Novel use of n-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(s)-glycine or salt thereof

Abstract

Provided is novel use of N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine or a salt thereof for use in preventing or treating bronchiectasis.

Description

New use of N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine or its salt Technical Field

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

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

[0003] This compound is a neutrophil elastase inhibitor developed by a Japanese company and first launched on the market in 2002. In 2020, it was approved for marketing in China for the treatment of acute lung injury or acute respiratory distress syndrome.

[0004] Prior art has disclosed injections and inhalation formulations of this compound. For example, Document 1 discloses a lyophilized injection formulation of this compound, comprising N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine monosodium salt tetrahydrate and at least one pH adjuster selected from trisodium phosphate or its hydrate, sodium hydroxide, or potassium hydroxide. Document 2 discloses an inhalation formulation comprising N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine monosodium salt or its hydrate, a pH adjuster, and an osmotic pressure regulator. No literature directly reports that N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine or its salt can be used to treat bronchiectasis.

[0005] Bronchiectasis, also known as bronchiectasis, refers to a heterogeneous group of diseases characterized by recurrent purulent bronchial inflammation following acute or chronic respiratory infections and bronchial obstruction, leading to structural destruction and thickening of the bronchial walls, resulting in abnormal and persistent bronchial dilation. Bronchiectasis can be primary or secondary. Clinical manifestations include persistent or recurrent cough, coughing up large amounts of purulent sputum, and / or recurrent hemoptysis, which can lead to respiratory dysfunction and cor pulmonale. Bronchiectasis is primarily categorized as cystic fibrosis (CF)-induced bronchiectasis and non-CF-induced bronchiectasis.

[0006] Some neutrophil elastase inhibitors have been clinically tested for the treatment of bronchiectasis, such as AZD 9668 (Reference 3) and BAY 85-8501 (Reference 4). The results of AZD 9668 in the treatment of patients with bronchiectasis showed improvements in some lung function (FEV1, SVC) and some inflammatory biomarkers in sputum (IL-8, IL-6), but no significant differences were observed in sputum neutrophil count, neutrophil elastase (NE) activity, sputum weight, or quality of life compared with the placebo group. In a study of BAY 85-8501 in the treatment of non-cystic fibrosis bronchiectasis, with the exception of a slight increase in sputum inflammatory factor IL-8 levels, no statistically significant differences were observed in other biomarkers, sputum weight, sputum NE content, NE activity, or lung function compared with the placebo group. Therefore, there is an urgent need to develop an effective therapeutic drug for bronchiectasis.

[0007] Document 1CN1263736 C

[0008] Document 2WO2022143722 A1

[0009] Document 3 "Efficacy, safety and effect on biomarkers of AZD9668 in cystic fibrosis", "European Respiratory Journal"

[0010] Reference 4H Watz et al. Pulm Pharmacol Ther (2019) Summary of the Invention

[0011] The present invention provides use of N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine or a salt thereof in preparing a medicament for preventing or treating bronchiectasis.

[0012] Wherein, the dosage of N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine or its salt is 0.1-500 mg / kg;

[0013] As a preferred embodiment of the present invention, the N-[2-[[[4-(2,2-dimethyl-1-oxopropoxy)phenyl]sulfonyl]amino]benzoyl]-(S)-glycine or its salt is a monosodium salt;

[0014] As a preferred embodiment of the present invention, the present invention provides a 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.

[0015] The bronchiectasis described in the present invention is non-cystic fibrosis bronchiectasis and cystic fibrosis bronchiectasis.

[0016] The second aspect of the present invention provides a pharmaceutical preparation containing 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.

[0017] The pharmaceutical preparation is selected from a lyophilized preparation for injection or an inhalation preparation.

[0018] The lyophilized preparation for injection contains compound A or a salt thereof and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient is selected from one or more combinations of excipients, pH regulators, stabilizers, solubilizers, and the like.

[0019] The inhalation preparation contains Compound A or a salt thereof and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient is optionally selected from a combination of one or more of a pH regulator, an osmotic pressure regulator, a surfactant, etc. The inhalation preparation can be mixed with a carrier (such as water, physiological saline, etc.) and then atomized by an inhalation dispenser for inhalation.

[0020] Preferred excipients of the present invention include: lactose, glucose, maltose, mannitol, xylitol, sorbitol, sodium chloride, etc.; mannitol is preferred.

[0021] Preferred pH adjusters 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.

[0022] Preferred osmotic pressure regulators in inhalants include sodium chloride, potassium chloride, glucose, calcium chloride, magnesium chloride, sorbitol, xylitol, and the like.

[0023] Preferred surfactants of the present invention include: sodium lauryl sulfate, triolein, poloxamer, polysorbate 60, polysorbate 80, polyoxyethylene, castor oil, and the like.

[0024] The present invention further provides a use of an inhalation preparation in preparing 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.

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

[0026] The present invention will be described in further detail below with reference to the examples, but the embodiments of the invention are not limited thereto. Unless otherwise specified, the experimental animals, reagents, detection methods, data statistical methods, etc. used in the specific examples of the present invention can be obtained by conventional methods in the art.

[0027] Example 1

[0028] Animal experiments

[0029] Male SD rats were divided into 5 groups, each with 10 rats, namely, a blank control group, a model group, and a group treated with 2.5 mg / mL, 7.5 mg / mL, and 25 mg / mL of inhaled Compound A monosodium salt. Except for the blank control group, the rats in the other groups were treated with a bronchiectasis rat model according to the method described in the literature (Shanghai Experimental Animal Science, 2000, 20(2): pp. 65-68). One hour after modeling, the rats in the inhaled Compound A monosodium salt groups were given inhalation of various concentrations of Compound A monosodium salt (nebulized using a compressed nebulizer and inhaled through the rats' mouths and noses) for 30 minutes. The rats in the blank control group and the model group were given 0.9% NaCl by nebulization for 30 minutes. Each group of animals was given the drug twice, with an interval of approximately 8 hours. The rats were killed 24 hours after modeling, the left lung was ligated, and the right lung bronchoalveolar lavage was performed. The total white blood cell count, eosinophils, lymphocytes and macrophages in the lavage fluid were counted; part of the bronchi and left lung were homogenized and the neutrophil elastase activity in the bronchial and lung tissues was measured.

[0030] Table 1. Inhalation dose delivered to rats by aerosol administration of Compound A monosodium salt

[0031] The neutrophil elastase (NE) activity of rats in each group is shown in the following table.

[0032] Table 2. Neutrophil elastase activity in rats of each group (Mean±SD)

[0033] Note: Compared with the blank control group: # P<0.05; compared with the model group: * P<0.05, ** P<0.01,***P<0.001.

[0034] Animal experiments show that the compound of the present invention has a good therapeutic effect on bronchiectasis model rats.

[0035] Example 2

[0036] To evaluate the effects of treatment in people with bronchiectasis

[0037] Ten patients who were diagnosed with bronchiectasis after admission were selected and randomly divided into a treatment group and a control group. There were 5 cases in the treatment group and 5 cases in the control group. There was no significant difference in gender ratio, average age, and disease severity between the two groups.

[0038] Inclusion criteria:

[0039] Subjects must meet all of the following criteria to be included in this study:

[0040] (1) Age ≥ 18 years old, regardless of gender;

[0041] (2) High Resolution CT (HRCT) of the chest shows bronchiectasis affecting one or more lobes of the lung, and is diagnosed by a clinician as non-cystic fibrosis bronchiectasis (NCFBE) (clinical manifestations include chronic cough, large amounts of sputum, and / or intermittent symptoms of varying severity such as shortness of breath and respiratory failure). If the subject has undergone HRCT examination in the same hospital within 12 months, it is considered valid and there is no need to undergo HRCT examination again during the screening period;

[0042] (3) have a history of chronic expectoration and are still producing sputum during the screening period, and can provide sputum samples sufficient for microscopic examination (if the subject is unable to cough up sputum on his own, samples can be collected by induced coughing);

[0043] (4) at least 2 episodes of acute exacerbation of bronchiectasis within 12 months before screening, as confirmed by the investigator;

[0044] (5) If long-term bronchodilator treatment (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;

[0045] (6) expected survival time is greater than 12 months;

[0046] The subjects fully understand the purpose, nature, methods and possible adverse events of the trial, voluntarily participate in the trial and sign the informed consent form, or the informed consent form is provided by the legally authorized representative.

[0047] Exclusion criteria:

[0048] Subjects who meet any of the following conditions are not eligible to participate in this study:

[0049] (1) Subjects with pulmonary hypertension or a primary diagnosis of chronic obstructive pulmonary disease (COPD) or asthma as determined by the investigator at screening;

[0050] (2) A history of malignant tumor within 5 years before screening (excluding cured basal cell carcinoma of the skin, carcinoma in situ, and papillary thyroid carcinoma, and those who survived lung cancer surgery for at least 5 years without receiving anti-tumor treatment) or a history of anti-tumor treatment;

[0051] (3) bronchiectasis caused by cystic fibrosis as determined by the investigator (HRCT showed the above lung lesions as the main manifestation);

[0052] (4) Currently being treated for non-tuberculous mycobacterial lung infection, allergic bronchopulmonary aspergillosis, or tuberculosis, or active and currently symptomatic lung infection caused by the novel coronavirus (COVID-19);

[0053] (6) Hemoptysis (excluding coughing up a small amount of blood-streaked sputum or blood clots smaller than the size of a fingernail) within 4 weeks before screening and requiring urgent medical intervention;

[0054] (7) Participants who have participated in other drug or medical device trials within 3 months before the trial or are currently participating in other clinical trials;

[0055] (8) Pregnant women, breastfeeding women and women who may become pregnant;

[0056] The researcher believes that the subject is unsuitable to participate in this study for any reason.

[0057] Effectiveness evaluation indicators:

[0058] The incidence of acute exacerbation of bronchiectasis in patients treated after enrollment.

[0059] The changes in sputum volume, sputum viscosity and active NE concentration in sputum of patients after treatment compared with the screening period.

[0060] Changes in FEV1 of patients treated after enrollment compared with that at screening.

[0061] Changes in QOL-B respiratory symptom scores of patients treated after enrollment compared with those at screening.

[0062] Treatment: Both groups received conventional treatment, including oxygen inhalation, asthma relief, expectoration, and anti-infection. The treatment group received aerosol inhalation of Compound A monosodium salt three times daily, while the control group received aerosol inhalation of normal saline three times daily.

[0063] The changes in sputum output of the two groups of patients on days 0, 14, and 28 are shown in Table 3 below.

[0064] Table 3. Changes in sputum volume in the two groups of patients (Mean±SD)

[0065] The data show that the compound of the present invention can be effectively improved in patients with bronchiectasis by inhalation of the compound.

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.

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