Table 24); and there were no significant differences in serum ALT levels among mice in the 180 mg / kg dose group (G5) (Figure 16; Table 24).

[0266] Table 24 Statistics of ALT levels in mouse serum Note: Mean ± standard error; *p < 0.05 vs Model; ##p < 0.001 vs Control; One-way ANOVA

[0267] 4. Liver Histopathological Analysis (H&E Staining, Oil Red O Staining)

[0268] At the end of the experiment on day 22, liver tissues were obtained for fixation, embedding, sectioning, staining, and then histopathological analysis.

[0269] The results of H&E staining showed that compared with the control group (G1), the hepatic cords in the liver tissue of the model group (G2) and the three-dose drug-treated groups (G3-G5) were irregularly arranged, and there were a large number of lipid droplet vacuoles and macrovesicular fatty degeneration; compared with the model group (G2), the number of fat vacuoles in the livers of mice in the three-dose drug-treated groups (G3-G5) was significantly reduced, among which the degree of vacuolar fatty lesions in the livers of mice in the drug-treated group with a dose of 180 mg / kg (G5) was greatly improved (Figure 17).

[0270] The results of Oil Red O staining showed that compared with the control group (G1), the Oil Red O-stained areas in the livers of the mice in the model group (G2) and the three-dose drug-treated groups (G3-G5) were significantly increased, and obvious lipid accumulation and lipid droplet accumulation were observed; compared with the model group (G2), the number of lipid droplets in the livers of the mice in the three-dose drug-treated groups (G3-G5) was significantly reduced, among which the lipid droplets in the livers of the mice in the drug-treated group with a dose of 180 mg / kg (G5) were small and the degree of lipid droplet accumulation was greatly improved ( Figure 17 ).

[0271] Experimental conclusion:

[0272] An alcoholic hepatitis model (Gao-binge model) was induced by short-term alcohol liquid feed. The experimental results showed that compared with the normal control group, the liver index of the model group and the three dose groups was significantly increased. The results showed that feeding with alcohol liquid feed and a single gavage of alcohol (5g / kg) caused liver enlargement and lesions.

[0273] Compared with the model group, the latency of loss of righting reflex in mice treated with 90 mg / kg (G4) showed an upward trend, but no significant difference, and the recovery period of loss of righting reflex was significantly reduced. The latency of loss of righting reflex in mice treated with 180 mg / kg (G5) was significantly increased, and the recovery period of loss of righting reflex was significantly reduced. This indicates that the suspension of Form B of the compound of Formula (III) can delay the onset of intoxication in mice and shorten the recovery time of the righting reflex in mice, demonstrating its effective alcohol sobering and anti-intoxication effects.

[0274] Compared with the normal control group, serum ALT levels in the model group and the three dosing groups increased, indicating that alcoholic hepatitis caused varying degrees of liver damage in mice. Compared with the model group, serum ALT levels in mice treated with 45 mg / kg (G3) and 90 mg / kg (G4) were significantly reduced. Serum ALT levels in mice treated with 180 mg / kg (G5) showed a decreasing trend, but no significant difference was found. This suggests that the suspension of Form B of the compound of Formula (III) can reduce serum ALT levels in mice and, to a certain extent, alleviate alcohol-induced liver damage in mice.

[0275] Pathological H&E staining and Oil Red O staining results showed that compared with the liver tissue of mice in the normal control group, the liver cords in the model group and the three dose-treated groups were irregularly arranged and had a large number of lipid droplet vacuoles or lipid droplet and macrovesicular steatosis, indicating that feeding with alcohol liquid feed and a single oral administration of alcohol (5g / kg) caused liver damage, steatosis, and varying degrees of lipid accumulation in mice. After treatment with three different doses of suspension of Form B of the compound of Formula (III), the number of fat vacuoles in the mouse liver decreased and the degree of lipid droplet accumulation decreased, indicating that the suspension of Form B of the compound of Formula (III) has an ameliorative effect on alcohol-induced liver steatosis in mice.

[0276] In summary, the suspension of Form B of the compound of Formula (III) demonstrated significant efficacy in an alcoholic hepatitis model. It significantly shortened the righting reflex recovery time in mice, reduced serum ALT levels in mice, alleviated alcohol-induced liver damage in mice, and improved liver lipid accumulation in mice, indicating that the suspension of Form B of the compound of Formula (III) has a protective effect against alcoholic hepatitis.

[0277] Experimental Example 13: Study on the efficacy of OVA-induced asthma model in mice

[0278] Purpose of the experiment:

[0279] In this study, an asthma model was established in BALB / c mice by inducing ovalbumin (OVA), and the pharmacodynamic effect of the suspension of the crystal form B of the compound of formula (III) was evaluated in the OVA-induced asthma model in mice.

[0280] Experimental process:

[0281] 1) Modeling and Grouping: A total of 72 female BALB / c mice were used in this study. Modeling procedures: The sensitization phase involved intraperitoneal injection of 0.2 mL of OVA (20 μg of OVA + 31 mg of Al(OH)) on days 1, 7, and 14. The challenge phase began on day 21 with nebulized inhalation of a 5% OVA solution (30 mL for 30 minutes) for 7 days.

[0282] 2) Administration of the test substance: All administration methods were oral. The normal control group (G1) and the model group (G2) were administered with 0.9% normal saline. Group 3 (G3) was administered with dexamethasone sodium phosphate at a dose of 3 mg / kg, intraperitoneally, once a day; Group 4 (G4) was administered with a suspension of the B form of the compound of formula (III) at a dose of 45 mg / kg, by gavage, twice a day; Group 5 (G5) was administered with a suspension of the B form of the compound of formula (III) at a dose of 90 mg / kg, by gavage, twice a day; Group 6 (G6) was administered with a suspension of the B form of the compound of formula (III) at a dose of 180 mg / kg, by gavage, twice a day. The administration cycle was 28 days.

[0283] Table 25 Modeling, grouping and drug administration

[0284] 3) Detection indicators: behavioral testing and BALF bronchoalveolar lavage fluid cell analysis.

[0285] 4) Indicator testing: Behavioral assessment of cough and wheeze indicators includes cough and wheeze latency and frequency; morphological scoring includes nasal scratching frequency and wheezing severity. BALF bronchoalveolar lavage fluid cellular analysis includes analysis of total cells, eosinophils, and basophils.

[0286] After the aerosol challenge phase, mice were placed in an acrylic box with the sides covered with black stickers to create a black background for easy observation of their behavior. Videos were recorded to assess behavioral indicators, including the number of nose scratches and coughs within 10 minutes, the cough-wheeze latency (the time it took for the mouse to first cough or wheeze), and the severity of the wheeze. The scoring criteria are shown in Table 26.

[0287] Table 26 Scoring criteria

[0288] After behavioral testing, mice were anesthetized and sacrificed, secured to an operating table, and the neck hair was disinfected with 75% alcohol. Surgical scissors were used to trim the neck fur, the chest cavity was opened, and hemostats were used to fully expose the lungs. The trachea was bluntly dissected and tied with silk suture to prevent the lavage fluid from leaking out of the mouth and nose. Using a 1mL sterile syringe, 0.8mL of normal saline was drawn. The needle was inserted between two cartilaginous rings in the trachea and the alveoli were lavaged 3-5 times to obtain BALF. A 1.5mL EP tube (rinsed with 200μL of 2% glacial acetic acid solution and then discarded) was filled with BALF and gently shaken. The glacial acetic acid was used to lyse the red blood cells. The BALF was centrifuged at 1500 rpm for 10 minutes at 4°C. The supernatant was discarded and the cells were resuspended in phosphate-buffered saline.

[0289] After resuspending the cells, blow them evenly and count the eosinophils and basophils using a hemocytometer. Count the top cells, not the bottom, and count the left cells, not the right. The cell calculation formula is: total cells = n / 4 × 104 × dilution factor / L (n = the total number of cells in 4 large squares). Prepare a cell smear with the remaining mixed cells and perform Swiss-Giemsa staining as follows:

[0290] (1) Take a smear and let it dry naturally;

[0291] (2) Add 2-3 drops of Swiss-Giemsa complex stain to cover the entire specimen smear and stain for 1-2 minutes;

[0292] (3) Add an equal amount of 0.01 M phosphate buffer solution (pH 6.4-6.8) dropwise, shake gently, mix thoroughly with Swiss-Giemsa staining solution, and stain for 3-5 minutes;

[0293] (4) Wash with water, dry, and examine under a microscope.

[0294] 5) Statistical Analysis: Data are presented as mean ± standard error. One-way ANOVA was used for significance analysis. When the number of groups was small or did not conform to a normal distribution, the Mann-Whitney nonparametric test was used. P < 0.05 was considered significant.

[0295] Experimental results:

[0296] 1. Behavioral investigation of OVA-induced asthmatic mice

[0297] As shown in Figure 18, the number of nose scratching in the model group mice increased but not significantly compared to the control group (Figure 18; Table 27). Compared to the model group, the number of nose scratching in mice in all groups after administration showed an improvement trend (Figure 18; Table 27).

[0298] Table 27 Statistics of the number of times mice scratched their noses on day 28 Note: Mean ± standard error; One-way ANOVA

[0299] Figure 19 shows the number of coughs and wheezes in mice on day 28. Compared with the control group, the number of coughs and wheezes in the model group was significantly increased (***p<0.001; Figure 19; Table 28). Compared with the model group, the number of coughs and wheezes in the positive drug group was significantly reduced (***p<0.001; Figure 19; Table 28). Compared with the model group, the drug administration groups (G4 and G5) were given a suspension of the B form of the compound of formula (III) at a dose of 45 mg / kg and 90 mg / kg, respectively, by gavage twice a day, and the number of coughs and wheezes in the mice was significantly reduced (*p<0.05; Figure 19; Table 28). The drug administration group (G6) was given a suspension of the B form of the compound of formula (III) at a dose of 180 mg / kg, by gavage twice a day, and the number of coughs and wheezes in the mice was significantly reduced (***p<0.001; Figure 19; Table 28).

[0300] Table 28 Statistics of the number of coughs and asthma in mice on day 28 Note: Mean ± standard error; *p < 0.05 vs Model; ***p < 0.001 vs Model; One-way ANOVA

[0301] Figure 20 shows the cough and asthma latency of mice on day 28. Compared with the control group, the cough and asthma latency of mice in the model group was significantly reduced (***p<0.001; Figure 20; Table 29). Compared with the model group, the cough and asthma latency of mice in the positive drug group was significantly increased (***p<0.001; Figure 20; Table 29). Compared with the model group, the drug administration groups (G4 and G5) were given a suspension of the B form of the compound of formula (III) at a dose of 45 mg / kg and 90 mg / kg, respectively, by gavage, twice a day. The cough and asthma latency of mice showed an upward trend (p>0.05, Figure 20; Table 29). The drug administration group (G6) was given a suspension of the B form of the compound of formula (III) at a dose of 180 mg / kg, by gavage, twice a day. The cough and asthma latency of mice was significantly increased (***p<0.001; Figure 20; Table 29).

[0302] Table 29 Statistics of the incubation period of cough and asthma in mice on day 28 Note: Mean ± standard error; ***p < 0.001 vs Model; One-way ANOVA

[0303] Figure 21 is the behavioral score of asthma severity. Behavioral scoring was performed by observing the breathing and scratching of the mice. Compared with the control group, the asthma severity of the mice in the model group was significantly increased (***p<0.001; Figure 21; Table 30). Compared with the model group, the asthma severity of the mice in the positive drug group was significantly reduced (***p<0.001; Figure 21; Table 30). Compared with the model group, when the dose of the drug group was 45 mg / kg (G4), the asthma severity of the mice did not change significantly after oral administration twice a day (Figure 21; Table 30). When the dose of the drug group was 90 mg / kg (G5), the asthma severity of the mice was significantly reduced after oral administration twice a day (**p<0.01; Figure 21; Table 30). When the dose of the drug group was 180 mg / kg (G6), the asthma severity of the mice was significantly reduced after oral administration twice a day (***p<0.001; Figure 21; Table 30).

[0304] Table 30 Statistics of behavioral scores of mice panting degree on day 28 Note: Mean ± standard error; **p < 0.01 vs Model; ***p < 0.001 vs Model; One-way ANOVA

[0305] 2. BALF Cell Analysis of OVA-Induced Asthma Mice

[0306] Figure 22 shows the total cell count in the BALF. Compared with the control group, the total cell count in the BALF of the model group mice was significantly increased (**p<0.01; Figure 22; Table 31). Compared with the model group, the total cell count in the BALF of the positive drug group mice was significantly decreased (*p<0.05; Figure 22; Table 31). Compared with the model group, the drug-treated groups (G4-G6) were gavaged with a suspension of Form B of the compound of Formula (III) at doses of 45 mg / kg (G4), 90 mg / kg (G5), and 180 mg / kg (G6), twice daily. The total cell count in the BALF of the mice decreased in a dose-dependent manner (Figure 22; Table 31). Among them, when the drug-treated group was gavaged at a dose of 180 mg / kg (G6), twice daily, the total cell count in the BALF of the mice was significantly decreased (*p<0.05; Figure 22; Table 31).

[0307] Table 31 Statistics of total cell counts in mouse BALF on day 28

[0308] Figure 23 shows the number of eosinophils in the BALF. Compared with the control group, the number of eosinophils in the BALF of the model group mice was significantly increased (***p<0.001; Figure 23; Table 32). Compared with the model group, the number of eosinophils in the BALF of the positive drug group mice was significantly reduced (*p<0.05; Figure 23; Table 32). Compared with the model group, when the dose of the drug group was 180 mg / kg (G6), the number of eosinophils in the BALF of the mice was significantly reduced by gavage twice a day (**p<0.01; Figure 23; Table 32).

[0309] Table 32 Statistics of eosinophil counts in mouse BALF on day 28

[0310] Figure 24 shows the number of basophils in the BALF. Compared with the control group, the number of basophils in the BALF of mice in the model group was significantly increased (**p < 0.01; Figure 24; Table 33). Compared with the model group, the number of basophils in the BALF of mice in the positive drug group showed a decreasing trend (p > 0.05, Figure 24; Table 33). When the drug group was given 180 mg / kg (G6) by gavage twice daily, the number of basophils in the BALF of mice decreased even more (p > 0.05, Figure 24; Table 33).

[0311] Table 33 Statistics of basophil counts in mouse BALF on day 28

[0312] Test conclusion:

[0313] Ovalbumin (OVA) was used to induce BALB / c mice to establish an asthma model. The experimental results showed that compared with the blank group, the number of coughs in the model group mice was significantly increased, the latency period of cough and asthma was significantly prolonged, the behavioral score of asthma severity was significantly increased, and the number of total cells, eosinophils, and basophils in BALF were significantly increased, indicating that the asthma model was successfully induced.

[0314] Compared with the model group, the number of coughs and wheezing in mice in the positive drug group was significantly reduced. When the drug-treated groups (G4-G6) were given a suspension of the B form of the compound of formula (III) at doses of 45 mg / kg (G4), 90 mg / kg (G5), and 180 mg / kg (G6), respectively, by gavage twice a day, the number of coughs and wheezing in mice was significantly reduced.

[0315] Compared with the model group, the latency of cough and asthma in mice in the positive drug group was significantly increased. In the drug-treated groups (G4 and G5), a suspension of Form B of the compound of formula (III) was administered orally at doses of 45 mg / kg and 90 mg / kg twice daily. The latency of cough and asthma in mice showed an upward trend. In the drug-treated group (G6), a dose of 180 mg / kg was administered orally twice daily.

[0316] Compared with the model group, the asthma severity scores of mice in the positive drug group were significantly reduced. The drug-treated groups (G5 and G6) were given a suspension of the B form of the compound of formula (III) at doses of 90 mg / kg and 180 mg / kg by gavage twice a day, and the asthma severity scores of the mice were significantly reduced.

[0317] Compared with the model group, the total cell number in the BALF of mice in the positive drug group was significantly reduced. When the drug-treated groups (G4-G6) were given a suspension of the B form of the compound of formula (III) at doses of 45 mg / kg (G4), 90 mg / kg (G5), and 180 mg / kg (G6), respectively, by gavage twice a day, the total cell number in the BALF of mice decreased in a dose-dependent manner.

[0318] Compared with the model group, the number of eosinophils in the BALF of mice in the positive drug group was significantly reduced. When the dose of the drug group was 180 mg / kg (G6), the drug was administered by gavage twice a day, and the number of eosinophils in the BALF of mice was significantly reduced.

[0319] Compared with the model group, the number of basophils in the BALF of mice in the positive drug group showed a decreasing trend. When the dose of the drug group was 180 mg / kg (G6), the drug was administered by gavage twice a day, and the number of basophils in the BALF of mice decreased more.

[0320] In summary, the suspension of Form B of the compound of Formula (III) exhibited superior efficacy in an OVA-induced asthma mouse model: significantly reducing the number of coughs, cough and wheeze latency, and cough and wheeze scores in asthmatic mice; and significantly reducing the number of total cells, eosinophils, and basophils in the BALF of asthmatic mice. These experimental results suggest that the suspension of Form B of the compound of Formula (III) can improve symptoms in asthma mice and has potential for treating asthma.

Claims

1. An oral preparation containing a pyridylphenyl compound, characterized in that, The oral preparation comprises an active ingredient, a pyridylphenyl compound, and a pharmaceutical excipient, wherein the active ingredient, the pyridylphenyl compound, comprises a compound of general formula (II), a pharmaceutically acceptable salt thereof, or a crystal form thereof: Wherein, The said selected from single bonds and double bonds; T1, T2, T3 or T4 are each independently selected from N, C or CR1; T5 is selected from C, CR5 or C═O; T6 is selected from C, CR6 or N; T7 is selected from N or CR7; When T5 is selected from C=O and T6 is selected from N, the selected from single bonds; L is selected from a single bond, -O-, -S-, -NR2- or -(CR3R4)n-; R1 is selected from H, F, Cl, Br, I, OH or NH2; R2 is selected from H and optionally C substituted by 1, 2 or 3 R a alkyl 1-3 alkyl; R3 or R4 are each independently selected from H, F, Cl, Br, I, OH, NH2, CN or C b alkyl optionally substituted with 1, 2 or 3 R 1-3 groups; R5, R6 or R7 are each independently selected from H, F, Cl, Br and I; n is selected from 1, 2 or 3; R a or R b are each independently selected from H, F, Cl, Br, I, OH, NH2, CN or CH3; The pharmaceutical excipient includes one or more fillers, one or more disintegrants, one or more binders, one or more lubricants or surfactants, or a combination of two or more of them.

2. The oral preparation according to claim 1, characterized in that, The compound of general formula (II), its pharmaceutically acceptable salt or its crystal form, wherein R2 is selected from H, CH3 or CH2CH3, and the CH3 or CH2CH3 is optionally substituted by 1, 2 or 3 R a substituents.

3. The oral preparation according to claim 2, characterized in that, The compound of general formula (II), its pharmaceutically acceptable salt or its crystal form, wherein R2 is selected from H, CH3 or CH2CH3.

4. The oral preparation according to any one of claims 1 to 3, characterized in that, The compound of the general formula (II), its pharmaceutically acceptable salt or its crystal form, wherein R3 or R4 are each independently selected from H, F, Cl, Br, I, OH, NH2, CN, CH3 or CH2CH3, and the CH3 or CH2CH3 is optionally substituted by 1, 2 or 3 R b substituents.

5. The oral preparation according to claim 4, characterized in that, The compound of general formula (II), its pharmaceutically acceptable salt or its crystal form, wherein R3 or R4 are each independently selected from H, F, Cl, Br, I, OH, NH2, CN, CH3 and CH2CH3.

6. The oral preparation according to claim 5, characterized in that, The compound of general formula (II), its pharmaceutically acceptable salt or its crystal form, wherein L is selected from a single bond, -O-, -S-, -NH-, -(CH2)2- or -CH2-.

7. The oral preparation according to any one of claims 1 to 6, characterized in that, The compound of general formula (II), its pharmaceutically acceptable salt or its crystal form, which is selected from Wherein, T3 or T4 are each independently selected from N and CR1; R1 or L is as defined in any one of claims 1 to 6.

8. The oral preparation according to claim 7, characterized in that, The compound of general formula (II), its pharmaceutically acceptable salt or its crystal form, which is selected from Wherein, R1 and L are as defined in claim 7.

9. The oral preparation according to claim 8, characterized in that, The compound of general formula (II), its pharmaceutically acceptable salt or its crystal form, which is selected from:

10. The oral preparation according to any one of claims 1 to 9, characterized in that, The oral preparation includes one or more fillers and one or more disintegrants; or The oral preparation includes one or more fillers, one or more disintegrants and one or more binders; or The oral preparation includes one or more fillers, one or more disintegrants, one or more binders and one or more lubricants; or The oral preparation includes one or more fillers, one or more disintegrants, one or more binders, one or more lubricants and one or more surfactants.

11. The oral preparation according to claim 10, characterized in that, The filler is selected from microcrystalline cellulose, mannitol or lactose, or a combination of two or more of them.

12. The oral preparation according to claim 10, characterized in that, The disintegrant is selected from sodium croscarmellose, sodium carboxymethyl starch, crospovidone or calcium carboxymethylcellulose, or a combination of two or more of them.

13. The oral preparation according to claim 10, characterized in that, The binder is selected from hypromellose, hydroxypropyl cellulose, polyvinylpyrrolidone or methylcellulose, or a combination of two or more of them.

14. The oral preparation according to claim 10, characterized in that, The lubricant is selected from magnesium stearate or colloidal silica, or a combination of two or more of them.

15. The oral preparation according to claim 10, characterized in that, The surfactant is sodium dodecyl sulfate.

16. The oral preparation according to claim 10, characterized in that, The oral preparation comprises a pyridylphenyl compound, one or more fillers, one or more disintegrants, one or more binders, one or more lubricants and one or more surfactants, wherein the pyridylphenyl compound comprises a compound of formula (Ⅲ), formula (Ⅳ), formula (Ⅴ), (Ⅵ), formula (Ⅶ) or formula (Ⅷ), a pharmaceutically acceptable salt thereof or a crystal form thereof:

17. The oral preparation according to claim 16, wherein The active ingredient also includes the B crystal form of the compound of formula (III), which is also referred to as the compound of formula (IX) in the present invention:

18. The oral preparation according to claim 16, wherein The active ingredient further includes a salt form of the compound of formula (III), wherein the salt form is selected from hydrochloride salts:

19. The oral preparation according to claim 18, characterized in that, The hydrochloride salt of the active ingredient compound of formula (Ⅲ), preferably its G crystal form.

20. The oral preparation according to claim 18, characterized in that, The salt of the compound of formula (Ⅲ) is selected from hydrochloride salts, preferably the molar ratio of the compound of formula (Ⅲ) to hydrochloric acid is 1:0 to 3.1, more preferably 1:0.5 to 2.5, still more preferably 1:1.0 to 2.1, and most preferably 1:1.0 or 1:2.

0.

21. The oral preparation according to claim 16, wherein The active ingredient RASP inhibitor pyridinophenyl compound may be selected from the compound of formula (III), the B crystal form of the compound of formula (III), and the content of the active ingredient (calculated as the anhydrous substance) is 1% to 75% of the total weight of the composition, preferably 10% to 60%, more preferably 20% to 50%, still more preferably 30% to 40%, and most preferably 32.68%.

22. The oral preparation according to claim 16, wherein, The active ingredient RASP inhibitor pyridinophenyl compound may be selected from the hydrochloride of the compound of formula (III) or the G crystal form of the hydrochloride of the compound of formula (III), and the content of the active ingredient (calculated as the free anhydrous state) is 1% to 75% of the total weight of the composition, preferably 10% to 60%, more preferably 20% to 50%, still more preferably 30% to 40%, and most preferably 33.33%.

23. The oral preparation according to claims 21 and 22, characterized in that, The oral preparation may include one or more of a filler, a disintegrant, a binder, a lubricant, and a surfactant.

24. The oral preparation according to claim 23, wherein The one or more fillers are selected from at least one of lactose, microcrystalline cellulose, mannitol, pregelatinized starch, anhydrous calcium hydrogen phosphate, calcium sulfate, calcium carbonate, dextrin, maltose, sorbitol, trehalose, or xylitol.

25. The oral preparation according to claim 24, characterized in that, The content of the filler is 0.1% to 75% of the total weight of the composition, preferably 5% to 70%, more preferably 10% to 65%, still more preferably 20% to 63%, and most preferably 60.95%, 60.94%, 58.98%, 57.02%, 54.08%, 53.59%, 47.90%, 30.47%, 29.49%, 28.51%, 27.04%, 27.12%, 26.47%, or 23.95%.

26. The oral preparation according to claim 25, characterized in that, The filler may include two kinds, selected from microcrystalline cellulose and mannitol or microcrystalline cellulose and lactose. Among them, the weight ratio of microcrystalline cellulose to mannitol is 0:1, 5:3, 3:1, 1:1, 1:0, preferably 1:1 or 1:0; the weight ratio of microcrystalline cellulose to lactose is 1.02:1, 5:3, 3:1, 1:1, 1:0, preferably 1:1, 1:0, or 1.02:

1.

27. The oral preparation according to claim 23, wherein The one or more disintegrants are selected from at least one of sodium croscarmellose, sodium carboxymethyl starch, crospovidone, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, alginic acid, chitosan, and corn starch.

28. The oral preparation according to claim 27, characterized in that, The content of the disintegrant is 0.1% to 20% of the total weight of the composition, preferably 0.5% to 15%, more preferably 1% to 10%, and most preferably 1.00%, 1.96%, 2.00%, 3.92%, 5.88%, or 7.84%.

29. The oral preparation according to claim 23, characterized in that, The one or more binders are selected from at least one of hypromellose, methylcellulose, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, sodium carboxymethyl cellulose, and ethyl cellulose.

30. The oral preparation according to claim 29, characterized in that, The content of the binder is 0.1% to 5% of the total weight of the composition, preferably 0.5% to 4%, more preferably 1% to 3%, and most preferably 1.47% or 1.50%.

31. The oral preparation according to claim 23, characterized in that, The one or more lubricants are selected from at least one of magnesium stearate, colloidal silica, colloidal silicon dioxide, talc, hydrogenated vegetable oil, and polyethylene glycols.

32. The oral preparation according to claim 31, wherein The content of the lubricant is 0.1% to 5% of the total weight of the composition, preferably 0.3% to 3%, more preferably 0.4% to 2%, and most preferably 0.49%, 0.98% or 1.00%.

33. The oral preparation according to claim 23, characterized in that, The surfactant is selected from sodium dodecyl sulfate.

34. The oral preparation according to claim 33, characterized in that, The content of the surfactant sodium dodecyl sulfate is 0.1% to 5% of the total weight, preferably 0.3% to 3%, more preferably 0.5% to 2%, and most preferably 0.98%.

35. The oral preparation according to any one of claims 21 to 34, characterized in that, In a preferred embodiment, a pharmaceutical composition is provided, comprising the following ingredients by weight (the active ingredient is in anhydrous form): 1) 1% to 75% of 2-(2-amino-4-(5-amino-6-(2-hydroxypropan-2-yl)pyridin-3-yl)phenyl)propan-2-ol or its B crystal form (monohydrate); 2) 0.1% to 75% of a filler selected from one or two of lactose, microcrystalline cellulose or mannitol; 3) 0.1% to 20% of a disintegrant selected from one or more of sodium croscarmellose, sodium carboxymethyl starch, crospovidone or calcium carboxymethylcellulose; 4) 0.1% to 5% of a binder selected from one or more of hypromellose, methylcellulose or polyvinylpyrrolidone; 5) 0.1% to 5% of a lubricant selected from one of magnesium stearate or colloidal silicon dioxide; 6) 0.1% to 5% of a surfactant selected from sodium dodecyl sulfate (SDS).

36. The oral preparation according to any one of claims 21 to 34, characterized in that, In a further preferred embodiment, a pharmaceutical composition is also provided, comprising the following ingredients by weight (the active ingredient is in anhydrous form): 1) 30% to 40% of 2-(2-amino-4-(5-amino-6-(2-hydroxypropan-2-yl)pyridin-3-yl)phenyl)propan-2-ol or its B crystal form (monohydrate); 2) 20% to 65% of a filler selected from microcrystalline cellulose and lactose, wherein the weight ratio of microcrystalline cellulose to lactose is preferably 1:1 or 1.02:1; 3) 1% to 8% of a disintegrant selected from one or more of sodium croscarmellose, sodium carboxymethyl starch, crospovidone or calcium carboxymethylcellulose; 4) 1% to 3% of a binder selected from hypromellose; 5) 0.5% to 1% of a lubricant selected from one of magnesium stearate or colloidal silicon dioxide; 6) 0.5% to 1% of a surfactant selected from sodium dodecyl sulfate (SDS).

37. The oral preparation according to any one of claims 21 to 34, wherein In a more preferred embodiment, a pharmaceutical composition is also provided, comprising the following ingredients by weight (the active ingredient is in anhydrous form): 1) 30% to 40% of 2-(2-amino-4-(5-amino-6-(2-hydroxypropan-2-yl)pyridin-3-yl)phenyl)propan-2-ol or its B crystal form (monohydrate); 2) 30% to 65% of a filler selected from microcrystalline cellulose and mannitol, wherein the weight ratio of microcrystalline cellulose to mannitol is preferably 1:1 or 1:0; 3) 1% to 2% of a disintegrant selected from sodium croscarmellose; 4) 1% to 2% of a binder selected from one or more of hypromellose, methylcellulose or polyvinylpyrrolidone; 5) 0.5% to 1% of a lubricant selected from magnesium stearate.

38. The oral preparation according to any one of claims 21 to 34, characterized in that, In the most preferred embodiment, a pharmaceutical composition is also provided, comprising the following ingredients by weight (the active ingredient is anhydrous): 1) 32.68% of 2-(2-amino-4-(5-amino-6-(2-hydroxypropan-2-yl)pyridin-3-yl)phenyl)propan-2-ol or its B crystal form (monohydrate); 2) 60.94% of a filler selected from mannitol and microcrystalline cellulose, wherein the weight ratio of mannitol to microcrystalline cellulose is preferably 1:1; 3) 1.96% of a disintegrant selected from sodium croscarmellose; 4) 1.47% of a binder selected from hypromellose; 5) 0.98% of a lubricant selected from magnesium stearate.

39. The oral preparation according to any one of claims 21 to 34, wherein In a preferred embodiment, a pharmaceutical composition is provided, comprising the following ingredients by weight (the active ingredient is in the anhydrous free form): 1) 1% to 75% of the hydrochloride of 2-(2-amino-4-(5-amino-6-(2-hydroxypropan-2-yl)pyridin-3-yl)phenyl)propan-2-ol or its G crystal form of the hydrochloride, wherein preferably 10% to 60%, more preferably 20% to 50%, still more preferably 30% to 40%, and most preferably 33.33%; 2) 0.1% to 75% of a filler selected from one or both of microcrystalline cellulose or mannitol, wherein preferably 5% to 70%, more preferably 10% to 65%, still more preferably 20% to 63%, and most preferably 23.95% or 47.90%, and wherein the weight ratio of microcrystalline cellulose to mannitol is 1:1 or 1:0; 3) 0.1% to 20% of a disintegrant selected from one or more of sodium croscarmellose, sodium carboxymethyl starch, and crospovidone, wherein preferably 0.5% to 15%, more preferably 1% to 10%, and most preferably 1.00% or 2.00%; 4) 0.1% to 5% of a binder selected from one or more of hypromellose, methylcellulose, or hydroxypropylcellulose, wherein preferably 0.5% to 4%, more preferably 1% to 3%, and most preferably 1.50%; 5) 0.1% to 5% of a lubricant selected from magnesium stearate, wherein preferably 0.4% to 2%, and most preferably 1.00%.

40. The oral preparation according to any one of claims 21 to 34, characterized in that, In the most preferred embodiment, a pharmaceutical composition is provided, comprising the following ingredients by weight (the active ingredient is in the anhydrous free form): 1) 33.33% of the hydrochloride of 2-(2-amino-4-(5-amino-6-(2-hydroxypropan-2-yl)pyridin-3-yl)phenyl)propan-2-ol or its G crystal form of the hydrochloride; 2) 47.90% of a filler selected from microcrystalline cellulose; 3) 2.00% of a disintegrant selected from sodium croscarmellose; 4) 1.50% of a binder selected from hypromellose; 5) 1.00% of a lubricant selected from magnesium stearate.

41. The method for preparing an oral preparation according to any one of claims 1 to 40, wherein the preparation method is selected from one of wet granulation, dry granulation process, and powder direct compression process, and wet granulation is preferred.

42. The preparation method of the oral preparation according to claims 1 to 41, wherein the filler, disintegrant, binder, lubricant or surfactant is added internally or externally.

43. Use of the oral preparation according to any one of claims 1 to 42 in the preparation of a medicament for treating chronic cough, asthma and alcoholic liver diseases.

44. The application according to claim 43, wherein The alcoholic liver diseases include alcoholic fatty liver, alcoholic hepatitis, alcoholic liver fibrosis or cirrhosis.

45. The application according to claim 44, characterized in that, The application is the application of the compound of formula (II) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating alcoholic fatty liver.

46. The application according to claim 44, characterized in that, The application is the application of the compound of formula (II) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating alcoholic hepatitis.

47. The application according to claim 44, characterized in that, The application is the application of the compound of formula (II) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating alcoholic liver fibrosis.

48. The application according to claim 44, wherein The application is the application of the compound of formula (II) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cirrhosis.

49. The G crystal form of the hydrochloride salt of a compound of formula (III), characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 18.82 ± 0.20°, 25.45 ± 0.20° and 28.17 ± 0.20°. The G crystal form according to claim 49, characterized in that, The G crystal form of the hydrochloride salt of the compound of formula (III), which is characterized in that using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 14.08 ± 0.20°, 16.84 ± 0.20°, 18.82 ± 0.20°, 25.45 ± 0.20°, 27.41 ± 0.20°, 28.17 ± 0.20°, 28.40 ± 0.20° and 35.79 ± 0.20°.

51. The G crystal form according to claim 50, characterized in that, The G crystal form of the hydrochloride salt of the compound of formula (III), which is characterized in that using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of this crystal form has characteristic diffraction peaks at the following 2θ angles: 7.41 ± 0.20°, 8.64 ± 0.20°, 14.08 ± 0.20°, 15.32 ± 0.20°, 16.84 ± 0.20°, 17.30 ± 0.20°, 18.82 ± 0.20°, 20.61 ± 0.20°, 20.88 ± 0.20°, 22.82 ± 0.20°, 24.59 ± 0.20°, 25.45 ± 0.20°, 25.74 ± 0.20°, 27.41 ± 0.20°, 28.17 ± 0.20°, 28.40 ± 0.20°, 29.80 ± 0.20°, 30.07 ± 0.20° and 35.79 ± 0.20°.

52. The G crystal form according to claim 51, characterized in that, The G crystal form of the hydrochloride salt of the compound of formula (III), the XRPD pattern of which is as shown in Figure 1.

53. The G crystal form according to claims 49 to 52, characterized in that, The G crystal form of the hydrochloride salt of the compound of formula (III), the thermogravimetric analysis curve (TGA) of which shows a weight loss of 0.9% at 90 °C. Its differential scanning calorimetry curve (DSC) has an endothermic peak at 144.8 °C and 148.5 °C respectively, and the TGA and DSC patterns are as shown in Figure 2.

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