Use of combination drugs of nitroimidazole derivatives in the preparation of drugs for the prevention and treatment of drug-resistant tuberculosis

Abstract

This invention discloses the use of a combination of nitroimidazole derivatives in the preparation of drugs for the prevention and treatment of drug-resistant tuberculosis, belonging to the field of biomedical technology. This invention fills the clinical research gap regarding the use of combination drugs of nitroimidazole derivatives in the prevention and treatment of drug-resistant tuberculosis, providing a method for its application in the preparation of drugs for this purpose. This invention demonstrates good therapeutic effects against drug-resistant tuberculosis by combining nitroimidazole derivatives with various other anti-tuberculosis drugs, and shows promise as a new drug for the prevention and treatment of drug-resistant tuberculosis.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to the use of a combination drug of a nitroimidazole derivative in the preparation of drugs for the prevention and treatment of drug-resistant tuberculosis. Background Technology

[0002] Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis. Mycobacterium tuberculosis mainly invades the lungs, which is called pulmonary tuberculosis. It can also invade other organs such as the liver, kidneys, brain, and lymph nodes, which is called extrapulmonary tuberculosis.

[0003] The World Health Organization's 2024 Global Tuberculosis Report revealed that there were an estimated 10.8 million people with tuberculosis worldwide in 2023, with an incidence rate of 134 per 100,000, making tuberculosis the leading infectious disease globally once again. In 2023, 1.25 million people died from tuberculosis globally, making it the leading cause of death from a single infectious disease worldwide. Among all new cases, 400,000 (3.7%) were multidrug-resistant (MDR / rifampicin) tuberculosis patients, with a resistance rate of 3.2% among treatment-naïve patients and 16% among retreatment patients.

[0004] Multidrug-resistant tuberculosis (MDR-TB) refers to resistance to at least the first-line anti-tuberculosis drugs rifampin and isoniazid. It is generally caused by primary infection with drug-resistant Mycobacterium tuberculosis or secondary drug-resistant bacteria resulting from inappropriate medication use, and its treatment success rate is approximately 50% to 80%. Extensively drug-resistant tuberculosis (DDR-TB) refers to resistance to any fluoroquinolone, bedaquiline, or linezolid in addition to the first-line drugs rifampin and isoniazid, with an even lower cure rate. Rifampin is the most important first-line anti-tuberculosis drug, and approximately 80% of rifampin-resistant tuberculosis cases are MDR-TB. The prevalence, treatment regimens, and prognosis of rifampin-resistant tuberculosis are similar to those of MDR-TB; therefore, the treatment strategies for MDR / extensively drug-resistant / rifampin-resistant tuberculosis are also largely consistent.

[0005] The core difference between drug-sensitive and drug-resistant tuberculosis lies in the response mechanism of Mycobacterium tuberculosis to anti-tuberculosis drugs and the choice of treatment regimen. The pathogens of drug-sensitive tuberculosis are sensitive to first-line drugs (such as isoniazid and rifampin), and their resistance mechanism mainly relies on the normal function of target genes (such as katG and rpoB). A standardized 6-month short-course regimen (2HRZE / 4HR) can achieve a cure rate of over 95%. In contrast, drug-resistant tuberculosis, due to gene mutations (such as rpoB mutations leading to rifampin resistance), enhanced drug efflux pumps, or metabolic dormancy, develops resistance to first-line and even second-line drugs. Depending on the type of resistance (such as MDR-TB or XDR-TB), multiple effective drugs must be selected, combined with novel drugs, for a long-term treatment of 12-24 months, reducing the cure rate to 50-70%. Drug-sensitive tuberculosis is low-cost and easy to manage, while drug-resistant tuberculosis faces public health challenges such as high drug toxicity, high costs and high transmission risks, requiring rapid molecular diagnostics, all-oral short-course regimens and global collaborative prevention and control. The two present a stark contrast in treatment strategies and disease burden.

[0006] As one of the countries with a high burden of multidrug-resistant tuberculosis (MDR / rifampicin-resistant tuberculosis), China faces a severe shortage of new drugs for the treatment of MDR / rifampicin-resistant tuberculosis, making clinical treatment extremely difficult. In the past five years, the success rate of treating MDR / rifampicin-resistant tuberculosis in my country has been only 51-54%, which is related to factors such as the need for multiple second-line anti-tuberculosis drugs to be used simultaneously in standard long-term treatment of MDR / rifampicin-resistant tuberculosis, a treatment course of 18-24 months, significant adverse reactions to second-line anti-tuberculosis drugs, and difficulty in adhering to the treatment regimen.

[0007] CN201680006991.1 discloses a nitroimidazole derivative for treating pulmonary tuberculosis, and CN201780045398.2 discloses the crystal form and salt form of a nitroimidazole compound, and its application in the preparation of drugs for the prevention and treatment of Mycobacterium tuberculosis or other microbial infections. The benzene sulfonate structure of the representative compound is shown in the formula. As shown.

[0008]

[0009] Mode

[0010] CN202411371393 discloses the use of a nitroimidazole derivative and its combination with other drugs in the preparation of drugs for drug-sensitive pulmonary tuberculosis. Through animal experiments, Phase I clinical trials, and Phase IIa clinical trials, the dosage and administration method were optimized, verifying the therapeutic effect of the nitroimidazole derivative and its benzenesulfonate on drug-sensitive pulmonary tuberculosis. However, it does not provide a combination drug trial of the compound of formula I with other drugs for drug-sensitive pulmonary tuberculosis, and it does not address multidrug-resistant tuberculosis. Summary of the Invention

[0011] To address the issue of nitroimidazole derivatives (such as formula) To fill the clinical research gap regarding the prevention or treatment of drug-resistant tuberculosis, this invention provides the use of a combination of nitroimidazole derivatives in the preparation of drugs for the prevention and treatment of drug-resistant tuberculosis, aiming to achieve a more superior effect in the prevention and treatment of drug-resistant tuberculosis.

[0012] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0013] This invention provides the use of a nitroimidazole derivative or a pharmaceutically acceptable salt thereof or a combination thereof in the preparation of a drug for the prevention and treatment of drug-resistant tuberculosis, characterized in that: the nitroimidazole derivative is selected from compounds with the following structural formulas:

[0014] , , , , , , , , , , , , , , , , , , , , , , or ;

[0015] The combined drug is a nitroimidazole derivative or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, administered separately or simultaneously, in combination with other antituberculosis drugs; the other antituberculosis drugs are selected from at least one of a second antituberculosis drug, a third antituberculosis drug, a fourth antituberculosis drug, a fifth antituberculosis drug, or a sixth antituberculosis drug;

[0016] The second anti-tuberculosis drug is a mycobacterial ATP synthase inhibitor;

[0017] The third anti-tuberculosis drug is an oxazolidinone compound;

[0018] The fourth anti-tuberculosis drug is a fluoroquinolone compound;

[0019] The fifth anti-tuberculosis drug is a phenazine compound;

[0020] The sixth anti-tuberculosis drug is selected from at least one of pyrazinamide, PBTZ-169 (benzothiazide), SQ109, GSK-3036656 (oxaborane), Telacebec / Q203, OPC-167832, BTZ-043, rifampin, rifapentine, rifabutin, isoniazid, ethionamide, prothionamide, ethambutol, or cycloserine.

[0021] Preferably, in the above-described uses, the pharmaceutically acceptable salt is a benzenesulfonate.

[0022] Preferably, in the above-mentioned uses, the second anti-tuberculosis drug is selected from bedaquiline and its pharmaceutically acceptable salts, sudapyridine, TBAJ-587 (diarylquinolines), or TBAJ-876.

[0023] Preferably, in the above-mentioned uses, the third anti-tuberculosis drug is selected from linezolid, contezolid, terdizolid, OTB-658, sutezolid, or delpazolid.

[0024] Preferably, in the above-mentioned uses, the fourth anti-tuberculosis drug is selected from moxifloxacin, levofloxacin, sitafloxacin, or gatifloxacin.

[0025] Preferably, in the above-mentioned uses, the fifth anti-tuberculosis drug is selected from clofazimine or pyfazimine.

[0026] Preferably, in the above-mentioned uses, the sixth anti-tuberculosis drug is selected from pyrazinamide, OPC-167832 or ethambutol.

[0027] Preferably, in the above-mentioned uses, the other anti-tuberculosis drug is a second anti-tuberculosis drug (i.e., a combination of two drugs).

[0028] Alternatively, a third anti-tuberculosis drug (i.e., a combination of two drugs).

[0029] Alternatively, the fourth anti-tuberculosis drug (i.e., a combination of two drugs).

[0030] Alternatively, the fifth anti-tuberculosis drug (i.e., a combination of two drugs).

[0031] Alternatively, the sixth anti-tuberculosis drug (i.e., a combination of two drugs).

[0032] Alternatively, a second and a third anti-tuberculosis drug (i.e., a three-drug combination).

[0033] Alternatively, a second anti-tuberculosis drug and a sixth anti-tuberculosis drug (i.e., a three-drug combination).

[0034] Alternatively, a second, third, and fourth anti-tuberculosis drug (i.e., a four-drug combination).

[0035] Alternatively, a second, third, and fifth anti-tuberculosis drug (i.e., a four-drug combination).

[0036] Alternatively, a second, third, fourth, and fifth anti-tuberculosis drug (i.e., a five-drug combination).

[0037] Alternatively, a second, third, fourth, and sixth anti-tuberculosis drug (i.e., a five-drug combination).

[0038] More preferably, in the above-mentioned uses, the other anti-tuberculosis drug is bedaquiline and its pharmaceutically acceptable salt (i.e., a combination of a nitroimidazole derivative or its pharmaceutically acceptable salt or a pharmaceutical composition thereof and bedaquiline and its pharmaceutically acceptable salt).

[0039] Alternatively, linezolid (i.e., a combination of a nitroimidazole derivative or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof and linezolid).

[0040] Alternatively, moxifloxacin or levofloxacin (i.e., a combination of a nitroimidazole derivative or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof and moxifloxacin or levofloxacin).

[0041] Alternatively, clofazimine (i.e., a combination of a nitroimidazole derivative or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof and clofazimine).

[0042] Alternatively, pyrazinamide (i.e., a combination of a nitroimidazole derivative or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof and pyrazinamide).

[0043] Alternatively, bedaquiline and its pharmaceutically acceptable salts and linezolid (i.e., a combination of a nitroimidazole derivative or its pharmaceutically acceptable salt or a pharmaceutical composition thereof with bedaquiline and its pharmaceutically acceptable salts and linezolid).

[0044] Alternatively, bedaquiline and its pharmaceutically acceptable salts and pyrazinamide (i.e., a combination of three drugs: a nitroimidazole derivative or its pharmaceutically acceptable salt or a pharmaceutical composition thereof, and bedaquiline and its pharmaceutically acceptable salt and pyrazinamide).

[0045] Alternatively, bedaquiline and its pharmaceutically acceptable salts, linezolid and moxifloxacin (i.e., a combination of nitroimidazole derivatives or their pharmaceutically acceptable salts or pharmaceutical compositions thereof with bedaquiline and its pharmaceutically acceptable salts, linezolid and moxifloxacin).

[0046] Alternatively, bedaquiline and its pharmaceutically acceptable salts, linezolid and levofloxacin (i.e., a combination of nitroimidazole derivatives or their pharmaceutically acceptable salts or pharmaceutical compositions thereof with bedaquiline and its pharmaceutically acceptable salts, linezolid and levofloxacin).

[0047] Alternatively, bedaquiline and its pharmaceutically acceptable salts, linezolid and clofazimine (i.e., a combination of nitroimidazole derivatives or their pharmaceutically acceptable salts or pharmaceutical compositions thereof with bedaquiline and its pharmaceutically acceptable salts, linezolid and clofazimine).

[0048] Alternatively, bedaquiline and its pharmaceutically acceptable salts, linezolid, moxifloxacin and clofazimine (i.e., a combination of five drugs: a nitroimidazole derivative or its pharmaceutically acceptable salt or a pharmaceutical composition thereof, and bedaquiline and its pharmaceutically acceptable salts, linezolid, moxifloxacin and clofazimine).

[0049] Alternatively, bedaquiline and its pharmaceutically acceptable salts, linezolid, levofloxacin and clofazimine (i.e., a combination of five drugs: a nitroimidazole derivative or its pharmaceutically acceptable salt or a pharmaceutical composition thereof, and bedaquiline and its pharmaceutically acceptable salts, linezolid, levofloxacin and clofazimine).

[0050] Alternatively, bedaquiline and its pharmaceutically acceptable salts, linezolid, moxifloxacin and pyrazinamide (i.e., a combination of five drugs, namely nitroimidazole derivatives or their pharmaceutically acceptable salts or pharmaceutical compositions thereof, with bedaquiline and its pharmaceutically acceptable salts, linezolid, moxifloxacin and pyrazinamide).

[0051] Alternatively, bedaquiline and its pharmaceutically acceptable salts, linezolid, levofloxacin and pyrazinamide (i.e., a combination of five drugs, namely nitroimidazole derivatives or their pharmaceutically acceptable salts or pharmaceutical compositions thereof, with bedaquiline and its pharmaceutically acceptable salts, linezolid, levofloxacin and pyrazinamide).

[0052] In the above-mentioned uses, the effective ingredient dose of the nitroimidazole derivative or its pharmaceutically acceptable salt or the pharmaceutical composition thereof is 100-800 mg / day or 200-600 mg / day.

[0053] Preferably, in the above-described uses, the effective ingredient dose of the nitroimidazole derivative or its pharmaceutically acceptable salt or the pharmaceutical composition thereof is 100 mg / day, 200 mg / day or 400 mg / day.

[0054] In the above-mentioned uses, the effective dose of bedaquiline and its pharmaceutically acceptable salt is 10~600mg / day, 20~550mg / day, 30~520mg / day, 60~500mg / day, 100~480mg / day, 120~450mg / day, or 200~400mg / day.

[0055] Preferably, in the above-mentioned uses, the effective dose of the bedaquiline and its pharmaceutically acceptable salt is 10 mg / day, 20 mg / day, 30 mg / day, 60 mg / day, 100 mg / day, 120 mg / day, 200 mg / day, or 400 mg / day.

[0056] In the above-mentioned uses, the effective dose of linezolid is 37.5~1500mg / day, 75~1400mg / day, 150~1300mg / day, 300~1200mg / day, 300~600mg / day, or 600~1200mg / day.

[0057] Preferably, in the above-mentioned uses, the effective dose of linezolid is 37.5 mg / day, 75 mg / day, 150 mg / day, 300 mg / day, 450 mg / day, 600 mg / day, or 1200 mg / day.

[0058] In the above-mentioned uses, the effective dose of moxifloxacin is 100~1000mg / day or 400~800mg / day.

[0059] Preferably, in the above-mentioned uses, the effective ingredient dosage of moxifloxacin is 400 mg / day or 800 mg / day.

[0060] In the above-mentioned uses, the effective dose of levofloxacin is 150~1500mg / day, 200~1400mg / day, 300~1300mg / day, 400~1200mg / day, 500~1000mg / day, or 750~1000mg / day.

[0061] Preferably, in the above-mentioned uses, the effective ingredient dosage of levofloxacin is 750 mg / day, 1000 mg / day, or 1500 mg / day.

[0062] In the above-mentioned uses, the effective dose of clofazimine is 20~300mg / day, 50~250mg / day, or 100~200mg / day.

[0063] Preferably, in the above-mentioned uses, the effective dose of clofazimine is 50 mg / day, 100 mg / day, 200 mg / day, or 250 mg / day.

[0064] In the above-mentioned uses, the effective ingredient dosage of the pyrazinamide is 450~4000 mg / day.

[0065] Preferably, in the above-mentioned uses, the effective ingredient dosage of the pyrazinamide is 450 mg / day, 1000 mg / day, or 4000 mg / day.

[0066] In the above-mentioned uses, the administration regimen of the nitroimidazole derivative or its pharmaceutically acceptable salt or pharmaceutical composition is once daily, twice daily or three times daily.

[0067] In the above-mentioned uses, the administration regimen of bedaquiline and its pharmaceutically acceptable salts is once daily, twice daily, three times daily, once weekly, twice weekly, or three times weekly.

[0068] In the above-mentioned uses, the linezolid is administered once daily, twice daily, or three times daily.

[0069] In the above-mentioned uses, the moxifloxacin is administered once daily, twice daily, or three times daily.

[0070] In the above-mentioned uses, the administration regimen of levofloxacin is once daily, twice daily, or three times daily.

[0071] In the above-mentioned uses, the dosing regimen of clofazimine is once daily, twice daily, three times daily, once every two days, once weekly, twice weekly, or three times weekly.

[0072] In the above-mentioned uses, the administration regimen of the pyrazinamide is once daily, twice daily, three times daily, once every two days, twice weekly, or three times weekly.

[0073] Preferably, in the above-mentioned uses, the drug-resistant tuberculosis is rifampicin-resistant tuberculosis (RR-TB), isoniazid-resistant tuberculosis, single-drug-resistant tuberculosis, multidrug-resistant tuberculosis (MDR-TB), pre-extensively drug-resistant tuberculosis (pre-XDR-TB), or extensively drug-resistant tuberculosis (XDR-TB).

[0074] More specifically, in the above-mentioned uses, the administration regimen of the nitroimidazole derivative or its pharmaceutically acceptable salt or the pharmaceutical composition thereof is 100 mg or 200 mg twice daily, orally within half an hour after a meal.

[0075] More specifically, in the above-mentioned uses, the dosing regimen of the bedaquiline and its pharmaceutically acceptable salts is 400 mg once daily for the first 2 weeks, followed by a change to 200 mg three times a week (with one day between doses, for example, Monday, Wednesday, and Friday or Tuesday, Thursday, and Saturday), taken orally with breakfast.

[0076] More specifically, in the above-mentioned uses, the administration regimen of linezolid is 600 mg once daily, taken orally within half an hour after a meal.

[0077] More specifically, in the above-mentioned uses, the dosage regimen of moxifloxacin is 400 mg once daily, taken orally within half an hour after a meal.

[0078] More specifically, in the above-mentioned uses, the dosage regimen of levofloxacin is 750 mg once daily for individuals weighing ≤50 kg, and 1000 mg once daily for individuals weighing >50 kg, taken orally within half an hour after a meal.

[0079] More specifically, in the above-mentioned uses, the dosing regimen of clofazimine is once daily, 100 mg or 200 mg each time, orally within half an hour after a meal.

[0080] In this invention, pharmaceutically acceptable salts include their acid addition salts and base addition salts. Suitable acid addition salts are formed by acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed by bases that form pharmaceutically acceptable salts. A review of suitable salts can be found, for example, in “Remington’s Pharmaceutical Sciences,” Mack Publishing Company, Easton, Pa., (2005); and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use,” Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of this invention are known to those skilled in the art.

[0081] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobroms, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetate, trifluoroacetate, propionates, hexanoates, octanoates, decanoates, undecenoates, glycolates, gluconates, lactates, sebates, adipates, glutarate, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartates, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbic acid salts, salicylates, 4-aminosalicylic acid salts, and naphthalene disulfonates. These salts can be prepared by known methods.

[0082] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that maintain the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by known methods.

[0083] In this invention, the pharmaceutical composition uses the nitroimidazole derivative or its pharmaceutically acceptable salt as the active ingredient, supplemented by a pharmaceutically acceptable carrier.

[0084] In this invention, the dosage of the active ingredient is based on compounds, such as compounds of Formula I administered by... count.

[0085] In this invention, among the other anti-tuberculosis drugs (including the second, third, fourth, fifth, and sixth anti-tuberculosis drugs), except for bedaquiline which can be used in its pharmaceutically acceptable salt, other specific drugs such as contezolid, TBAJ-587, sulzezolid, moxifloxacin, clofazimine, and pyrazinamide can also be used in their corresponding pharmaceutically acceptable salts to achieve similar technical effects in preventing and treating drug-resistant pulmonary tuberculosis.

[0086] The beneficial effects of this invention are:

[0087] This invention achieves excellent results in terms of efficacy, safety, and tolerability by combining nitroimidazole derivatives with a variety of other anti-tuberculosis drugs, demonstrating good therapeutic effects on drug-resistant pulmonary tuberculosis and showing promise as a new drug combination for the prevention and treatment of drug-resistant pulmonary tuberculosis. Attached Figure Description

[0088] Figure 1 These are lung CT images before and after treatment in Group A of Example 3.

[0089] Figure 2 These are lung CT images of Group B before and after treatment in Example 3. Detailed Implementation

[0090] The following specific embodiments will be provided to explain the solution of the present invention. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0091] Drugs and reagents:

[0092] The formula disclosed in CN201780045398.2 Compound benzenesulfonate;

[0093] Chemical structural formula: .

[0094] Delamani: A nitroimidazole antituberculosis drug manufactured by Otsuka Pharmaceutical Co., Ltd.

[0095] Chemical structural formula: .

[0096] In this embodiment of the invention, formula The dosage of compound benzyl sulfonate tablets is expressed in formula Compounds.

[0097] Example Study of Pharmaceutical Formula Compound benzenesulfonate: Dosage form: tablets, strength: 50 mg.

[0098] Table 1 Other anti-tuberculosis drugs

[0099]

[0100] Research Foundation

[0101] Preclinical research data indicate that, based on the chemical composition of Delamani, a novel nitroimidazole antituberculosis drug has been optimized and screened to have no cardiotoxicity and better efficacy. The compound benzenesulfonate exhibits outstanding inhibitory activity against drug-sensitive and multidrug-resistant Mycobacterium tuberculosis isolated from clinical samples in China. Compared with similar marketed drugs, it has significant advantages in terms of safety and efficacy: 1) more significant in vivo efficacy in different animal infection models; 2) higher distribution in lung tissue, the target organ; 3) safer and without cardiotoxicity.

[0102] Phase I clinical trials have been completed. (Evaluation) Safety, tolerability, and pharmacokinetic characteristics of the compound benzenesulfonate in healthy adult subjects after single and multiple administrations. Results showed that oral administration... The compound benzenesulfonate tablets demonstrated good safety, tolerability, and pharmacokinetic characteristics in subjects. No cardiotoxicity was observed.

[0103] The Phase IIa clinical trial has been completed. The Phase IIa clinical trial protocol was designed as follows: A randomized, open-label, multicenter, phase IIa clinical trial (CN119157877A) was conducted to evaluate the early bactericidal activity, safety, tolerability, and pharmacokinetic characteristics of benzyl sulfonate tablets in drug-sensitive pulmonary tuberculosis patients. The primary objective was to evaluate the efficacy of benzyl sulfonate tablets as a control, using delamani tablets as a control. The preliminary efficacy of benzyl sulfonate tablets in combination therapy in drug-sensitive pulmonary tuberculosis patients provides evidence for a phase III clinical trial. Phase IIa clinical data indicate... Compound benzyl sulfonate tablets are more effective and safer than the marketed control drug delamani: 1) Efficacy: Formula The early bactericidal activity (EBATTP) of the benzenesulfonate tablets was superior to that of Delamani in all groups, according to the logarithm of the average rate of decrease in the number of live bacteria (CFU) per milliliter of sputum per day. CT imaging results indicated that, compared with the control group, the formula... The benzenesulfonate compound group showed significant radiographic efficacy, with marked reduction in lung cavities and significant absorption of lesions; 2) Safety: The compound benzyl sulfonate tablets have a good safety profile for treating adult patients with pulmonary tuberculosis, do not affect QTc, have no cardiotoxicity, and are significantly safer than the benchmark drug delamani.

[0104] The main differences between the Phase IIa clinical trial and the clinical trial of this invention are twofold: 1) The Phase IIa clinical trial was conducted in sensitive tuberculosis patients and tested EBA, while this invention tested the effectiveness SSC in drug-resistant tuberculosis patients; 2) The Phase IIa drug grouping was monotherapy, while this invention is combination therapy.

[0105] Example 1: A multicenter, randomized, double-blind, positive-drug-controlled phase III clinical study of the efficacy and safety of compound I and delamani in rifampicin-resistant pulmonary tuberculosis patients.

[0106] This example is a multicenter, randomized, double-blind, positive-drug-controlled phase III study designed to evaluate the efficacy, safety, and pharmacokinetic characteristics of compound I compared with delamanni, in combination with bedaquiline, linezolid, and levofloxacin / clofazimine for 24 weeks in patients with rifampicin-resistant pulmonary tuberculosis.

[0107] In this example, all patients with rifampicin-resistant pulmonary tuberculosis were treated with clofazimine if the drug sensitivity test showed resistance to fluoroquinolones, and levofloxacin / moxifloxacin if the patients were sensitive to fluoroquinolones.

[0108] Primary endpoint: Sputum culture conversion rate (SCC, %) in the Formula I compound group and the Delamane group after 24 weeks of treatment.

[0109] Secondary endpoints: 1. Time to negative sputum culture in the Formula I compound group and the Delamani group after 24 weeks of treatment; 2. Treatment success rate in the Formula I compound group and the Delamani group at 24 weeks of follow-up; 3. Incidence of adverse events and serious adverse events in the Formula I compound group and the Delamani group at 24 weeks of treatment; 4. Pharmacokinetic characteristics of Formula I compound.

[0110] The specific grouping details for the treatment methods are as follows:

[0111] 1. Experimental Group 1:

[0112] 1) Compound of Formula I, dosage: 100mg or 200mg BID, taken continuously for 24 weeks.

[0113] 2) Bedaquiline fumarate tablets, dosage and administration: 400mg once daily for the first 2 weeks of treatment; thereafter adjust to 200mg three times a week (can be administered on Monday, Wednesday, and Friday or Tuesday, Thursday, and Saturday), taken with food, for a total of 24 weeks.

[0114] 3) Linezolid tablets, dosage: 600mg once daily for 24 weeks.

[0115] 4) Levofloxacin, dosage and administration: depending on body weight, patients ≤50kg take 750mg once daily; patients >50kg take 1000mg once daily for 24 weeks.

[0116] 2. Experimental Group Two:

[0117] 1) Compound of Formula I, dosage: 100mg or 200mg BID, taken continuously for 24 weeks.

[0118] 2) Bedaquiline fumarate tablets, dosage and administration: 400mg once daily for the first 2 weeks of treatment; thereafter adjust to 200mg three times a week (can be administered on Monday, Wednesday, and Friday or Tuesday, Thursday, and Saturday), taken with food, for a total of 24 weeks.

[0119] 3) Linezolid tablets, dosage: 600mg once daily for 24 weeks.

[0120] 4) Moxifloxacin, dosage: 400mg, once daily.

[0121] 3. Experimental Group Three:

[0122] 1) Compound of Formula I, dosage: 100mg or 200mg BID, taken continuously for 24 weeks.

[0123] 2) Bedaquiline fumarate tablets, dosage and administration: 400mg once daily for the first 2 weeks of treatment; thereafter adjust to 200mg three times a week (can be administered on Monday, Wednesday, and Friday or Tuesday, Thursday, and Saturday), taken with food, for a total of 24 weeks.

[0124] 3) Linezolid tablets, dosage: 600mg once daily for 24 weeks.

[0125] 4) Clofazimine, dosage: 100mg once daily for 24 weeks.

[0126] 4. Control group:

[0127] 1) Delamani tablets, dosage: 100mg BID, continue for 24 weeks.

[0128] 2) Bedaquiline fumarate tablets, dosage and administration: 400mg once daily for the first 2 weeks of treatment; thereafter adjust to 200mg three times a week (can be administered on Monday, Wednesday, and Friday or Tuesday, Thursday, and Saturday), taken with food, for a total of 24 weeks.

[0129] 3) Linezolid tablets, dosage: 600mg once daily for 24 weeks.

[0130] 4) Levofloxacin, dosage: 750mg once daily for patients ≤50kg; 1000mg once daily for patients >50kg, for 24 weeks; or clofazimine, dosage: 100mg once daily, for 24 weeks.

[0131] Inclusion criteria: 1. Age: 14 years and above, regardless of gender; 2. Weight: 30kg~100kg (inclusive); 3. Clinically diagnosed pulmonary tuberculosis patients, with drug sensitivity testing confirming resistance to at least rifampin; 4. Positive sputum smear for acid-fast bacilli; 5. Patients currently undergoing anti-tuberculosis treatment or using drugs with anti-tuberculosis effects, who agree to discontinue all anti-tuberculosis drug treatments prior to treatment; 6. Women of childbearing age, who agree to use highly effective contraception throughout the study period and for at least 6 months after discontinuation of medication; 7. Fully understand the purpose and requirements of this trial, voluntarily sign a written informed consent form, and agree to abide by the relevant provisions in the informed consent form.

[0132] Exclusion criteria: 1. Patients who cannot use delamani, bedaquiline, or linezolid for any reason; 2. Patients who have used delamani, bedaquiline, or linezolid for more than 1 month; 3. Patients with hematogenous disseminated pulmonary tuberculosis or severe extrapulmonary tuberculosis as determined by the investigator; 4. Patients with a history of torsades de pointes or risk factors for ventricular tachycardia; 5. Patients with any serious cardiovascular disease within 6 months prior to enrollment; 6. Patients with peripheral neuropathy (CTCAE grade 3 or 4); 7. Patients with a history of gastrointestinal surgery or resection that may affect the absorption and / or excretion of oral medications; 8. Patients with any unstable or serious cardiovascular, renal, hepatic, hematologic, neoplastic, endocrine, metabolic, psychological, or rheumatic diseases as determined by the investigator; 9. Patients with a history of alcohol dependence or drug abuse within 6 months prior to screening; 10. Patients who have used other investigational drugs in clinical trials within 3 months prior to administration; 11. Patients using drugs that cause myelosuppression; 12. Patients using serotonin reuptake inhibitors or tricyclic antiseptics. 13. Medications that cause QT interval prolongation, such as antidepressants, serotonin, and serotonin receptor agonists; 14. Chronic systemic corticosteroid therapy; 15. Individuals clinically confirmed by investigators to be allergic to any investigational drug or related substance; 16. Women who test positive during the screening period of pregnancy or who are breastfeeding; 17. Patients with hepatitis B e antigen positive; positive hepatitis C virus (HCV) antibody; positive HIV antibody test; 18. Significantly abnormal laboratory tests; 19. Significantly abnormal electrocardiogram (ECG) examination.

[0133] Example 2: Evaluation of early efficacy, safety, and pharmacokinetics of Formula I compound in combination with other rifampin-resistant tuberculosis drugs.

[0134] This embodiment is a single-arm, single-center clinical trial for patients with multidrug-resistant tuberculosis.

[0135] 1. Grouping method and design: All patients in this embodiment are pulmonary tuberculosis patients resistant to rifampin. Based on this, the patients are treated with BJLC (B-bedaquiline, J-form I compound, L-linezolid, C-clofazimine) or BJLM (B-bedaquiline, J-form I compound, L-linezolid, M-moxifloxacin) regimens for anti-tuberculosis treatment according to the drug sensitivity results.

[0136] 2. Determine the anti-tuberculosis treatment regimen: The anti-tuberculosis treatment regimen was selected based on the drug sensitivity test results of the subjects. If the test showed sensitivity to M, BJLM was used; if the test showed resistance to M, BJLC was used. At the same time, two patients in each group received BJL treatment.

[0137] Wherein, B represents bedaquiline, 400 mg once daily for the first two weeks, and 200 mg three times a week starting from the third week; J represents compound I, 100 mg or 200 mg twice daily; L represents linezolid, 600 mg once daily; C represents clofazimine, 100 mg or 200 mg once daily; and M represents moxifloxacin, 400 mg once daily.

[0138] 3. Inclusion criteria: a. Patients diagnosed with active pulmonary tuberculosis by comprehensive clinical evaluation (including clinical symptoms and / or chest imaging) and requiring initiation of multidrug-resistant anti-tuberculosis treatment; b. Age between 18 and 70 years; c. Microbiological testing confirms the presence of Mycobacterium tuberculosis, and drug susceptibility testing confirms resistance to rifampin; d. Voluntarily sign the informed consent form for participation in this project and be able and willing to accept follow-up visits; e. For female participants of childbearing age, a negative pregnancy test is required within 3 days prior to the study, and effective contraception, such as condoms or intrauterine devices, must be used during the study period. Women of childbearing age must have menopause or a history of related surgery.

[0139] 4. Exclusion criteria: a. Resistance to one or any combination of Formula I compounds, bedaquiline, linezolid, clofazimine; b. Intolerance or allergy to one or any combination of Formula I compounds, bedaquiline, linezolid, clofazimine, or fluoroquinolones; c. Concomitant lung infection not caused by Mycobacterium tuberculosis or other microorganisms affecting treatment outcome; d. Concomitant use of drugs that affect the observation of efficacy in this study or have contraindications for use; e. Use of any immunosuppressant or systemic glucocorticoids for more than 2 weeks prior to screening; f. Any currently used or planned use of any drug known to significantly prolong QTc interval. The following medications are contraindicated during the recruitment period, including but not limited to: amiodarone, amitriptyline, chloroquine, chlorpromazine, cisapride, dipyridamole, irthyroxine, procaine, quinidine, or sotalol; g. poorly controlled diabetes with a predisposition to improvement according to the investigator; h. HIV positive; i. comorbid severe autoimmune diseases, severe liver or kidney dysfunction, mental illness, hematologic disorders, or malignancies; j. laboratory parameters within 14 days prior to recruitment: ① serum AST and ALT ≥ 3 times the upper limit of normal (ULN), ② creatinine ≥ 2 times the upper limit of normal, ③ hemoglobin ≤ 70 ④ Platelet count ≤50x10^9 / L, ⑤ Serum potassium ≥5.5 mmol / L or ≤3.5 mmol / L; k, ECG QTcF ≥450ms (one retest is allowed during the screening phase to reassess eligibility), with risk factors for QT interval prolongation, such as arrhythmia, myocardial ischemia, etc., and a history or family history of long QT syndrome; l, pregnant or lactating women; m, weight <30kg or ≥90kg; n, patients who have participated in other drug clinical trials within 3 months of the screening period; o, patients deemed unsuitable for the study by other investigators.

[0140] Example 3: Formula A multicenter, open-label, randomized, positive-drug-controlled clinical study (JD-RISE) comparing the efficacy and safety of different combination regimens of benzyl sulfonate tablets with the delamani regimen in rifampicin-resistant pulmonary tuberculosis patients.

[0141] 1. Experimental Objectives and Endpoints

[0142] Main objective: To evaluate the efficacy of the Delamani tablet regimen as a control. The preliminary efficacy of combination therapy with different doses of benzyl sulfonate tablets in rifampicin-resistant pulmonary tuberculosis patients provides evidence for a phase III clinical trial.

[0143] Secondary objective: (1) Evaluation Safety of compound benzyl sulfonate tablets in treating rifampicin-resistant pulmonary tuberculosis patients; (2) Evaluation Pharmacokinetic characteristics of the compound benzyl sulfonate tablets in patients with rifampicin-resistant pulmonary tuberculosis.

[0144] Primary endpoint: Sputum culture conversion rate (SCC, %) in each treatment group after 8 weeks of treatment.

[0145] Secondary endpoints: (1) Time to negative sputum culture in each treatment group after 8 weeks of treatment; (2) Time to positive report (TTP) in each treatment group after 8 weeks of treatment; (3) Incidence of adverse events and serious adverse events in each group at 8 weeks of treatment; (4) Formula Pharmacokinetic characteristics of the compound benzenesulfonate.

[0146] 2. Experimental Design

[0147] This embodiment is a multicenter, randomized, open-label, positive-drug-controlled clinical study designed to evaluate different doses of the formula. The efficacy, safety, and pharmacokinetic characteristics of benzylsulfonate compounds compared with delamani, in combination with bedaquiline, linezolid, levofloxacin (moxifloxacin) / clofazimine, etc., for 8 weeks in patients with rifampicin-resistant pulmonary tuberculosis.

[0148] This embodiment includes a screening period and a study treatment period. The screening period will not exceed 2 weeks, and at least 60 subjects will be enrolled and randomly assigned to the following 3 groups in a 1:1:1 ratio: Group A Compound benzenesulfonate regimen 100mg group (BJLLfx(M) / C), Group B formula The study included two groups: the benzenesulfonate regimen 200 mg group (BJLLfx(M) / C) and the delamani regimen group (BDLLfx / C). Subjects were stratified and randomized according to their fluoroquinolone resistance. At least 15 fluoroquinolone-resistant patients were included.

[0149] Treatment completion was defined as the completion of 8 weeks of treatment, after which participants transitioned to standard treatment chosen by their clinicians. Participants submitted at least one overnight sputum culture during the screening period. Eligible participants needed to have fluoroquinolone resistance confirmed (drug susceptibility results within 3 months or resistance mutation testing during the screening period). Upon successful screening, participants were randomly assigned to treatment groups based on fluoroquinolone resistance status. All participants were admitted to the ward one day before the first dose (D-1) and hospitalized for 8 days. The date of the first dose was defined as D1. All patients received treatment for 8 weeks.

[0150] Subjects enrolled solely based on a positive sputum smear submitted one overnight sputum sample (16 hours prior) and one single sputum sample before administration on day 1 (D1) for sputum culture and smear preparation for Mycobacterium tuberculosis. Sputum samples were collected at least on day 1 and within one week during hospitalization.

[0151] After discharge, patients returned to the research center for follow-up at W4 (±3d), W6 (±3d), and W8 (-3d) for safety and efficacy assessments, and were given overnight sputum collection kits, sputum collection record forms, investigational drugs, and subject diary cards.

[0152] Contains Subjects in groups A and B of the benzenesulfonate compound were admitted to the ward at W8 for PK blood sampling. To ensure PK blood sampling after the last dose, patients in both groups A and B should be admitted to the research center with at least one day of medication remaining. Blood sampling continued for 5 days. Patients in group C completed the study upon their last follow-up visit.

[0153] During treatment visits, patients should be instructed to bring any remaining medication, arrive at the research center on an empty stomach, have their blood sample collected, and then take the day's test drug. If safety assessment results are abnormal, the investigator will determine their clinical significance and implement appropriate follow-up and management. At each follow-up visit, one 16-hour overnight sputum sample will be collected for sputum culture, and one single sputum sample will be collected for sputum smear. After week 8 of treatment, treatment will be discontinued, and the patient will switch to the investigator-recommended standard treatment. If adverse events occur when the patient discontinues medication, follow-up should continue until the patient's condition returns to normal or baseline levels, or until these levels no longer change.

[0154] The sputum culture baseline is determined by the researchers based on participant enrollment. If a participant is enrolled due to both a positive sputum smear and a positive sputum culture during the screening period, the positive sputum culture during the screening period is used as the baseline. If a participant is enrolled solely because their sputum smear met the inclusion criteria, any positive sputum culture submitted during the screening period, D-1, and W1 visit hospitalization can be used as the baseline. Baseline sputum culture results are tracked regularly throughout the study. If the baseline sputum culture result is negative, the investigational drug is discontinued and the participant is discharged.

[0155] 3. Dosing regimen

[0156] The dosing regimen in this embodiment is divided into three groups:

[0157] Group A: BJLLfx(M) / C: Formula Compound benzyl sulfonate 100mg BID + bedaquiline + linezolid + levofloxacin (moxifloxacin) / clofazimine;

[0158] Group B: BJLLfx(M) / C: Formula Compound benzyl sulfonate 200mg BID + bedaquiline + linezolid + levofloxacin (moxifloxacin) / clofazimine;

[0159] Group C: BDLLfx / C: Delamani + Bedaquinoline + Linezolid + Levofloxacin / Clofazine.

[0160] All cases in this embodiment are pulmonary tuberculosis patients resistant to rifampin. Based on this, if the patients are sensitive to fluoroquinolones, levofloxacin or moxifloxacin is selected for groups A and B, and levofloxacin is selected for group C; if the patients are resistant to fluoroquinolones, clofazimine is used for all groups.

[0161] The dosages of different drugs in each group are as follows:

[0162] Bedaquiline fumarate tablets (B): For the first 2 weeks of treatment, take 400 mg once daily; then adjust to 200 mg three times a week (can be taken on Monday, Wednesday, Friday or Tuesday, Thursday, Saturday), orally with breakfast, for a total of 8 weeks.

[0163] Mode Compound benzenesulfonate tablets (J): 100 mg or 200 mg twice daily, taken orally within half an hour after a meal, for 8 consecutive weeks.

[0164] Delamani tablets (D): 100 mg twice daily, taken orally within half an hour after a meal, for 8 consecutive weeks.

[0165] Linezolid tablets (L): 600 mg once daily, taken orally within half an hour after a meal, for 8 consecutive weeks.

[0166] Moxifloxacin hydrochloride tablets (M): 400 mg once daily, taken orally within half an hour after a meal, for 8 consecutive weeks.

[0167] Levofloxacin tablets (Lfx): Depending on body weight, patients ≤50kg take 750mg once daily; patients >50kg take 1000mg once daily, orally within half an hour after a meal, for 8 consecutive weeks.

[0168] Clofazimine soft capsules (C): 100 mg once daily, taken orally within half an hour after a meal, for 8 consecutive weeks.

[0169] Take the above medications with warm water. Do not break the tablets (except for levofloxacin). Record your medication usage as required. Collect the next cycle of medication each time you return to the center for follow-up.

[0170] 4. Test subjects

[0171] Treatment of rifampicin-resistant / multidrug-resistant tuberculosis (RR / MDR-TB) is the most important and impactful type of resistance, and has always been a challenge in tuberculosis treatment. This study selected patients with rifampicin-resistant pulmonary tuberculosis as the research population, including rifampicin-resistant RR-TB, multidrug-resistant MDR-TB, and pre-extensively drug-resistant pre-XDR-TB.

[0172] 4.1 Inclusion criteria: All of the following inclusion criteria must be met to be included in this trial: (1) Age: 14 years old ≤ age ≤ 65 years old, male or female; (2) Weight: 40 kg ≤ weight ≤ 90 kg; (3) Clinically diagnosed pulmonary tuberculosis patients, drug sensitivity test confirmed resistance to at least rifampin, and able to accept molecular drug sensitivity or phenotypic drug sensitivity test results within 3 months prior to enrollment; (4) Positive sputum acid-fast bacilli smear (at least one ≥2+ or two 1+), and imaging showing solid lesions in the lungs; (5) If the patient is undergoing anti-tuberculosis treatment or using drugs with anti-tuberculosis effects, agree to discontinue all anti-tuberculosis drug treatment in the early stage of treatment and complete 7 days of washout; (6) Women of childbearing age agree to use highly effective contraceptive measures throughout the study period and for at least 6 months after drug discontinuation. Male subjects whose partners are women of childbearing age must agree to use appropriate contraceptive methods throughout the study period and for at least 6 months after drug discontinuation; (7) Fully understand the purpose and requirements of this trial, voluntarily sign the written informed consent form and agree to abide by the relevant provisions in the informed consent form.

[0173] 4.2 Exclusion Criteria

[0174] Patients meeting any of the following exclusion criteria will be excluded: (1) those who cannot use Delamani, Bedaquiline, or Linezolid for any reason; (2) those who have used Delamani, Bedaquiline, or Linezolid for more than one month (if evidence of drug resistance can be provided, they may be included); (3) patients with hematogenous disseminated pulmonary tuberculosis or severe extrapulmonary tuberculosis as determined by the investigator; or patients with pulmonary tuberculosis who, as assessed by the investigator, may require surgical treatment within 8 weeks; (4) those with a history of torsades de pointes ventricular tachycardia or a history of risk factors, including long QT. (5) Individuals with any of the following cardiovascular diseases or other conditions within the 6 months prior to enrollment: a) Myocardial infarction; b) Cardiac surgery or coronary revascularization (coronary artery bypass grafting / percutaneous coronary angioplasty); c) Unstable angina; d) Congestive heart failure (New York Heart Association functional class III or IV); e) Transient ischemic attack or severe cerebrovascular disease; (6) Peripheral neuropathy CTCAE Grade 3 or 4; Grade 1 or 2 peripheral neuropathy that the investigator judges may progress / worsen during the study; patients with optic neuritis; (7) patients with a history of gastrointestinal surgery or resection that may affect the absorption and / or excretion of oral medications; (8) patients whose investigators judge them to be unsuitable for this trial due to any unstable or serious cardiovascular, renal, hepatic, blood, tumor, endocrine, metabolic, mental or rheumatic diseases; (9) patients with a history of alcohol dependence or drug abuse within 6 months prior to screening, which the investigators believe may affect subject safety and trial compliance; (10) patients who have used other clinical trial investigation drugs within 3 months prior to administration; (11) patients who have used drugs that cause bone marrow suppression; (12) patients who have used drugs that cause serotonin reuptake inhibitors, tricyclic antidepressants, serotonin, serotonin receptor agonists, etc.; (13) patients who have used drugs that cause QT interstitial encephalopathy. Drugs that prolong the treatment period, such as: quinidine, procainamide, amiodarone, sotalol, etc.; (14) chronic systemic corticosteroid therapy, with cumulative use for more than 4 weeks within 3 months prior to enrollment; (15) those who are clinically confirmed by the investigator to be allergic to any investigational drug or related substance; (16) women who have a positive pregnancy test during the screening period or are breastfeeding; (17) patients with hepatitis B e antigen positive, i.e., positive for hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) and hepatitis B core antibody (HBcAb); positive for hepatitis C virus (HCV) antibody and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the upper limit of normal; positive for HIV antibody test; positive for syphilis antibody test and in the active stage of syphilis; (18) those with any of the following laboratory tests: a) hemoglobin < 80 g / L; b) platelet count < 75 × 10 9 / L; c) Aspartate aminotransferase (AST) > 3 times the upper limit of normal; d) Alanine aminotransferase (ALT) > 3 times the upper limit of normal; e) Serum total bilirubin (TBIL) > 2 times the upper limit of normal; f) Serum creatinine (Cr) > 1.5 times the upper limit of normal; g) Serum amylase > 2 times the upper limit of normal; (19) The following abnormalities were found on the electrocardiogram: a) at least two QTcF intervals >450ms (male) or >470ms (female); b) pathological Q waves (defined as >40ms or deep >0.4-0.5mV); c) electrocardiogram suggesting pre-excitation syndrome; d) electrocardiogram suggesting left or right bundle branch block; or second or third degree heart block; e) intraventricular conduction delay with QRS duration >120ms; f) bradycardia with sinus heart rate <50bpm; (20) any condition that the investigator judges to affect the subject's adherence to the study protocol, or any serious medical or psychological condition that may affect the interpretation of efficacy and safety data, or any condition that may affect the subject's safety by participating in the trial.

[0175] Qualified participants were randomly assigned to the following three groups in a 1:1:1 ratio: Group A Compound benzenesulfonate regimen 100mg group (BJLLfx(M) / C), Group B formula The study included two groups: the benzyl sulfonate regimen 200 mg group (BJLLfx(M) / C) and the delamani regimen group (BDLLfx / C). Patients were randomized based on fluoroquinolone resistance. If fluoroquinolone-sensitive, groups A and B received levofloxacin or moxifloxacin, while group C received levofloxacin. If fluoroquinolone-resistant, all groups received clofazimine. At least 15 fluoroquinolone-resistant patients were included. To accommodate a small number of patients with potentially negative baseline sputum cultures, additional randomization numbers were assigned to ensure the m-mITT analysis set included 60 participants.

[0176] This clinical trial was conducted at six centers: 01- Beijing Chest Hospital, Capital Medical University; 02- Wuhan Pulmonary Hospital; 03- Chengdu Public Health Clinical Medical Center; 04- Changsha Central Hospital; 05- Shandong Provincial Public Health Clinical Center; and 06- Nanjing Second Hospital. A total of 63 participants were enrolled.

[0177] This embodiment enrolled a total of 63 subjects, who were randomly divided into group A in a 1:1:1 ratio: Compound benzenesulfonate 100mg BID group, group B: formula Compound benzenesulfonate 200mg BID group, group C: positive control delamani, 21 cases in each group. Dropout rate: 1 person dropped out in group C, 1 person was invalid (negative during screening period and W1); 1 person dropped out in group B. Efficacy data: 21 people in group A, 20 people in group B, and 19 people in group C. Specifically, group A1: formula Compound benzenesulfonate 100mg BID + bedaquiline + linezolid + levofloxacin, 9 cases; Group A2: formula Compound benzyl sulfonate 100mg BID + bedaquiline + linezolid + moxifloxacin, 3 cases; Group A3: formula Compound benzenesulfonate 100mg BID + bedaquiline + linezolid + clofazimine, 9 cases; Group B1: formula Compound benzenesulfonate 200mg BID + bedaquiline + linezolid + levofloxacin, 8 cases; Group B2: formula Compound benzyl sulfonate 200mg BID + bedaquiline + linezolid + moxifloxacin, 4 cases; Group B3: formula The following groups were included: Group A (200mg BID of benzyl sulfonate), Bedaquiline, Linezolid, and Clofazimine (8 cases); Group C1 (Delamani), Bedaquiline, Linezolid, and Levofloxacin (13 cases); and Group C2 (Delamani), Bedaquiline, Linezolid, and Clofazimine (6 cases). Results were statistically analyzed across groups A, B, and C.

[0178] According to the "Technical Guidelines for Clinical Trials of Anti-Tuberculosis Drugs," sputum culture can demonstrate efficacy by measuring the negative conversion rate of Mycobacterium tuberculosis in sputum cultures during treatment. Both negative conversion time analysis and fixed-time-point negative conversion rate analysis are considered reasonable predictors of clinical benefit. The negative conversion rate of sputum cultures and the median time to negative conversion within a specified period objectively and reliably represent the anti-tuberculosis effect of anti-tuberculosis drugs. In this clinical trial, the primary endpoint was the negative conversion rate (SCC, %) of sputum cultures in each treatment group after 8 weeks of treatment. Sputum culture was performed using the liquid culture method. The reporting time was recorded after a positive result was obtained from the culture instrument; if no positive result was found after 42 days of culture, the result was reported as negative.

[0179] The specimen used for effectiveness evaluation in this embodiment is sputum. Subjects can collect sputum specimens using the natural coughing method. For those with difficulty coughing up sputum, nebulized inhalation with a warm solution of 10% sodium chloride or other nebulization methods based on clinical practice can be used to facilitate sputum expectoration. Sputum collection requirements include one 16-hour overnight sputum sample and one single sputum sample. The overnight sputum sample is all sputum collected from 4 PM the day before the visit to 8 AM the morning of the visit; the single sputum sample is the morning sputum sample collected on the day of the visit.

[0180] During the screening period, at least two single sputum samples should be submitted for sputum smear confirmation and one overnight sputum sample for sputum culture. For subjects with positive sputum smears, one single sputum sample and one overnight sputum sample should be collected on the day of admission to the ward (D-1) and submitted to the research center on D1. During hospitalization, at least one single sputum sample and one overnight sputum sample should be collected. Starting from W4, at each visit, one 16-hour overnight sputum sample should be submitted for sputum culture and one single sputum sample for sputum smear examination.

[0181] The sputum culture baseline is determined by the researchers based on the enrollment status of the subjects. If a subject is enrolled due to a positive sputum smear and a positive sputum culture during the screening period, then the positive sputum culture during the screening period is used as the baseline. If a subject is enrolled only because the sputum smear result meets the inclusion criteria, then any positive sputum culture submitted during the screening period, D-1, and W1 visit hospitalization can be used as the baseline.

[0182] The items and instructions for sputum collection at different visit points are shown in Table 2 below.

[0183] Table 2 Requirements and testing items for sputum collection at different time points

[0184]

[0185] 5. Research Results

[0186] 5.1 Safety Results and Tolerability Evaluation

[0187] Mode The benzenesulfonate group showed good overall safety and tolerability, significantly superior to the control drug, delamani. No deaths, hepatotoxicity, or treatment interruptions / discontinuations due to adverse events occurred during the trial. The benzenesulfonate group showed better cardiac safety: the incidence of drug-related QT interval prolongation in the control group (38.1%) was [formula missing]. The compound benzenesulfonate was twice the dose of the two dosage groups (19.0%).

[0188] 5.2 Validity Results

[0189] The validity results are shown in Table 3 below.

[0190] Table 3 Validity Results

[0191]

[0192] Tuberculosis Bacterial Clearance Efficiency Formula The benzenesulfonate group showed better results: two sputum cultures were negative, with 13 cases (61.90%) in group A and 14 cases (70.00%) in group B, significantly higher than the 52.63% in group C. The results indicate that... The benzenesulfonate group of compounds all showed faster, more efficient, and superior tuberculosis clearance capabilities than Delamani.

[0193] Four cases in the Delamani group had positive sputum cultures after 8 weeks of treatment. The benzenesulfonate group showed twice the efficacy of the two dosage groups, suggesting that the control drug was less effective than the test drug.

[0194] It is evident that in drug-resistant pulmonary tuberculosis patients, regardless of whether they are sensitive to or resistant to fluoroquinolones, the formula... The benzenesulfonate group of compounds showed faster, more efficient, and better tuberculosis clearance capabilities, with fewer toxic side effects and greater safety. After 8 weeks of administration, the sputum culture negative conversion rate was about 17% higher than that of the control drug, Delamani.

[0195] 5.3 CT scan imaging results

[0196] Based on the lung CT scan: Group A Compound benzenesulfonate 100mg BID group ( Figure 1 After 8 weeks of treatment, the inflammatory lesions showed significant absorption, the consolidation / ground-glass opacity decreased significantly, bronchial wall thickening improved, and no new lesions appeared. A 16-week follow-up after discontinuation showed continued absorption of the lesions, with only a small amount of bronchiectasis and fibrous bands remaining. There was no recurrent exudation / consolidation, the active tuberculous lesions stabilized, and the cavities significantly decreased in size. (Group B) Compound benzenesulfonate 200mg BID group ( Figure 2 After 8 weeks of treatment, the consolidation / ground-glass opacity subsided significantly, the air bronchogram disappeared, and the pleural thickening was relieved. At the 16-week follow-up after discontinuation of medication, the lesions were basically completely absorbed, and the lung field translucency returned to normal. The cavities were significantly absorbed, and the patient was completely cured.

[0197] Based on the imaging results, both Group A and Group B demonstrated rapid and effective absorption and clearance of tuberculous lesions, with significant absorption of inflammatory lesions after 8 weeks of treatment.

[0198] In the treatment of drug-resistant tuberculosis, the most important efficacy indicator is bacteriological indicators, and the most important bacteriological indicator is the sputum culture negative conversion rate. In this invention, a sputum culture negative conversion is defined as: two consecutive negative sputum cultures (each at least 7 days apart), and no further positive sputum cultures within a specified time frame. This invention... In the two combination therapy groups of the compound benzylsulfonate, the primary endpoint was the sputum culture negative conversion rate (SCC, %) after 8 weeks of treatment. Group A had a SCC of 61.90%, Group B 70.00%, and Group C 52.63%. Both Group A and Group B had significantly higher sputum culture negative conversion rates than Group C.

[0199] Pre- and post-treatment lung imaging evaluation is another important indicator of effectiveness. For example... Figures 1-2 As shown, the lung CT results before and after treatment revealed the formula. In both groups A and B, patients treated with benzenesulfonate showed better absorption and resolution of lung lesions. Furthermore, in terms of safety, groups A and B demonstrated better safety than group C.

[0200] As can be seen, the present invention... The combination therapy regimen of benzenesulfonate compounds has achieved excellent results in terms of efficacy, safety, and tolerability in the treatment of drug-resistant pulmonary tuberculosis.

Claims

1. The use of a combination of a nitroimidazole derivative or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the preparation of a drug for the prevention and treatment of drug-resistant tuberculosis, characterized in that: The nitroimidazole derivative is selected from compounds with the following structural formulas: , , , , , , , , , , , , , , , , , , , , , , or ; The combined drug is a nitroimidazole derivative or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, administered separately or simultaneously, in combination with other antituberculosis drugs; the other antituberculosis drugs are selected from at least one of a second antituberculosis drug, a third antituberculosis drug, a fourth antituberculosis drug, a fifth antituberculosis drug, or a sixth antituberculosis drug; The second anti-tuberculosis drug is a mycobacterial ATP synthase inhibitor; The third anti-tuberculosis drug is an oxazolidinone compound; The fourth anti-tuberculosis drug is a fluoroquinolone compound; The fifth anti-tuberculosis drug is a phenazine compound; The sixth anti-tuberculosis drug is selected from at least one of pyrazinamide, PBTZ-169, SQ109, GSK-3036656, Telasebec / Q203, OPC-167832, BTZ-043, rifampin, rifapentine, rifabutin, isoniazid, ethionamide, prothionamide, ethambutol, or cycloserine.

2. The use according to claim 1, characterized in that: The pharmaceutically acceptable salt is benzenesulfonate.

3. The use according to claim 1, characterized in that: At least one of the following must be met: The second anti-tuberculosis drug is selected from bedaquiline and its pharmaceutically acceptable salts, sudapyridine, TBAJ-587 or TBAJ-876; The third anti-tuberculosis drug is selected from linezolid, contezolid, terdizol, OTB-658, sulzezolid, or delpazolid; The fourth anti-tuberculosis drug is selected from moxifloxacin, levofloxacin, sitafloxacin, or gatifloxacin. The fifth anti-tuberculosis drug is selected from clofazimine or pyfazimine; The sixth anti-tuberculosis drug is selected from pyrazinamide, OPC-167832, or ethambutol.

4. The use according to claim 1, characterized in that: The other anti-tuberculosis drugs mentioned are secondary anti-tuberculosis drugs. Or, the third anti-tuberculosis drug, Or, the fourth anti-tuberculosis drug, Or, the fifth anti-tuberculosis drug, Or, the sixth anti-tuberculosis drug, Or, a second and a third anti-tuberculosis drug, Alternatively, the second and sixth anti-tuberculosis drugs, Or, a second, third, and fourth anti-tuberculosis drug, Or, the second, third, and fifth anti-tuberculosis drugs, Alternatively, a second, third, fourth, and fifth anti-tuberculosis drug. Alternatively, a second, third, fourth, and sixth anti-tuberculosis drug.

5. The use according to claim 4, characterized in that: The other anti-tuberculosis drugs mentioned are bedaquiline and its pharmaceutically acceptable salts. Alternatively, linezolid. Alternatively, moxifloxacin or levofloxacin. Alternatively, chlorfazimine. Or, pyrazinamide Alternatively, bedaquiline and its pharmaceutically acceptable salts and linezolid. Alternatively, bedaquiline and its pharmaceutically acceptable salts and pyrazinamides. Alternatively, bedaquiline and its pharmaceutically acceptable salts, linezolid, and moxifloxacin. Alternatively, bedaquiline and its pharmaceutically acceptable salts, linezolid, and levofloxacin. Alternatively, bedaquiline and its pharmaceutically acceptable salts, linezolid, and clofazimine. Alternatively, bedaquiline and its pharmaceutically acceptable salts, linezolid, moxifloxacin, and clofazimine. Alternatively, bedaquiline and its pharmaceutically acceptable salts, linezolid, levofloxacin, and clofazimine. Alternatively, bedaquiline and its pharmaceutically acceptable salts, linezolid, moxifloxacin, and pyrazinamide. Alternatively, bedaquiline and its pharmaceutically acceptable salts, linezolid, levofloxacin, and pyrazinamide.

6. The use according to claim 5, characterized in that: At least one of the following must be met: The effective ingredient dose of the nitroimidazole derivative or its pharmaceutically acceptable salt or the pharmaceutical composition thereof is 100-800 mg / day or 200-600 mg / day; preferably 100 mg / day, 200 mg / day or 400 mg / day; The effective dose of the bedaquiline and its pharmaceutically acceptable salt is 10-600 mg / day, 20-550 mg / day, 30-520 mg / day, 60-500 mg / day, 100-480 mg / day, 120-450 mg / day, or 200-400 mg / day; preferably 10 mg / day, 20 mg / day, 30 mg / day, 60 mg / day, 100 mg / day, 120 mg / day, 200 mg / day, or 400 mg / day; The effective dose of linezolid is 37.5~1500 mg / day, 75~1400 mg / day, 150~1300 mg / day, 300~1200 mg / day, 300~600 mg / day, or 600~1200 mg / day; preferably 37.5 mg / day, 75 mg / day, 150 mg / day, 300 mg / day, 450 mg / day, 600 mg / day, or 1200 mg / day. The effective dose of the moxifloxacin is 100-1000 mg / day or 400-800 mg / day; preferably 400 mg / day or 800 mg / day. The effective dose of the levofloxacin is 150-1500 mg / day, 200-1400 mg / day, 300-1300 mg / day, 400-1200 mg / day, 500-1000 mg / day, or 750-1000 mg / day; preferably 750 mg / day, 1000 mg / day, or 1500 mg / day. The effective dose of clofazimine is 20-300 mg / day, 50-250 mg / day, or 100-200 mg / day; preferably 50 mg / day, 100 mg / day, 200 mg / day, or 250 mg / day. The effective dose of the pyrazinamide is 450~4000 mg / day; preferably 450 mg / day, 1000 mg / day or 4000 mg / day.

7. The use according to claim 5, characterized in that: At least one of the following must be met: The dosing regimen of the nitroimidazole derivative or its pharmaceutically acceptable salt or pharmaceutical composition is once daily, twice daily or three times daily; The dosing regimens of the bedaquiline and its pharmaceutically acceptable salts are once daily, twice daily, three times daily, once weekly, twice weekly, or three times weekly; The linezolid dosage regimen is once daily, twice daily, or three times daily; The moxifloxacin dosing regimen is once daily, twice daily, or three times daily; The levofloxacin dosing regimen is once daily, twice daily, or three times daily; The clofazimine dosing regimen is once daily, twice daily, three times daily, once every two days, once weekly, twice weekly, or three times weekly; The pyrazinamide is administered once daily, twice daily, three times daily, once every two days, twice weekly, or three times weekly.

8. The use according to any one of claims 1 to 7, characterized in that: The drug-resistant tuberculosis refers to rifampicin-resistant tuberculosis, isoniazid-resistant tuberculosis, single-drug-resistant tuberculosis, multidrug-resistant tuberculosis, quasi-extensively drug-resistant tuberculosis, or extensively drug-resistant tuberculosis.

9. The use according to claim 5, characterized in that: At least one of the following must be met: The administration regimen of the nitroimidazole derivative or its pharmaceutically acceptable salt or pharmaceutical composition is 100 mg or 200 mg twice daily, orally within half an hour after a meal. The dosing regimen for bedaquiline and its pharmaceutically acceptable salts is 400 mg once daily for the first 2 weeks, followed by 200 mg three times weekly, taken orally with breakfast. The linezolid dosage regimen is 600 mg once daily, taken orally within half an hour after a meal; The recommended dosage of moxifloxacin is 400 mg once daily, taken orally within half an hour after a meal. The recommended dosing regimen for levofloxacin is 750 mg once daily for individuals weighing ≤50 kg, and 1000 mg once daily for individuals weighing >50 kg, taken orally within half an hour after a meal. The recommended dosing regimen for clofazimine is once daily, 100 mg or 200 mg, taken orally within half an hour after a meal.

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