Pharmaceutical composition of dipeptidyl peptidase small-molecule inhibitor

Abstract

The invention relates to a pharmaceutical composition containing a dipeptidyl peptidase 1 (DPP1) small-molecule inhibitor compound A, a preparation method of the pharmaceutical composition, and application of the pharmaceutical composition in treatment of diseases or conditions related to fibrosis bronchiectasis, in particular to a pharmaceutical composition containing a dipeptidyl peptidase 1 (DPP1) small-molecule inhibitor compound A, a preparation method of the pharmaceutical composition and application of the pharmaceutical composition in treatment of fibrosis bronchiectasis related diseases or conditions.

Description

A pharmaceutical composition of a dipeptidyl peptidase small molecule inhibitor Technical Field

[0001] The present invention relates to the technical field of chemical preparations, and in particular to a pharmaceutical composition of a dipeptidyl peptidase small molecule inhibitor compound A for treating diseases related to fibrotic bronchiectasis and a preparation method thereof. Background Art

[0002] Non-cystic fibrosis bronchiectasis is caused by recurrent suppurative infections due to various etiologies, resulting in repeated damage and / or obstruction of small and medium-sized bronchi, causing structural damage to the bronchial wall and abnormal and persistent bronchiectasis. Clinical manifestations include chronic cough, copious sputum production, and / or intermittent hemoptysis, with or without shortness of breath and respiratory failure, among other symptoms of varying severity. Any condition that damages the bronchial wall can potentially cause bronchiectasis, including infection, immunodeficiency, rheumatic disease, bronchial asthma, and chronic obstructive pulmonary disease (COPD). The most common and characteristic symptom is chronic cough and sputum production associated with mucopurulent discharge. With disease progression and / or worsening lung function, dyspnea, fatigue, and hemoptysis may also develop. The incidence and prevalence of bronchiectasis have increased internationally in recent years. According to statistics, by 2013, the incidence of bronchiectasis in the UK population had risen to 31.1 per 100,000 people, and the prevalence had increased to 525.8 per 100,000. In 2012, the incidence of bronchiectasis in Spain was approximately 48.1 / 100,000, and the prevalence of bronchiectasis in adults in the United States was approximately 139 / 100,000.

[0003] Acute lung injury / acute respiratory distress syndrome (ARDS) is characterized by diffuse interstitial and alveolar edema caused by damage to pulmonary capillary endothelial and alveolar epithelial cells during noncardiac illnesses such as severe infection, shock, trauma, and burns, leading to acute hypoxemic respiratory insufficiency or failure. Its pathophysiology is characterized by reduced lung volume, decreased lung compliance, and severe ventilation / perfusion imbalance. Clinically, it presents as progressive hypoxemia and respiratory distress, and lung imaging reveals heterogeneous exudative lesions. Accurately estimating the incidence and mortality of ARDS is difficult due to varying definitions and the heterogeneity of the disease. A 2007 review by Rubenfeld and Herridge reported an incidence of ARDS ranging from 13.5 to 58.7 cases per 100,000 person-years, with a mortality rate ranging from approximately 34% to 57.9%.

[0004] Compound A, disclosed in WO2022042591A1, is a potent and highly selective small molecule inhibitor of dipeptidyl peptidase 1 (DPP1), intended for the treatment of bronchiectasis (including both non-cystic fibrosis bronchiectasis and cystic fibrosis bronchiectasis) and lower respiratory tract diseases caused by acute lung injury / acute respiratory distress syndrome. Preclinical studies have demonstrated that Compound A significantly inhibits rat bone marrow NE enzyme activity and LPS-induced acute lung injury in mice, demonstrating promising pharmacodynamics.

[0005] Summary of the Invention

[0006] The present invention provides a pharmaceutical composition of Compound A, comprising Compound A and a pharmaceutically acceptable excipient. The composition exhibits stable quality, good stability, high bioavailability, and rapid dissolution. When developed as an immediate-release tablet, the composition exhibits advantages such as stable quality, accurate dosage, convenient transportation, and low production cost. Upon administration, the drug is rapidly released and absorbed by the body.

[0007] The present invention provides a pharmaceutical composition comprising compound A and a pharmaceutically acceptable excipient. The structure of compound A is shown below:

[0008] The present invention provides a pharmaceutical composition, wherein the pharmaceutically acceptable excipients include one or more, such as fillers, disintegrants, lubricants, antioxidants, binders, flavoring agents, colorants, coating materials, etc.

[0009] The present invention provides a pharmaceutical composition comprising compound A and a filler.

[0010] The present invention provides a pharmaceutical composition comprising compound A, a filler and a disintegrant.

[0011] The present invention provides a pharmaceutical composition comprising compound A, a filler, a disintegrant, and a lubricant.

[0012] The present invention provides a pharmaceutical composition comprising compound A, a filler, a disintegrant, a lubricant, and a coating material.

[0013] The present invention provides an oral pharmaceutical composition comprising Compound A and a pharmaceutically acceptable excipient, specifically comprising: (1) Compound A, (2) a filler, (3) a lubricant, (4) a disintegrant, and (5) a coating material, wherein the structure of Compound A is as follows:

[0014] In certain embodiments, the content of Compound A in the pharmaceutical composition of the present invention is 1% to 40% of the total mass percentage of the composition, in certain embodiments, the content of Compound A is 1% to 20% of the total mass percentage of the composition, in certain embodiments, the content of Compound A is 2.5% to 10% of the total mass percentage of the composition, in certain embodiments, in certain embodiments, the content of Compound A is 5% to 10% of the total mass percentage of the composition, and the content of Compound A is 5% of the total mass percentage of the composition.

[0015] The present invention provides a pharmaceutical composition, wherein the particle size distribution d(0.9) of compound A is less than or equal to 150 μm, preferably less than or equal to 100 μm, and more preferably less than or equal to 85 μm.

[0016] In the pharmaceutical composition of the present invention, compound A is processed by one or more of sieving, mechanical grinding, and air flow grinding.

[0017] In the pharmaceutical composition of the present invention, the filler can be selected from one or more of lactose, microcrystalline cellulose, sucrose, glucose, powdered cellulose, calcium phosphate, calcium hydrogen phosphate, calcium carbonate, aluminum silicate, dextrin, starch (including corn starch, potato starch or amylopectin), pregelatinized starch, sodium chloride, potassium chloride, mannitol or sorbitol.

[0018] In certain embodiments, the filler in the pharmaceutical composition of the present invention is selected from one or more of lactose, microcrystalline cellulose or mannitol.

[0019] In certain embodiments, the content of the filler in the pharmaceutical composition of the present invention is 67% to 99% of the total mass percentage of the composition. In certain embodiments, the content of the filler is 70% to 99% of the total mass percentage of the composition. In certain embodiments, the content of the filler is 80% to 90% of the total mass percentage of the composition. In certain embodiments, the content of the filler is 89% of the total mass percentage of the composition.

[0020] In certain embodiments, the fillers in the pharmaceutical composition of the present invention are mannitol and microcrystalline cellulose, and the mass percentage of mannitol and microcrystalline cellulose is 5:1 to 1:1. In certain embodiments, the mass percentage of mannitol and microcrystalline cellulose is 4:1 to 1:1. In certain embodiments, the mass percentage of mannitol and microcrystalline cellulose is 3:1 to 1:1. In certain embodiments, the mass percentage of mannitol and microcrystalline cellulose is 2:1 to 1:1. In certain embodiments, the mass percentage of mannitol and microcrystalline cellulose is 1:1.

[0021] In certain embodiments, the fillers in the pharmaceutical composition of the present invention are lactose and microcrystalline cellulose, and the mass percentage of lactose and microcrystalline cellulose is 5:1 to 1:1. In certain embodiments, the mass percentage of lactose and microcrystalline cellulose is 4:1 to 1:1. In certain embodiments, the mass percentage of lactose and microcrystalline cellulose is 3:1 to 1:1. In certain embodiments, the mass percentage of lactose and microcrystalline cellulose is 2:1 to 1:1. In certain embodiments, the mass percentage of lactose and microcrystalline cellulose is 3:1.

[0022] In the pharmaceutical composition of the present invention, the disintegrant can be selected from one or more of starch, pregelatinized starch, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethyl cellulose.

[0023] In certain embodiments, the content of disintegrant in the pharmaceutical composition of the present invention is 0.5% to 10% of the total mass percentage of the composition, in certain embodiments, the content of disintegrant is 1% to 10% of the total mass percentage of the composition, in certain embodiments, the content of disintegrant is 2% to 9% of the total mass percentage of the composition, in certain embodiments, the content of disintegrant is 3% to 8% of the total mass percentage of the composition, in certain embodiments, the content of disintegrant is 3% to 7% of the total mass percentage of the composition, and in certain embodiments, the content of disintegrant is 5% of the total mass percentage of the composition.

[0024] In certain embodiments, the disintegrant in the pharmaceutical compositions of the present invention is crospovidone.

[0025] In certain embodiments, the content of cross-linked polyvinylpyrrolidone in the pharmaceutical composition of the present invention is 0.5% to 10% of the total mass percentage of the composition. In certain embodiments, the content of cross-linked polyvinylpyrrolidone is 1% to 7% of the total mass percentage of the composition. In certain embodiments, the content of cross-linked polyvinylpyrrolidone is 3% to 7% of the total mass percentage of the composition. In certain embodiments, the content of cross-linked polyvinylpyrrolidone is 3% to 5% of the total mass percentage of the composition. In certain embodiments, the content of cross-linked polyvinylpyrrolidone in the pharmaceutical composition of the present invention is 5% of the total mass percentage of the composition.

[0026] In the pharmaceutical composition of the present invention, the lubricant can be selected from one or more of stearic acid, magnesium stearate, calcium stearate, aluminum stearate, palmitic acid, glyceryl behenate, polyethylene glycols of different molecular weights, hydrogenated castor oil or sodium stearyl fumarate.

[0027] In certain embodiments, the content of the lubricant in the pharmaceutical composition of the present invention is 0.25% to 2% of the total mass percentage of the composition. In certain embodiments, the content of the lubricant is 0.5% to 1.5% of the total mass percentage of the composition. In certain embodiments, the content of the lubricant is 1% to 1.5% of the total mass percentage of the composition. In certain embodiments, the content of the lubricant is 1% of the total mass percentage of the composition.

[0028] In certain embodiments, the lubricant in the pharmaceutical compositions of the present invention is magnesium stearate.

[0029] In certain embodiments, the content of magnesium stearate in the pharmaceutical composition of the present invention is 0.25% to 2% of the total mass percentage of the composition. In certain embodiments, the content of magnesium stearate is 0.5% to 1.5% of the total mass percentage of the composition. In certain embodiments, the content of magnesium stearate is 1% to 1.5% of the total mass percentage of the composition. In certain embodiments, the content of magnesium stearate is 1% of the total mass percentage of the composition.

[0030] In certain embodiments, the pharmaceutical composition of the present invention further comprises a binder. The binder can be selected from one or more of starch slurry, povidone, hydroxypropyl cellulose, hypromellose, ethyl cellulose, sodium carboxymethyl cellulose, xanthan gum, gum arabic, gelatin, guar gum, or carbomer.

[0031] In certain embodiments, the binder content in the pharmaceutical composition of the present invention is 0.1% to 10% of the total mass percentage of the composition. In certain embodiments, the binder content is 3% to 10% of the total mass percentage of the composition. In certain embodiments, the binder content is 3% to 7% of the total mass percentage of the composition. In certain embodiments, the binder content is 7% of the total mass percentage of the composition.

[0032] In certain embodiments, the binder in the pharmaceutical composition of the present invention is selected from povidone.

[0033] In certain embodiments, the binder in the pharmaceutical composition of the present invention is selected from povidone, and its content is 0.1% to 10% of the total mass percentage of the composition. In certain embodiments, the povidone content is 3% to 10% of the total mass percentage of the composition. In certain embodiments, the povidone content is 3% to 7% of the total mass percentage of the composition. In certain embodiments, the povidone content is 7% of the total mass percentage of the composition.

[0034] In certain embodiments, the pharmaceutical composition of the present invention further comprises a coating material. The coating material can be selected from a film coating premix (gastric soluble) or a mixture of one or more of the following coating materials: polyvinyl alcohol, hypromellose, talc, polyethylene glycol, polyethylene glycol-polyvinyl alcohol copolymer, titanium dioxide, mono- and di-caprylic acid capric glyceride, and lake.

[0035] In certain embodiments, the target coating weight gain in the pharmaceutical compositions of the present invention is 0.5% to 10% of the tablet core weight. In certain embodiments, the target coating weight gain is 1% to 6% of the tablet core weight. In certain embodiments, the target coating weight gain is 2% to 4% of the tablet core weight.

[0036] In certain embodiments, the coating material in the pharmaceutical composition of the present invention is selected from film coating premix (gastric soluble type).

[0037] In certain experimental protocols, the coating material in the pharmaceutical composition of the present invention is selected from a film coating premix (gastric soluble), and the target coating weight gain is 0.5% to 10% of the tablet core weight. In certain embodiments, the target coating weight gain is 1% to 6% of the tablet core weight, and in certain embodiments, the target coating weight gain is 2% to 4% of the tablet core weight.

[0038] The pharmaceutical composition of the present invention can be prepared into tablets, capsules, granules or powders.

[0039] The present invention also relates to a pharmaceutical composition comprising (1) compound A, (2) a filler, (3) a lubricant, (4) a disintegrant, and (5) a coating material.

[0040] The present invention also relates to a pharmaceutical composition comprising:

[0041] (1) Compound A, whose content is 1% to 20% by weight of the total weight of the composition, preferably 2.5% to 10%, more preferably 5%;

[0042] (2) filler, the content of which accounts for 70% to 99% of the total mass percentage of the composition, preferably 80% to 90%, more preferably 89%;

[0043] (3) a lubricant, the content of which is 0.25% to 2% by weight of the total weight of the composition, preferably 0.5% to 1.5%, more preferably 1%;

[0044] (4) Disintegrant, the content of which is 0.5% to 10% by weight of the total weight of the composition, preferably 3% to 7%, more preferably 5%.

[0045] (5) Coating material: the target coating weight gain is 0.5% to 10% of the tablet core weight, preferably 1% to 6%, and more preferably 2% to 4%.

[0046] The present invention also relates to a pharmaceutical composition comprising:

[0047] (1) Compound A, whose content is 1% to 20% by weight of the total weight of the composition, preferably 2.5% to 10%, more preferably 5%;

[0048] (2) a filler, wherein the filler is mannitol and microcrystalline cellulose, the mass ratio of the two being 3:1 to 1:1, preferably 1:1, and the content of the filler is 70% to 99% of the total mass percentage of the composition, preferably 80% to 90%, more preferably 89%;

[0049] (3) a lubricant, wherein the lubricant is magnesium stearate, and its content is 0.25% to 2% by weight of the total weight percentage of the composition, preferably 0.5% to 1.5%, and more preferably 1%;

[0050] (4) a disintegrant, wherein the disintegrant is cross-linked polyvinylpyrrolidone, and its content is 0.5% to 10% by weight of the total weight percentage of the composition, preferably 3% to 7%, and more preferably 5%.

[0051] (5) Coating material, wherein the coating powder is a film coating premix (gastric soluble type), and the target coating weight gain is 0.5% to 10% of the tablet core weight, preferably 1% to 6%, and more preferably 2% to 4%.

[0052] In certain embodiments, the unit dose of the pharmaceutical composition preparation of the present invention is selected from 1 mg to 100 mg, calculated as active compound A, preferably 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 75 mg, and 100 mg.

[0053] In certain embodiments, the pharmaceutical compositions of the present invention are tablets.

[0054] In certain embodiments, the pharmaceutical composition of the present invention, calculated as active compound A, has a dosage per unit of tablet selected from 1 mg to 100 mg, preferably 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 75 mg, 100 mg.

[0055] In the pharmaceutical composition of the present invention, the active substance Compound A is present in an amount of 1 to 100 mg, in some embodiments, in an amount of 2 to 80 mg; in some embodiments, in an amount of 2 to 60 mg; in some embodiments, in an amount of 2 to 50 mg; in some embodiments, in an amount of 5 to 50 mg; in some embodiments, in an amount of 5 to 40 mg; in some embodiments, in an amount of 5 to 30 mg; in some embodiments, in an amount of 5 to 20 mg; in some embodiments, in an amount of 5 to 10 mg; in some embodiments, in an amount of 10 to 80 mg; in some embodiments, in an amount of 10 to 60 mg; in some embodiments, in an amount of 10 to 50 mg; in some embodiments, in an amount of 20 to 80 mg; in some embodiments, in an amount of 20 to 60 mg; in some embodiments, in an amount of 20 to 50 mg; in some embodiments, in an amount of 30 to 50 mg.

[0056] The pharmaceutical composition of the present invention is a tablet or capsule preparation, and the active substance is present in an amount of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg; in certain embodiments, it is present in an amount of 5 mg, 10 mg or 20 mg; in certain embodiments, it is present in an amount of 5 mg or 20 mg.

[0057] The present invention also provides a preparation process of the pharmaceutical composition, which comprises one or more of a dry granulation process, a wet granulation process, and a powder direct tableting process.

[0058] In certain embodiments, the unit preparation of the pharmaceutical composition of the present invention contains 5 mg of Compound A, 44.5 mg of mannitol, 44.5 mg of microcrystalline cellulose, 3 mg of coating powder, 5 mg of cross-linked polyvinylpyrrolidone, and 1 mg of magnesium stearate, or the unit preparation of the pharmaceutical composition contains 20 mg of Compound A, 178 mg of mannitol, 178 mg of microcrystalline cellulose, 20 mg of cross-linked polyvinylpyrrolidone, 4 mg of magnesium stearate, and 12 mg of coating powder.

[0059] The present invention also provides a method for preparing the preparation of the pharmaceutical composition, comprising the following steps:

[0060] (1) crushing compound A;

[0061] (2) adding compound A, filler, and disintegrant into a mixer for premixing;

[0062] (3) Add the lubricant into the mixer and mix thoroughly with the premixed powder; compress the tablets, apply film coating, and package.

[0063] The mixer equipment includes but is not limited to mixing materials by driving a stirring blade or a cutting blade to rotate at high speed, such as a wet mixing granulator, a high-energy mixer, or mixing materials in a container by rotating the equipment container, such as one or more of a three-dimensional mixer and a hopper mixer.

[0064] The present invention adopts a wet mixing granulator to premix raw and auxiliary materials during the drug preparation process, optimizes the mixing process, reduces the mixing steps such as moderate addition and multi-step mixing in traditional mixing, shortens the mixing time, increases the mixing efficiency, and achieves better material mixing uniformity than traditional mixing methods.

[0065] The present invention also provides use of the pharmaceutical composition in preparing a medicament for treating diseases associated with fibrosing bronchiectasis, wherein the diseases associated with fibrosing bronchiectasis are selected from bronchiectasis (including non-cystic fibrosis bronchiectasis and cystic fibrosis bronchiectasis) and lower respiratory tract diseases caused by acute lung injury / acute respiratory distress syndrome.

[0066] Unless otherwise specified, the "content" of each ingredient in the present invention refers to the mass percentage of the substance in the total mass of the composition. The weight percentage of each component of a preparation such as a tablet or capsule is the mass percentage of the component in the tablet or capsule filling (including active agents and various excipients).

[0067] The pharmaceutical preparation provided by the present invention has good stability and bioavailability. DETAILED DESCRIPTION

[0068] The present invention will be described in detail below through examples. Where specific conditions are not specified in the examples, the experimental methods are carried out according to conventional conditions. The examples are provided to better illustrate the present invention, but it should not be understood that the present invention is limited to the examples. Any non-essential improvements and adjustments made by those skilled in the art to the embodiments based on the above invention are still within the scope of protection of the present invention.

[0069] Unless otherwise specified, the materials used in the examples of the present invention are all commercially available.

[0070] Preparation of compound A:

[0071] (S)-N-((S)-1-Cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound A)

[0072] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide(compound A)

[0073] Step 1: (S)-tert-Butyl (1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamate (1B)

[0074] (S)-tert-butyl(1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamate(1B)

[0075] Compound 1A (0.29 g, 0.85 mmol, synthesis method referenced by WO 2016016242 A1) was dissolved in 1,4-dioxane (10 mL) and water (0.4 mL). Intermediate 2a (0.35 g, 1.27 mmol, preparation method referenced by WO 2016016242), potassium carbonate (0.24 g, 1.70 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (70 mg, 0.09 mmol) were added. The mixture was reacted at 90°C for 3 h. The mixture was cooled to room temperature, and saturated aqueous sodium chloride solution (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA (v / v) = 4:1) to afford the title compound 1B as a white solid, 0.34 g, 99.0%.

[0076] LC-MS (ESI): m / z = 412.1 [M+H] + .

[0077] Step 2: (S)-2-amino-3-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propionitrile (1C)

[0078] (S)-2-amino-3-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile(1C)

[0079] 1B (0.34 g, 0.83 mmol) was dissolved in formic acid (5 mL). After addition, the reaction was allowed to react at room temperature overnight. The mixture was concentrated to dryness, and ethyl acetate (25 mL) was added. Saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated and extracted with ethyl acetate (25 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude title compound 1C (pale yellow solid, 0.21 g, 69.5%).

[0080] LC-MS (ESI): m / z = 312.1 [M+H] + .

[0081] Step 3: (S)-tert-butyl 2-(((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (1D)

[0082] (S)-tert-butyl2-(((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate(1D)

[0083] Dissolve 1C (0.21 g, 0.60 mmol) in DMF (10 mL), then add DIPEA (0.23 g, 1.80 mmol), HATU (0.34 g, 0.90 mmol), and INT-3 (0.22 g, 0.90 mmol, preparation method according to WO2015110826). Allow to react overnight at room temperature. Saturated ammonium chloride was added dropwise to quench the reaction. Saturated sodium chloride (30 mL) was added, and the mixture was extracted with ethyl acetate (25 mL). The organic phase was washed with saturated sodium chloride (3 times 25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound 1D (pale yellow solid, 0.32 g, 99.0%), which was used directly in the next step.

[0084] LC-MS(ESI):m / z=483.1[M-57+H] + .

[0085] Step 4: (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (Compound A)

[0086] (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide(compound A)

[0087] 1D (0.32 g, 0.59 mmol) was dissolved in formic acid (2.5 mL). After complete addition, the mixture was reacted at 50°C for 10 min. The solution was concentrated to dryness, and ethyl acetate (20 mL) was added. Saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The organic layer was separated and extracted with ethyl acetate (25 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain the title compound A (0.15 g, 58.0%).

[0088] LC-MS (ESI): m / z = 439.1 [M+H] + .

[0089] 1 H NMR (400MHz, CDCl3) δ7.43-7.22(m,5H),7.12(d,1H),5.19(dd,1H),4.18-4.04(m,1H),4.05 -3.95(m,1H),3.78(m,1H),3.46(s,3H),3.41-3.17(m,3H),3.03-2.87(m,3H),1.88(m,2H).

[0090] Examples 1 to 3

[0091] The formulations of Examples 1-3 are shown in Table 1.

[0092] The preparation steps are as follows:

[0093] (1) Compound A was mechanically crushed.

[0094] (2) Compound A, lactose, microcrystalline cellulose, povidone and cross-linked povidone were added to a wet mixing granulator, and stirring (500 rpm) and shearing blades (2000 rpm) were turned on to mix the materials thoroughly.

[0095] (3) Keep the stirring and shearing blades on, add an appropriate amount of purified water to the granulator to make a suitable soft material, sieve with a 20 mesh sieve, and granulate. Dry the wet granules at below 60℃.

[0096] (4) After the dry granules are sieved through a 20-mesh sieve, magnesium stearate is added and mixed evenly. The tablets are compressed using a 6.5 mm round punch to obtain plain tablets.

[0097] (5) Add water to the Colorcon film coating premix (gastric soluble type) and stir to prepare a coating solution with a solid content of 30%. Place the plain tablets in a high-efficiency coating machine and use the coating solution to spray coat the tablets. The target coating weight gain is 2% to 4% of the tablet core weight to obtain film-coated tablets.

[0098] Table 1 Composition and dissolution of Examples 1 to 3

[0099] Conclusion: When 3%-7% cross-linked polyvinylpyrrolidone is used as a disintegrant, the product can disintegrate rapidly and dissolve more completely.

[0100] Examples 4 and 5

[0101] The formulations of Examples 4-5 are shown in Table 2.

[0102] The preparation steps are the same as in Examples 1 to 3.

[0103] Table 2 Composition and dissolution of Examples 4 and 5

[0104] Conclusion: Combined with the dissolution results of Example 2, when 0.5% to 1.5% magnesium stearate is used, the product can disintegrate and dissolve rapidly and has sufficient lubrication properties during the production process.

[0105] Examples 6 to 8

[0106] The formulations of Examples 6-8 are shown in Table 3.

[0107] The preparation steps are as follows:

[0108] (1) Compound A was mechanically crushed.

[0109] (2) Compound A, mannitol, microcrystalline cellulose, and crospovidone were added to a wet mixing granulator, and stirring and shearing paddles were turned on to mix the materials thoroughly;

[0110] (3) Add the above mixture into a hopper mixer, add magnesium stearate and mix thoroughly. The mixed material is tableted to obtain the product.

[0111] Table 3 Compositions of Examples 6 to 8 and Content Uniformity of Tablets

[0112] Conclusion: When microcrystalline cellulose alone or mannitol and microcrystalline cellulose are used in combination at a ratio of 3:1 to 1:1, the tablets have uniform content, good compressibility and stable quality.

[0113] Example 9

[0114] Compound A was mixed evenly with lactose, microcrystalline cellulose and mannitol at a ratio of 1:5 and placed in a wide-mouth glass container of appropriate size.

[0115] The above mixture was placed under 60°C closed, 92.5% RH (relative humidity) open, 40°C / 75% RH closed, and 40°C / 75% RH open conditions, and the change in impurities after 2 weeks was measured.

[0116] Table 4 Stability of compound A after mixing with different fillers

[0117] Conclusion: According to the results of the two-week investigation, compound A can maintain good stability after being mixed with various fillers. Among them, mannitol and microcrystalline cellulose have less impurity growth and better stability after being mixed with compound A.

[0118] Example 10

[0119] The composition of the formulation of Example 10 is shown in Table 5.

[0120] The preparation steps are the same as in Examples 6 to 8.

[0121] Table 5 Composition of Example 10

[0122] Tablets of different hardness were prepared, and their dissolution was relatively complete, as shown in Table 6 below.

[0123] Table 6 Dissolution of tablets with different hardness in Examples 8 and 10

[0124] Within the scope of investigation, tablet hardness has no effect on the dissolution curve, the product has a beautiful appearance and good mechanical strength.

[0125] The products of Examples 8 and 10 were packaged in double aluminum blisters and placed in a test environment at 40°C and RH75% for 6 months. The dissolution and content determination results remained consistent with the results in month 0, with only a slight increase in the total amount of impurities, indicating good stability. The specific results are shown in Table 7 below.

[0126] Table 7 Stability of Examples 8 and 10

[0127] Examples 11-14

[0128] Compound A was processed into different particle sizes using different methods. The formulation composition was the same as in Example 10, and the preparation steps were the same as in Examples 6 to 8. The effects of different particle sizes of Compound A on the mixing uniformity of the preparation and the tablet dissolution curve were investigated.

[0129] Table 8 Content determination results

[0130] Table 9 Tablet dissolution curve results

[0131] The results showed that the particle size d(0.9) of the raw materials was in the range of 7.349 to 82.334 μm, the content uniformity of the prepared total blend samples and tablets was good, and the dissolution curves of the preparations were basically consistent.

[0132] Examples 15-16

[0133] The formulation composition is the same as that of Example 10, and the preparation steps are the same as those of Examples 6 to 8. Plain tablets are prepared and film-coated with a film coating premix (gastric soluble type). Samples with different coating weight gains are taken for dissolution curve detection.

[0134] Table 10 Dissolution curves of tablets with different coating weight gain

[0135] Within the study range, different coating weight gains had no significant effect on the tablet dissolution profile.

[0136] Example 17

[0137] The samples of Example 8 and Example 15 were packaged in double aluminum blister packaging (polyamide / aluminum / polyvinyl chloride cold-stamped solid pharmaceutical composite hard sheet, pharmaceutical aluminum foil) and PVDC blister packaging (polyvinyl chloride / polyvinylidene chloride, pharmaceutical aluminum foil), respectively. The samples were then stored under accelerated conditions (40°C / 75% RH) for six months to investigate the stability of the samples under different packaging conditions. The results are as follows: After six months, the stability of the samples packaged in the double aluminum blister packaging was significantly better than that of the samples packaged in the PVDC packaging.

[0138] Table 11 Stability of samples in different packaging

[0139] Examples 18-19

[0140] The formulation composition is the same as that of Example 10. Compound A, mannitol, microcrystalline cellulose and crospovidone are added to a wet mixing granulator. The stirring and shearing paddles are turned on to mix the materials. Samples are taken after mixing for different times to detect the uniformity of the mixture content.

[0141] Table 11 Content uniformity of samples at different mixing times

[0142] The wet mixing granulator is used to mix the materials, which can achieve a good mixing effect in a shorter time. Moreover, the material mixing uniformity is good at different mixing times within the research range.

[0143] Compound A biological test

[0144] 1. In vitro DPP1 enzyme activity detection experiment

[0145] Recombinant human DPP1 enzyme (R&D Systems, Cat.No 1071-CY) with a final concentration of 100 μg / mL was mixed with recombinant human cathepsin L (R&D System, Cat.No 952-CY) with a final concentration of 20 μg / mL and incubated at room temperature for 1 hour to activate the DPP1 enzyme. The activated DPP1 enzyme was diluted 100 times, and 5 μL of compounds of different concentrations and 5 μL of diluted DPP1 enzyme were added to a 384-well plate and incubated at room temperature for 30 minutes. After adding 10 μL of substrate Gly-Arg-AMC (bachem, Cat.No I-1215) with a concentration of 20 μM, the plate was incubated at room temperature for 60 minutes. The fluorescence intensity was detected by a microplate reader, where the excitation light was 380 nm and the emission light was 460 nm. The IC was calculated using the DosResp function of the Origin2019 software. 50 value.

[0146] Test results: The compounds of the present invention showed inhibitory activity against the DPP1 receptor. The IC50 values ​​of the example compounds against the DPP1 receptor were less than 100 nM. The test results of some examples are shown in Table 8.

[0147] Table 8 DPP1 inhibitory activity

[0148] Conclusion: Compound A of the present invention shows high inhibitory activity against DPP1 receptor.

[0149] 2. Pharmacokinetic test in rats

[0150] 1.1 Experimental Animals: Male SD rats, approximately 220 g, 6 to 8 weeks old, 6 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0151] 1.2 Experimental Design: On the day of the experiment, six SD rats were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0152] Table 9 Dosage information

[0153] Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; oral administration solvent: 0.5% MC; the control compound INS1007 is compound 2 in patent WO2015110826A1, prepared according to the patented method.

[0154] Before and after drug administration, 0.1 ml of blood was collected intraorbitally under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from the venous group at 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, and 24 hours; from the gavage group at 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, and 24 hours. All samples were stored at −80°C prior to analysis.

[0155] Table 10 Pharmacokinetic parameters of test compounds in rat plasma

[0156] Conclusion: The compound of the present invention has good bioavailability and pharmacokinetic characteristics.

[0157] 3. 14-day oral repeated dose toxicity test in rats

[0158] SD rats were randomly divided into groups according to body weight: a vehicle control group (0.5% MC), an INS1007 (30, 100, 300 mg / kg) group, and a compound A (30, 100, 300 mg / kg) group. Each treatment group had 16 rats, and the vehicle control group had 10 rats, half male and half female. The rats were given the corresponding concentration of drug or vehicle by oral gavage daily for 14 consecutive days, followed by a 7-day recovery period. During the treatment period, general symptoms, body weight, and food intake were observed in each group. At the end of the treatment period and the recovery period, hematology, serum biochemistry, and gross anatomical examinations were performed on each group.

[0159] Conclusion: At the same dose, compound A of the present invention is less toxic than INS1007 and has higher safety.

Claims

1. A pharmaceutical composition, wherein: It includes compound A and excipients, and the structure of compound A is shown below:

2. The pharmaceutical composition according to claim 1, wherein The content of compound A in the pharmaceutical composition is 1% to 20% by weight of the total mass of the composition, preferably 2.5% to 10%, and more preferably 5%.

3. The pharmaceutical composition according to claim 1 or 2, wherein The particle size distribution of the compound A is d(0.9) less than or equal to 150 μm, preferably less than or equal to 100 μm, and more preferably less than or equal to 85 μm.

4. The pharmaceutical composition according to claim 3, wherein The processing method of the compound A is one or more of screening, mechanical crushing and air flow crushing.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein The excipients include fillers, which are selected from one or more of lactose, microcrystalline cellulose, sucrose, glucose, powdered cellulose, calcium phosphate, calcium hydrogen phosphate, calcium carbonate, aluminum silicate, dextrin, starch, pregelatinized starch, sodium chloride, potassium chloride, mannitol or sorbitol, preferably one or more of lactose, microcrystalline cellulose or mannitol.

6. The pharmaceutical composition according to claim 5, wherein The filler is mannitol and microcrystalline cellulose, and the mass ratio of mannitol to microcrystalline cellulose is 3:1 to 1:1, preferably 1:

1.

7. The pharmaceutical composition according to claim 5, wherein The filler is lactose and microcrystalline cellulose, and the mass ratio of lactose to microcrystalline cellulose is 3:1 to 1:1, preferably 3:

1.

8. The pharmaceutical composition according to any one of claims 5 to 7, wherein The excipients also include disintegrants.

9. The pharmaceutical composition according to claim 8, wherein The disintegrant is one or more of starch, pregelatinized starch, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethyl cellulose, preferably cross-linked polyvinylpyrrolidone.

10. The pharmaceutical composition according to claim 9, wherein The content of the cross-linked polyvinylpyrrolidone is 0.5% to 10% by weight of the total weight of the composition, preferably 3% to 7%, and more preferably 5%.

11. The pharmaceutical composition according to any one of claims 8 to 10, wherein The excipients also include lubricants.

12. The pharmaceutical composition according to claim 11, wherein The lubricant is one or more of stearic acid, magnesium stearate, calcium stearate, aluminum stearate, palmitic acid, glyceryl behenate, polyethylene glycols of different molecular weights, hydrogenated castor oil, and sodium stearyl fumarate, preferably magnesium stearate.

13. The pharmaceutical composition according to claim 12, wherein The content of magnesium stearate is 0.25% to 2% by weight of the total mass percentage of the composition, preferably 0.5% to 1.5%, and more preferably 1%.

14. The pharmaceutical composition according to any one of claims 5 to 13, wherein Also includes an adhesive.

15. The pharmaceutical composition according to claim 14, wherein The binder is selected from one or more of starch slurry, povidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, xanthan gum, gum arabic, gelatin, guar gum or carbomer, preferably povidone, and the content of the povidone is 0.1% to 10% of the total mass percentage of the composition, preferably 3% to 7%, and more preferably 7%.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein The dosage form of the pharmaceutical composition is tablet, capsule, granule or powder.

17. The pharmaceutical composition according to claim 16, wherein The dosage form of the pharmaceutical composition is tablet.

18. The pharmaceutical composition according to claim 17, wherein The tablet also includes a film coating layer, which is coated with a gastric soluble film coating premix or a coating material, wherein the coating material is selected from one or more of polyvinyl alcohol, hydroxypropyl methylcellulose, talcum powder, polyethylene glycol, polyethylene glycol-polyvinyl alcohol copolymer, titanium dioxide, mono- and di-caprylic acid glyceride, and lake; preferably, a gastric soluble film coating premix is ​​used for coating; wherein the target coating weight gain is 0.5% to 10% of the weight of the tablet core, preferably 1% to 6%, and more preferably 2% to 4%.

19. A pharmaceutical composition, wherein: The pharmaceutical composition comprises compound A, a filler, a lubricant, a disintegrant and a coating material.

20. The pharmaceutical composition according to claim 19, wherein The content of compound A is 1% to 20% of the total mass percentage of the composition, preferably 2.5% to 10%, more preferably 5%; The filler content is 70% to 99% of the total mass percentage of the composition, preferably 80% to 90%, more preferably 89%; The lubricant content is 0.25% to 2% of the total mass percentage of the composition, preferably 0.5% to 1.5%, more preferably 1%; The content of the disintegrant is 0.5% to 10% by weight of the total weight of the composition, preferably 3% to 7%, more preferably 5%; The target coating weight gain of the coating material is 0.5% to 10% of the weight of the tablet core, preferably 1% to 6%, and more preferably 2% to 4%.

21. The pharmaceutical composition according to claim 19 or 20, wherein The filler is mannitol and microcrystalline cellulose, the mass ratio of mannitol to microcrystalline cellulose is 3:1 to 1:1, preferably 1:1; the lubricant is magnesium stearate; the disintegrant is cross-linked polyvinylpyrrolidone; and the coating material is a gastric soluble film coating premix.

22. The pharmaceutical composition according to any one of claims 1 to 21, wherein Calculated on the mass of active substance, the unit dose of the preparation is selected from 1 mg to 500 mg, preferably 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 75 mg, 100 mg, 150 mg or 200 mg.

23. The pharmaceutical composition according to any one of claims 1 to 22, wherein The unit preparation of the pharmaceutical composition contains 5 mg of Compound A, 44.5 mg of mannitol, 44.5 mg of microcrystalline cellulose, 5 mg of cross-linked polyvinylpyrrolidone, 1 mg of magnesium stearate, and 3 mg of coating powder; or the unit preparation of the pharmaceutical composition contains 20 mg of Compound A, 178 mg of mannitol, 178 mg of microcrystalline cellulose, 20 mg of cross-linked polyvinylpyrrolidone, 4 mg of magnesium stearate, and 12 mg of coating powder.

24. A method for preparing the pharmaceutical composition according to any one of claims 1 to 23, wherein: The preparation process is one or more of a dry granulation process, a wet granulation process, and a powder direct tableting process.

25. A method for preparing the pharmaceutical composition according to any one of claims 18 to 23, comprising the following steps: (1) crushing compound A; (2) adding compound A, filler and disintegrant into a mixer for premixing; (3) Add the lubricant into the mixer and mix it with the premixed powder thoroughly; press the tablets, apply a film coating, and package.

26. The preparation method according to claim 25, wherein: The mixer includes a mixer that mixes materials by driving a stirring blade and a shearing knife to rotate at high speed, preferably selected from a wet mixing granulator, a high-energy mixer, or a mixer in which materials are mixed in a container by rotating the equipment container, preferably selected from one or more of a three-dimensional mixer and a hopper mixer.

27. Use of the pharmaceutical composition according to any one of claims 1 to 23 in the preparation of a medicament for treating diseases associated with fibrotic bronchiectasis.

28. The use according to claim 27, wherein The disease associated with fibrosing bronchiectasis is selected from bronchiectasis, acute lung injury or lower respiratory tract disease caused by acute respiratory distress syndrome.

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