New application of N-[2-[[[4-(2, 2-dimethyl-1-oxopropoxy) phenyl] sulfonyl] amino] benzoyl]-(S)-glycine or salt thereof

Abstract

The present invention relates to a novel use of N-[2-[[[4-(2, 2-dimethyl-1-oxopropoxy) phenyl] sulfonyl] amino] benzoyl]-(S)-glycine or a salt thereof, said N-[2-[[[4-(2, 2-dimethyl-1-oxopropoxy) phenyl] sulfonyl] amino] benzoyl]-(S)-glycine or a salt thereof being useful in the prevention or treatment of bronchiectasis.

Description

Technical Field

[0001] The present invention relates to the use of N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine or a salt thereof in the preparation of a medicament for preventing or treating bronchiectasis. Background Art

[0002] N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine (abbreviated as Compound A in the present invention) has the following structure:

[0003]

[0004] This compound is a neutrophil elastase inhibitor, developed by a Japanese company and first marketed in 2002. It was approved for marketing in China in 2020 for the treatment of acute lung injury or acute respiratory distress syndrome.

[0005] The prior art has disclosed injectable and inhalable preparations of this compound. For example, Document 1 discloses a freeze-dried injectable preparation of this compound, containing N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine monosodium salt tetrahydrate, and at least one pH regulator selected from trisodium phosphate or its hydrate, sodium hydroxide or potassium hydroxide. Document 2 discloses an inhalable preparation containing N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine monosodium or its hydrate, a pH regulator and an osmotic pressure regulator. There is no literature directly reporting that N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine or a salt thereof can be used for the treatment of bronchiectasis.

[0006] Bronchiectasis, abbreviated as bronchiectasis, mainly refers to a general term for a heterogeneous group of diseases in which, after acute and chronic respiratory tract infections and bronchial obstruction, repeated bronchopurulent inflammations occur, resulting in damage to the bronchial wall structure, thickening of the wall, and causing abnormal and persistent dilation of the bronchi. It can be primary or secondary. The clinical manifestations are persistent or recurrent cough, expectoration of a large amount of purulent sputum and / or repeated hemoptysis, which can lead to respiratory function disorders and cor pulmonale. It is mainly divided into bronchiectasis caused by cystic fibrosis (CF) and bronchiectasis not caused by cystic fibrosis.

[0007] Clinical drugs for the treatment of bronchiectasis with neutrophil elastase inhibitors have been developed in part, such as AZD 9668 (Literature 3) and BAY 85-8501 (Literature 4). Among them, the results of AZD9668 used to treat bronchiectasis patients showed that some pulmonary functions (FEV1, SVC) of the patients and some inflammatory biomarkers (IL-8, IL-6) in sputum were improved, but there were no significant differences in the number of neutrophils in sputum, the activity of neutrophil elastase (NE), sputum weight, and quality of life compared with the placebo group. In the study of BAY 85-8501 for the treatment of non-cystic fibrosis bronchiectasis, there were no statistical differences in other biomarkers, sputum weight, NE content in sputum, NE activity, and pulmonary function compared with the placebo group, except for a slight increase in the level of the inflammatory factor IL-8 in sputum. Therefore, there is an urgent need to develop a therapeutic drug that can be effectively used for bronchiectasis.

[0008] Literature 1 CN1263736 C

[0009] Literature 2 WO2022143722 A1

[0010] Literature 3 “Efficacy, safety and effect on biomarkers of AZD9668 in cystic fibrosis”, 《European Respiratory Journal》

[0011] Literature 4 H Watz et al. Pulm Pharmacol Ther(2019) Summary of the Invention

[0012] The present invention provides the use of N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine or a salt thereof in the preparation of a drug for preventing or treating bronchiectasis.

[0013] Among them, the dose of the N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine or a salt thereof is 0.1-500 mg / kg;

[0014] As a preferred embodiment of the present invention, the N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine or a salt thereof is monosodium salt;

[0015] As a preferred embodiment of the present invention, the present invention provides the use of N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine monosodium salt hydrate in the preparation of a medicament for preventing or treating bronchiectasis.

[0016] The bronchiectasis described in the present invention is non-cystic fibrosis bronchiectasis or cystic fibrosis bronchiectasis.

[0017] The second aspect of the present invention provides a pharmaceutical preparation, which contains a therapeutically effective amount of N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine or its salt and a pharmaceutically acceptable excipient.

[0018] The pharmaceutical preparation is selected from freeze-dried injection preparations or inhalation preparations.

[0019] The freeze-dried injection preparation contains compound A or its salt and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient is arbitrarily selected from one or more combinations of excipients, pH regulators, stabilizers, solubilizers, etc.

[0020] The inhalation preparation contains compound A or its salt and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient is arbitrarily selected from one or more combinations of pH regulators, osmotic pressure regulators, surfactants, etc. The inhalation preparation can be inhaled after being atomized by an inhalation device after being mixed with a carrier (such as water, physiological saline, etc.).

[0021] Preferred excipients of the present invention include: lactose, glucose, maltose, mannitol, xylitol, sorbitol, sodium chloride, etc.; preferably mannitol.

[0022] Preferred pH regulators of the present invention include: sodium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, sodium hydroxide, potassium hydroxide, citric acid or its salts, tartaric acid or its salts, etc.

[0023] Preferred osmotic pressure regulators in the inhalant include: sodium chloride, potassium chloride, glucose, calcium chloride, magnesium chloride, sorbitol, xylitol, etc.

[0024] Preferred surfactants of the present invention include: sodium dodecyl sulfate, glyceryl trioleate, poloxamer, polysorbate-60, polysorbate-80, polyethylene oxide, castor oil, etc.

[0025] The present invention further provides a use of an inhalation preparation in the preparation of a medicament for preventing or treating bronchiectasis, wherein the inhalation preparation contains N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine or a salt thereof.

[0026] The present invention further provides a use of a freeze-dried injection preparation in the preparation of a medicament for preventing or treating bronchiectasis, wherein the freeze-dried injection preparation contains N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine or a salt thereof. Detailed implementation manners

[0027] The present invention will be further described in detail below in conjunction with embodiments, but the implementation manners of the invention are not limited thereto. Unless otherwise specified, experimental animals, reagents, detection methods, data statistics methods, etc. used in the specific embodiments of the present invention can be obtained by conventional methods in the art.

[0028] Example 1

[0029] Animal experiment

[0030] Male Sprague-Dawley (SD) rats were divided into 5 groups with 10 rats in each group, namely a blank control group, a model group, and groups of compound A monosodium salt for inhalation at 2.5 mg / mL, 7.5 mg / mL, and 25 mg / mL. Except for the blank control group, rats in the other groups were established as bronchiectasis rat models according to the method described in the literature (Shanghai Journal of Laboratory Animal Science, 2000, 20(2): pp. 65-68). 1 hour after modeling, rats in each dose group of compound A monosodium salt for inhalation were inhaled with each concentration of compound A monosodium salt (after atomization using a compressed atomizer and administered through the nose and mouth of the rats) for 30 minutes. Rats in the blank control group and the model group were atomized and inhaled with 0.9% NaCl for 30 minutes. Each group of animals was administered 2 times at an interval of about 8 hours. The rats were sacrificed 24 hours after modeling, the left lung was ligated, the right lung bronchi and alveoli were lavaged, and the total number of white blood cells, eosinophils, lymphocytes, and macrophages in the lavage fluid were counted; part of the bronchi and the left lung were homogenized and then the neutrophil elastase activity in the bronchial and lung tissues was measured.

[0031] Table 1. Delivery dose of compound A monosodium salt for inhalation in rats

[0032]

[0033]

[0034] The neutrophil elastase (NE) activities of rats in each group are shown in the following table.

[0035] Table 2. Neutrophil elastase activity in rats of each group (Mean±SD)

[0036]

[0037] Note: Compared with the blank control group: # P<0.05; compared with the model group: * P<0.05, ** P<0.01, ***P<0.001.

[0038] Animal experiments show that the compound of the present invention has a good therapeutic effect on rats with bronchiectasis model.

[0039] Example 2

[0040] Evaluate the therapeutic effect in patients with bronchiectasis

[0041] Select 10 patients diagnosed with bronchiectasis after admission, and randomly divide them into a treatment group and a control group. Among them, there are 5 patients in the treatment group and 5 patients in the control group. There are no significant differences in gender ratio, average age, disease severity, etc. between the two groups.

[0042] Inclusion criteria:

[0043] Subjects must meet all the following criteria to be included in this study:

[0044] (1) Age ≥ 18 years old, gender is not limited;

[0045] (2) Chest high-resolution CT (High Resolution CT, HRCT) shows bronchiectasis affecting one or more lung lobes, and is clinically diagnosed as non-cystic fibrosis bronchiectasis (NCFBE) (clinical manifestations are: chronic cough, a large amount of sputum and / or intermittent shortness of breath and respiratory failure, etc., with varying degrees of symptoms). If the subject has had an HRCT examination in the same hospital within 12 months, it is considered valid and there is no need to perform an HRCT examination again during the screening period;

[0046] (3) Have a history of chronic expectoration, and still produce sputum during the screening period, and can provide a sputum sample sufficient for microscopic examination (if the subject is unable to expectorate sputum independently, the sample can be collected by induced sputum);

[0047] (4) It is confirmed by the researcher that there are at least 2 acute exacerbations of bronchiectasis within 12 months before screening;

[0048] (5) If long-term treatment with bronchodilators (long-acting β-agonists and / or long-acting muscarinic antagonists) is required, the dose and regimen should be stable for at least 3 months before the screening visit and remain stable throughout the study period;

[0049] (6) The expected survival period is greater than 12 months;

[0050] The subjects fully understand the purpose, nature, methods of the trial and the possible adverse events, voluntarily participate in the trial and sign the informed consent form, or the informed consent form is provided by the legally authorized representative.

[0051] Exclusion criteria:

[0052] If the subject meets any of the following conditions, they cannot participate in this study:

[0053] (1) Subjects with pulmonary hypertension at the time of screening or those whose main diagnosis is determined by the researcher to be chronic obstructive pulmonary disease (COPD), asthma;

[0054] (2) History of malignant tumors within 5 years before screening (excluding cured basal cell carcinoma of the skin, carcinoma in situ and papillary thyroid carcinoma, those who have undergone lung cancer surgery for at least 5 years and have not received anti-tumor treatment and continue to survive can be included in the group) or history of anti-tumor treatment;

[0055] (3) Bronchiectasis caused by cystic fibrosis determined by the researcher (HRCT shows mainly upper lobe lesions);

[0056] (4) Currently being treated for non-tuberculous mycobacterial pulmonary infection, allergic bronchopulmonary aspergillosis or pulmonary tuberculosis, active and current symptomatic infection of the lungs caused by Coronavirus Disease 2019 (COVID-19);

[0057] (6) Hemoptysis occurred within 4 weeks before screening (except for a small amount of blood-streaked sputum or blood clots smaller than the size of a fingernail) and urgent medical intervention was required;

[0058] (7) Subjects who participated in other drug or medical device trials within 3 months before the trial or are currently participating in other clinical trials;

[0059] (8) Pregnant women, lactating women and women who may be pregnant;

[0060] The researcher believes that there are any reasons for the subject not to be suitable for participating in this study.

[0061] Effectiveness evaluation indicators:

[0062] The incidence of acute exacerbation of bronchiectasis in the treated patients after enrollment.

[0063] The changes in the sputum volume, sputum viscosity and active NE concentration in the sputum of the treated patients after enrollment compared with those at the time of screening.

[0064] Change in FEV1 of the treated patients after enrollment compared to that at screening.

[0065] Change in QOL-B respiratory symptom score of the treated patients after enrollment compared to that at screening.

[0066] Treatment regimen: Both groups of patients received conventional treatments such as oxygen inhalation, anti-asthmatic, expectorant, and anti-infection treatments. The treatment group received nebulized inhalation of compound A monosodium salt; 3 times a day; the control group received nebulized inhalation of normal saline: 3 times a day.

[0067] The changes in sputum volume of the two groups of patients on day 0, 14, and 28 are shown in Table 3 below.

[0068] Table 3. Changes in sputum volume of two groups of patients (Mean±SD)

[0069]

[0070] Data indicate that by nebulized inhalation of the compound inhalant of the present invention, the expectoration volume of patients with bronchiectasis can be effectively improved.

Claims

1. Use of N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine or a salt thereof in the preparation of a medicament for preventing or treating bronchiectasis.

2. The use according to claim 1, wherein, The dose of the N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine or a salt thereof is 0.1 - 500 mg / kg.

3. The use according to claim 1, wherein The N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine is a sodium salt.

4. The use according to claim 1, wherein The bronchiectasis is non-cystic fibrosis bronchiectasis or cystic fibrosis bronchiectasis.

5. A pharmaceutical preparation, which contains a therapeutically effective amount of N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine or a salt thereof and a pharmaceutically acceptable excipient.

6. The pharmaceutical preparation according to claim 5, which is a freeze-dried preparation for injection or an inhalation preparation.

7. Use of the pharmaceutical preparation according to claim 5 in the preparation of a medicament for preventing or treating bronchiectasis.

Images