Use of nitroimidazole derivatives and combination drugs in the preparation of drugs for drug-sensitive pulmonary tuberculosis

Abstract

This invention discloses the use of a nitroimidazole derivative and its combination with other drugs in the preparation of drugs for drug-sensitive pulmonary tuberculosis, belonging to the field of biomedical technology. This invention fills the research gap in the clinical application of nitroimidazole derivatives for the prevention and treatment of drug-sensitive pulmonary tuberculosis by providing a method for using a nitroimidazole derivative and its combination with other drugs in the preparation of drugs for drug-sensitive pulmonary tuberculosis. Through animal experiments, Phase I and Phase II clinical trials, and optimization of dosage and administration, this invention has demonstrated that the nitroimidazole derivative mentioned in this invention has no significant drug accumulation, no significant reproductive toxicity, no significant cardiotoxicity, and no QT interval prolongation. Compared with existing drugs such as Delamanide, it has a shorter treatment time, more significant efficacy, and higher safety. Especially on lung imaging, patients show significant reduction in cavity size or significant absorption of lesions, making it a promising new drug for the prevention and treatment of drug-sensitive pulmonary tuberculosis.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to the use of nitroimidazole derivatives and combination drugs in the preparation of drugs for drug-sensitive pulmonary tuberculosis. Background Technology

[0002] Tuberculosis (TB) is a contagious disease that poses a serious threat to human health worldwide. It is caused by Mycobacterium tuberculosis. The currently recommended treatment is combination chemotherapy, including rifampin, isoniazid, pyrazinamide, and ethambutol. However, this treatment is both lengthy and toxic.

[0003] Tuberculosis, especially drug-sensitive tuberculosis (DS-TB), has long suffered from a limited range of treatment options, directly impacting treatment outcomes and often resulting in either new infections (3-4%) or treatment failure (18-21%). For decades, only a few new drugs for drug-sensitive tuberculosis have been introduced to the global market, such as bedaquiline, delamani, and pretopomalid. However, all marketed tuberculosis drugs have significant side effects, including hepatotoxicity, cardiotoxicity, reproductive toxicity, bone marrow suppression, and nephrotoxicity. They also suffer from poor water solubility, non-linear dose-effects, and the potential risk of QT interval prolongation, which can be clinically fatal. Some existing tuberculosis treatments utilize combinations of multiple drugs recommended by the US Public Health Service, including a two-month regimen of isoniazid, rifampin, pyrazinamide, and ethambutol followed by a four-month regimen of isoniazid and rifampin alone. This regimen has been used for over 50 years, leading to severe drug resistance. Moreover, these drugs all suffer from two major problems: poor safety and high price.

[0004] Nitroimidazole derivatives of Formula I are a new type of anti-tuberculosis drug developed in recent years. Based on existing in vitro activity, pharmacokinetic, and in vivo efficacy results, this drug exhibits comparable in vitro anti-mycobacterial activity to deramani, with excellent in vivo efficacy, lung tissue distribution, and good safety. However, further research is needed on the early bactericidal activity, safety, tolerability, and pharmacokinetic characteristics of these nitroimidazole derivatives in clinical trials against drug-sensitive pulmonary tuberculosis patients. Summary of the Invention

[0005] To address the clinical research gap regarding the use of nitroimidazole derivatives (such as compound I) in the prevention or treatment of drug-sensitive pulmonary tuberculosis, this invention provides the use of nitroimidazole derivatives and their combination with other drugs in the preparation of drugs for treating drug-sensitive pulmonary tuberculosis.

[0006] To achieve the above-mentioned objectives, the technical solution adopted in this application is as follows:

[0007] In a first aspect, the present invention provides the use of a nitroimidazole derivative, a pharmaceutically acceptable form thereof, or a pharmaceutical composition thereof, in the preparation of a drug for treating drug-sensitive pulmonary tuberculosis; wherein the nitroimidazole derivative is selected from compounds with the following structural formulas:

[0008]

[0009] The pharmaceutically acceptable form is a pharmaceutically acceptable salt or optical isomer;

[0010] The effective dose of the nitroimidazole derivative, its pharmaceutically acceptable form, or its pharmaceutical composition thereof is 20 mg / day to 480 mg / day.

[0011] Preferably, in the above-mentioned uses, the nitroimidazole derivative is a compound represented by Formula I;

[0012]

[0013] Preferably, in the above-described uses, the salt is a benzenesulfonate.

[0014] Preferably, in the above-mentioned uses, the effective component dosage of the compound I benzenesulfonate is 20 mg / day to 400 mg / day.

[0015] More preferably, in the above-mentioned uses, the effective ingredient dosage of the compound I benzenesulfonate is 200 mg / day to 400 mg / day.

[0016] In the above-mentioned uses, the dosing regimen for compound I benzenesulfonate is once daily, twice daily, or three times daily.

[0017] Most preferably, in the above-mentioned uses, the dosage and method of administration of the active ingredient of Formula I compound benzenesulfonate is 100 mg BID or 200 mg BID.

[0018] This invention also provides the use of a nitroimidazole derivative, a pharmaceutically acceptable form thereof, or a combination thereof in the preparation of a drug for treating drug-sensitive pulmonary tuberculosis; wherein the nitroimidazole derivative is selected from compounds with the following structural formulas:

[0019]

[0020] The pharmaceutically acceptable form is a pharmaceutically acceptable salt or optical isomer;

[0021] The effective dose of the nitroimidazole derivative, its pharmaceutically acceptable form, or its pharmaceutical composition thereof is 20 mg / day to 480 mg / day;

[0022] The combined medication is a nitroimidazole derivative, its pharmaceutically acceptable form, or a pharmaceutical combination thereof, administered separately or simultaneously, along with other drugs for drug-sensitive tuberculosis.

[0023] Preferably, in the use of the above-mentioned combined drugs, the nitroimidazole derivative is a compound shown in Formula I;

[0024]

[0025] Preferably, in the use of the above-mentioned combined drugs, the salt is a benzenesulfonate.

[0026] Preferably, in the use of the above-mentioned combined drugs, the effective dose of the compound benzenesulfonate of Formula I is 20 mg / day to 400 mg / day.

[0027] More preferably, in the use of the above-mentioned combined drugs, the effective dose of the compound benzenesulfonate of Formula I is 200 mg / day to 400 mg / day.

[0028] Among the uses of the above-mentioned combined drugs, the dosing regimen of compound I benzenesulfonate is once daily, twice daily, or three times daily.

[0029] Most preferably, in the use of the above-mentioned combined drugs, the dosage and method of administration of the active ingredient of Formula I compound benzenesulfonate is 100 mg BID or 200 mg BID.

[0030] Among the uses of the aforementioned combined drugs, the other drugs for treating drug-sensitive pulmonary tuberculosis include at least one of bedaquiline, linezolid, moxifloxacin / levofloxacin, clofazimine, cycloserine, isoniazid, rifampin, pyrazinamide, or ethambutol.

[0031] 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.

[0032] "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 methods known in this patent.

[0033] "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.

[0034] In this invention, the pharmaceutical composition uses the nitroimidazole derivative described in this invention or its pharmaceutically acceptable form as the active ingredient, supplemented by a pharmaceutically acceptable carrier.

[0035] In this invention, the dosage of the active ingredient is based on compounds, such as compounds of Formula I.

[0036] Beneficial effects:

[0037] This invention has verified through animal experiments that the long-term toxicity tests of Formula I nitroimidazole derivatives and their benzenesulfonates in animals showed no significant abnormalities in tissue anatomy, no significant drug accumulation, no significant reproductive toxicity, and no significant cardiotoxicity. Phase I clinical trials have verified that Formula I nitroimidazole derivatives and their benzenesulfonates do not prolong the QT interval, and their cardiac safety is significantly better than that of Delamani. The half-lives of the parent drug and major metabolites of Formula I nitroimidazole derivatives and their benzenesulfonates are shorter than those of Delamani and its metabolites, indicating greater safety. In particular, Phase II clinical trials, and optimized dosage and administration methods, have verified that Formula I nitroimidazole derivatives and their benzenesulfonates, compared to Delamani and other drugs or combination therapies, result in shorter treatment duration and significant efficacy, with significant reduction in cavity size or absorption of lesions, and a significantly higher lesion / cavity absorption rate than standard anti-tuberculosis treatment. Formula I nitroimidazole derivatives and their benzenesulfonates have excellent safety profiles and are currently among the safest anti-tuberculosis drugs, showing excellent efficacy against drug-sensitive pulmonary tuberculosis, and are expected to serve as new drugs or combination therapies for the prevention and treatment of drug-sensitive pulmonary tuberculosis. Attached Figure Description

[0038] Figure 1 The figure shows the cardiotoxicity results of animal experiments for compound I benzenesulfonate.

[0039] Figure 2 This is a blood concentration graph of compound I, benzenesulfonate, after multiple doses.

[0040] Figure 3 This is a graph showing the change in the logarithm of colony-forming units over time in solid cultures of Mycobacterium tuberculosis in sputum from 0 to 14 days.

[0041] Figure 4 This is a comparison of the early bactericidal activity of compound I, benzenesulfonate, in the 200mg BID group and the delamani group.

[0042] Figure 5 This is a comparison of the early bactericidal activity of compound I benzenesulfonate 100mg BID group and de lamani group.

[0043] Figure 6 The images show the lung cavitation analysis before and after taking 200mg BID of compound I benzyl sulfonate from Case 1.

[0044] Figure 7 The images show the lung cavitation analysis before and after taking 200mg BID of compound I benzenesulfonate in Case 2.

[0045] Figure 8 The images show the lung cavitation analysis before and after taking 100mg BID of compound I benzyl sulfonate in case 3.

[0046] Figure 9The images show the lung cavitation analysis before and after taking 100mg BID of compound I benzyl sulfonate in case 4.

[0047] Figure 10 The images show the lung cavitation analysis before and after taking 200mg of benzenesulfonate (Formula I) QD in Case 5.

[0048] Figure 11 The images show the lung cavitation analysis before and after taking 200mg of benzenesulfonate (Formula I) QD in Case 6.

[0049] Figure 12 Imaging analysis of lung cavitation in Case 7 before and after FDC medication.

[0050] Figure 13 Imaging analysis of lung cavitation in Case 8, Delamani, before and after medication.

[0051] Figure 14 The graph shows the average blood concentration of the prototype benzenesulfonate compound of Formula I at different dosage groups.

[0052] Figure 15 The graph shows the blood concentrations of the main metabolites of compound I benzenesulfonate at different dosage levels. Detailed Implementation

[0053] 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.

[0054] Drugs and reagents:

[0055] The benzenesulfonate compound of formula I disclosed in CN201780045398.2;

[0056] Chemical structural formula:

[0057] Delamani: A nitroimidazole antituberculosis drug manufactured by Otsuka Pharmaceutical Co., Ltd.

[0058] Chemical structural formula:

[0059] FDC: Anti-tuberculosis drug combination preparation (a combination preparation consisting of four drugs: isoniazid, rifampin, ethambutol, and pyrazinamide at standard doses).

[0060] In this embodiment of the invention, the dosage of compound benzenesulfonate of formula I is calculated based on compound I.

[0061] Example 1: Animal Experiment

[0062] (1) SD rats were administered benzenesulfonate of Formula I by oral gavage at doses of 30, 120, and 480 mg / kg (calculated as Formula I compound) for 4 consecutive weeks, followed by a 4-week recovery period after drug withdrawal. No abnormalities were found in the general condition, body weight and food intake, ophthalmological examination, hematological and blood biochemical examinations, urine examination, organ weight and coefficients, gross anatomical observation and histopathological examination of the rats in each group.

[0063] Within the dosage range of 30-480 mg / kg, there was no significant sex difference in plasma exposure of compound I benzenesulfonate and its metabolites in male and female rats after the first and last administration. The increase in exposure was less than the increase in dose, and no accumulation was observed after 4 weeks of continuous administration. The no-adverse-effect level (NOAEL) of compound I benzenesulfonate administered orally to SD rats for 4 consecutive weeks was 480 mg / kg.

[0064] Therefore, it can be seen that the animal anatomical studies of the long-term toxicity test of compound I benzenesulfonate showed no obvious abnormalities and no obvious drug accumulation.

[0065] (2) Male SD rats were administered a solvent control and 30, 120, and 480 mg / kg (calculated as compound I) of benzenesulfonate of formula I via oral gavage once daily from 4 weeks before mating until the end of mating, and female rats from 2 weeks before mating until day 7 of gestation. The percentage of pregnant rats with reabsorbed fetuses was increased in the 480 mg / kg group. Apart from this, no significant abnormalities were observed in the body weight, food intake, and fertility of male and female rats in all groups of benzenesulfonate of formula I. No significant abnormalities were observed in any early embryonic development indicators in the 30 and 120 mg / kg groups. The no-analytical dose (NOAEL) of benzenesulfonate of formula I for parental male and female rats and fertility was 480 mg / kg, and the NOAEL for early embryonic development was 120 mg / kg.

[0066] Therefore, it can be seen that the benzenesulfonate compound of formula I has no obvious reproductive toxicity in animal experiments.

[0067] (3) A single oral gavage administration of 15, 60, or 300 mg / kg (calculated as compound I) of compound I to conscious, unrestrained Beagle dogs showed no effect on the electrocardiogram and blood pressure in lead II of the dogs.

[0068] (4) To compare the cardiotoxicity of compound I benzyl sulfonate with that of delamani, a 4-week parallel-controlled QD oral administration toxicology study was conducted in dogs. During weeks 1-4, the doses of compound I benzyl sulfonate were 15 mg / kg / day, 30 mg / kg / day and 100 mg / kg / day (based on compound I), and the doses of delamani were 50 mg / kg / day and 100 mg / kg / day, respectively.

[0069] The results are as follows Figure 1 As shown, after 4 weeks of continuous administration, the QT interval in the delamani group was significantly prolonged compared to before administration, and this was dose-dependent; while the QT interval in all groups of the benzenesulfonate compound of formula I tended to stabilize from day 14.

[0070] Therefore, it can be seen that the benzenesulfonate compound of formula I has no obvious cardiotoxicity in animal experiments.

[0071] Example 2: Phase I Clinical Study

[0072] Study objective: To evaluate the safety, tolerability, and effects of food intake on pharmacokinetics of compound I benzyl sulfonate tablets taken orally once on an empty stomach and multiple times after meals in healthy adult Chinese subjects.

[0073] Research Methods:

[0074] Part 1 was the single-dose escalation trial (SAD trial): There were six dose groups for the Formula I compound benzylsulfonate: 20 mg, 50 mg, 100 mg, 200 mg, 300 mg, and 400 mg (based on Formula I compound). The first dose group (20 mg) included 4 patients (including 1 receiving a placebo), and the remaining groups each included 10 patients (8 receiving Formula I compound benzylsulfonate tablets and 2 receiving placebo), for a total of 54 patients. Patients received a single dose of Formula I compound benzylsulfonate tablets or a placebo on day 1 under fasting conditions. PK sample collection and safety assessment were completed on day 5 (D5), and patients were discharged afterward.

[0075] Part II is a study on the effect of food intake on the pharmacokinetics of Compound I benzyl sulfonate tablets: 12 subjects were enrolled in a randomized, open-label, single-dose, two-period, double-crossover trial design. Based on the randomization results, Compound I benzyl sulfonate was taken on day 1 under fasting or postprandial conditions. After a 14-day washout period, Compound I benzyl sulfonate tablets were taken on day 15 under postprandial or fasting conditions.

[0076] Part III was a multiple-dose trial: This part consisted of two dose groups: Group 1 was a 100mg BID dose of Compound I benzenesulfonate tablets, and Group 2 was a 200mg BID dose of Compound I benzenesulfonate tablets. Twenty healthy subjects were enrolled and underwent a 14-day study with multiple doses administered after meals.

[0077] Table 1 shows the main pharmacokinetic parameters of compound I benzenesulfonate.

[0078]

[0079] In Table 1, the major metabolite of compound I, benzenesulfonate, has a half-life of 37.89 hours, and is expected to reach steady state around day 8. Therefore, a 14-day safety assessment is sufficient. (Based on Table 1 and...) Figure 2 (The blood drug concentration graph of compound I benzyl sulfonate after multiple dosings) shows that the half-life of the parent drug and the main metabolite of compound I benzyl sulfonate is shorter than that of delamani and its metabolites, making it safer; in the phase I clinical trial of compound I benzyl sulfonate, the blood drug concentrations of the two dosage groups after multiple dosings were far higher than its minimum inhibitory concentration against drug-resistant tuberculosis in vitro, ensuring efficacy.

[0080] Table 2 shows the compounds of Formula I, benzenesulfonate, delamane, and their corresponding major metabolites C. max IC with hERG inhibition 50 Compare

[0081]

[0082] Table 2 shows that the parent drug of compound I benzenesulfonate and its main metabolite C max IC50 much lower than hERG inhibition 50 The main metabolite C max IC approximately for hERG inhibition 50 One-fifth; the relevant data for Delamani comes from the publicly available review report for Delamani, and the parent drug C of Delamani. max IC below hERG inhibition 50 The main metabolite DM6705 has a Cmax that is approximately higher than the hERG inhibition IC50. 50 Four times that of DM6705. Clinical results suggest a correlation between QT interval prolongation and DM6705 concentration, and DM6705 is associated with the adverse effect of QT interval prolongation associated with Delamanide. The cardiac safety of the compound of formula I, benzenesulfonate, is significantly better than that of Delamanide.

[0083] Example 3: Phase II Clinical Study

[0084] 1. Phase II clinical dosing regimen:

[0085] Fifty-two patients with drug-sensitive pulmonary tuberculosis were enrolled and randomly divided into five groups: Group 1: 100 mg BID (based on Formula I compound benzylsulfonate); Group 2: 200 mg BID (based on Formula I compound benzylsulfonate); Group 3: 200 mg QD (based on Formula I compound benzylsulfonate); Group 4: Delamanide (100 mg BID); Group 5: FDC (standard anti-tuberculosis drug dose selected according to body weight). Each control group had 8 patients, and each of the three Formula I compound benzylsulfonate dose groups had 12 patients. Patients received continuous medication for 14 days. Sputum samples were collected overnight to measure the CFU count of Mycobacterium tuberculosis and assess the bactericidal activity of the investigational drug.

[0086] Primary efficacy endpoint: Logarithmic change in colony-forming units (log10 CFU, 0–2 days; 2–14 days; 0–14 days) in sputum Mycobacterium tuberculosis solid culture. Secondary efficacy endpoint: Change in positive reporting time (TTP, 0–14 days; 2–14 days; 0–14 days) in sputum Mycobacterium tuberculosis liquid culture.

[0087] 2. The early bactericidal activity, safety, tolerability, and pharmacokinetic characteristics of compound I benzenesulfonate tablets in drug-sensitive pulmonary tuberculosis patients are summarized as follows:

[0088] (1) Enrollment: 54 drug-sensitive pulmonary tuberculosis subjects were enrolled, of which 52 subjects took the investigational drug and were included in the safety analysis, and 50 subjects completed the administration of the investigational drug.

[0089] (2) Efficacy: CFU data were analyzed in 31 patients treated with Formula I benzylsulfonate (10 in the 200mg BID group, 10 in the 100mg BID group, and 11 in the 200mg QD group); 8 in the Delamanide group; and 7 in the FDC group. EBA cfu was superior to Delamanide in the Formula I benzylsulfonate targeted therapy group. TTP results were analyzed in 35 patients (9 in the 200mg QD group, 8 in the 100mg BID group, 9 in the 200mg BID group, 5 in the Delamanide group, and 4 in the FDC group). EBA in each Formula I benzylsulfonate group... TTP Superior to Delamani. In the Formula I compound benzyl sulfonate 100mg BID group, one patient had a negative sputum culture after 15 days of treatment. Of the 52 CT images received, 6 patients in the Formula I compound benzyl sulfonate group showed significant imaging efficacy, with significant reduction in cavity size or significant absorption of lesions.

[0090] (3) Safety: Treatment-related adverse events (TEAEs) related to the study drug occurred in each group: 1 case (8.33%) in the 100 mg BID group of Compound I benzyl sulfonate, 1 case (8.33%) in the 200 mg QD group of Compound I benzyl sulfonate, 1 case (9.09%) in the 200 mg BID group of Compound I benzyl sulfonate, 4 cases (44.44%) in the Delamani group, and 7 cases (87.50%) in the FDC group. One case (11.11%) in the Delamani group experienced a treatment-related treatment-related adverse event (SAE) related to the study drug. None of the 35 subjects in the Compound I benzyl sulfonate tablet group experienced grade 3 or higher AEs, SAEs, AEs leading to discontinuation of study drug use, or AEs leading to trial termination.

[0091] (4) PK: AUC at the same dose in Phase II 0-24 Slightly higher than the exposure levels in the 200 mg BID and 100 mg BID groups in the Phase I trial (Phase I: 200 mg BID group: original drug: 9754±2056; 5935±1315 ng / ml*h; metabolite: 4536±922; 2603±530 ng / ml*h; Phase II: 200 mg BID group: original drug: 13858±3606; metabolite: 6100±1747 ng / ml*h).

[0092] 3. Phase II clinical efficacy

[0093] (1) Bactericidal activity.

[0094] Table 3. Logarithmic variation of colony-forming units in solid culture of Mycobacterium tuberculosis in sputum (log 10 CFU / ml)

[0095]

[0096] Table 4 Early bactericidal activity of EBA (Log) 10 CFU / ml / day

[0097]

[0098] Note: CFU: Colony forming unit.

[0099] Through Tables 3-4 and Figures 3-5 (Comparison of early bactericidal activity of compound I benzyl sulfonate with Delamani and FDC and CFU count) It can be seen that during the 0-14 day period, compound I benzyl sulfonate has good bactericidal activity against drug-sensitive tuberculosis. The 100 mg BID group showed bactericidal activity comparable to Delamani, and the 200 mg BID group showed bactericidal activity superior to Delamani.

[0100] (2) Evaluation of therapeutic efficacy indicators (TTP).

[0101] Table 5. Changes in the time of positive reports in sputum mycobacterium tuberculosis liquid culture medium.

[0102]

[0103] Table 6 shows the early bactericidal activity of compound EBA (formula 1) benzenesulfonate. TTP

[0104]

[0105] The changes in positive reporting time (TTP, 0-14 days, 0-2 days, 2-14 days) in sputum culture medium for Mycobacterium tuberculosis are shown in Table 5. The median changes in TTP compared to baseline were -29.00, -3.50, -27.50, -2.00, and -121.75 hours in the five treatment groups after 14 days of treatment, respectively. The median EBA (TTP) values ​​for 0-14 days were -2.070, -0.250, -1.960, -0.140, and -8.700 hours, respectively, as shown in Table 6. A negative TTP change indicates a prolonged TTP time compared to baseline (i.e., a decrease in viable bacterial count, requiring a longer incubation period to report a positive result), while a positive change indicates a prolonged TTP time compared to baseline (i.e., an increase in viable bacterial count, requiring a shorter incubation period to report a positive result). The 100mg BID group and the 200mg BID group showed comparable TTP prolongation, with the 100mg BID group showing a trend of being superior to the 200mg QD group and the Delamani group. Therefore, the changes in TTP from 0 to 14 days suggest that all doses of compound I benzenesulfonate can prolong TTP and have good early bactericidal activity against Mycobacterium tuberculosis.

[0106] (3) Imaging analysis.

[0107] The formation of cavitary pulmonary tuberculosis cavities is related to bacterial load, virulence of Mycobacterium tuberculosis, and the body's immune function. Cavitous pulmonary tuberculosis is a more severe form of tuberculosis. The cavity damages blood vessels in the lung tissue, affecting the concentration of drugs in the diseased tissue, making it difficult for drugs within the cavity to reach an effective antibacterial concentration. Pulmonary cavities are a known important factor affecting the efficacy of anti-tuberculosis treatment. In patients with cavitary pulmonary tuberculosis who undergo standardized anti-tuberculosis treatment (at least four effective anti-tuberculosis drugs) for two months, approximately 5%-22% of patients experience significant cavity shrinkage or significant lesion absorption. Complete cavity closure takes even longer, and some patients may still have residual tuberculous cavities even after discontinuing medication.

[0108] A comparison of CT scan results from 50 subjects who completed the trial administration and 14 days after administration showed that in each dose group of compound I benzylsulfonate, two subjects exhibited significant radiographic efficacy, with marked reduction in cavity diameter (more than 50%), and some subjects also experienced lesion absorption. In the delamani group, one subject showed slight absorption of lung cavities (cavity diameter reduced by approximately 10%-20%), and in the FDC group, one subject showed significant cavity absorption. The lung concentration of compound I benzylsulfonate was significantly higher than that in plasma (45 times higher in the lungs than in plasma at 0.5 hours after administration) and other tissues, which is the basis for the breakthrough in lung efficacy. Compound I benzylsulfonate demonstrated excellent therapeutic effects, as shown in Table 7. Typical cases include... Figures 6-13 As shown.

[0109] Table 7 shows the therapeutic effects of compound I benzenesulfonate on drug-sensitive pulmonary tuberculosis.

[0110]

[0111] (4) Safety evaluation.

[0112] Table 8 Summary of AEs and Adverse Events

[0113]

[0114] Note: a) Grade 1 fatigue; Grade 1 QT interval prolongation. b) Grade 1 pruritic rash. c) Grade 1 abnormal liver function. d) SAE rash; Grade 1 rash; 1 person with elevated uric acid, Grade 1; Grade 1 elevated white blood cell count. e) 7 people with hyperuricemia, Grade 1-2; Grade 1 elevated bilirubin; Grade 1 rash; Grade 1 nausea; Grade 1 sinus tachycardia; Grade 1 constipation; elevated fibrinogen.

[0115] As shown in Table 8, the incidence of adverse reactions in all dosage groups of compound I benzyl sulfonate was lower than that in the delamani group and the FDC group, indicating that compound I benzyl sulfonate has a high clinical safety profile.

[0116] (5) Pharmacokinetics.

[0117] Table 9 shows the pharmacokinetic results of the Phase II clinical trial of compound I benzenesulfonate.

[0118]

[0119] Table 9 and Figure 14-15 As shown, the benzenesulfonate compound of Formula I has a short half-life and a low risk of drug accumulation. In the Phase II clinical trial, the drug exposure of the 200 mg BID group of the benzenesulfonate compound of Formula I was higher than that of the 100 mg BID group and the 200 mg QD group, and the drug exposure was correlated with the dose.

[0120] The concentration of Formula I compound benzyl sulfonate in the lungs is significantly higher than that in plasma (45 times higher in the lungs than in plasma 0.5 hours after administration) and other tissues, which forms the basis for the breakthrough in pulmonary efficacy. Formula I compound benzyl sulfonate exhibits excellent therapeutic effects, as shown in Table 10.

[0121] Table 10 shows the therapeutic effects of compound I benzenesulfonate on drug-sensitive pulmonary tuberculosis.

[0122]

Claims

1. Use of nitroimidazole derivatives, their pharmaceutically acceptable forms, or pharmaceutical compositions thereof in the preparation of drugs for treating drug-sensitive tuberculosis; wherein, The nitroimidazole derivative is of formula [formula missing]. The compound shown; Mode The salt is a benzenesulfonate.

Images