Use of nitroimidazole derivative or pharmaceutical combination in preparation of medicament against drug-sensitive tuberculosis

Abstract

The present invention relates to the field of biopharmaceutical technology, and in particular, to use of a nitroimidazole derivative or a pharmaceutical combination in the preparation of a medicament against drug-sensitive tuberculosis. Animal studies, phase I and phase II clinical trials, and the optimization of dosage and route of administration have demonstrated that the nitroimidazole derivative has no significant drug accumulation, no significant reproductive toxicity, no significant cardiotoxicity, and no QT prolongation effects. Compared with existing drugs such as delamanid, the nitroimidazole derivative has shorter treatment time, more significant therapeutic effects, and higher safety. Especially in pulmonary images, the cavities in patients are significantly reduced, or the lesions are significantly absorbed, suggesting that the nitroimidazole derivative is promising as a novel drug for preventing and treating drug-sensitive tuberculosis.

Description

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

[0001] The present application belongs to the technical field of biological medicine, and particularly relates to use of nitroimidazole derivatives and combination drugs in the preparation of drugs for treating drug-sensitive pulmonary tuberculosis. BACKGROUND

[0002] Tuberculosis (TB) is a contagious disease that poses a serious threat to global human health. The pathogenic bacteria is Mycobacterium tuberculosis. The current recommended treatment regimen is combination chemotherapy, including rifampicin, isoniazid, pyrazinamide and ethambutol. However, this treatment is both long and toxic.

[0003] Drug-sensitive tuberculosis (DS-TB) has always had the problem of few drug options, which directly affects the treatment effect of tuberculosis patients, and is usually accompanied by either new onset (3-4%) or failure of treatment (18-21%). For decades, only a few new drugs for drug-sensitive tuberculosis have been put on the market worldwide, such as bedaquiline, delamanid and pretomanid. However, the existing tuberculosis drugs all have considerable side effects, including hepatotoxicity, cardiotoxicity, reproductive toxicity, bone marrow suppression, nephrotoxicity, and the problems of poor water solubility and nonlinear dose effect, and also have the potential risk of QT interval prolongation, which may cause fatal side effects in clinical practice. The existing treatment of tuberculosis also uses the formula recommended by the US Public Health Service, which includes a combination of isoniazid, rifampicin, pyrazinamide and ethambutol for the first two months, and then a combination of isoniazid and rifampicin alone for four months, which has been used for more than 50 years, and the problem of drug resistance is extremely serious. Moreover, these drugs all have the problems of poor safety and high price.

[0004] The nitroimidazole derivative of formula I is a new drug for treating tuberculosis developed in recent years. According to the existing results of in vitro activity, pharmacokinetics and in vivo efficacy, the drug has an anti-mycobacterial activity in vitro comparable to that of delamanid, excellent in vivo efficacy, lung tissue distribution and good safety. However, the random, open, multi-center study on the early bactericidal activity, safety, tolerability and pharmacokinetic characteristics of the nitroimidazole derivative in the clinical study of drug-sensitive pulmonary tuberculosis patients still needs further research.

[0005] SUMMARY

[0006] In order to solve the research blank of nitroimidazole derivatives (such as the compound of formula I) in the prevention or treatment of drug-sensitive pulmonary tuberculosis patients in clinical research, the present application provides use of nitroimidazole derivatives and combination drugs in the preparation of drugs for treating drug-sensitive pulmonary tuberculosis.

[0007] To achieve the above-mentioned application purposes, the technical scheme adopted by the present application is as follows:

[0008] In a first aspect, the present application provides a use of a nitroimidazole derivative, a pharmaceutically acceptable form thereof or a pharmaceutical composition thereof in the preparation of a drug for resisting drug-sensitive pulmonary tuberculosis; wherein the nitroimidazole derivative is selected from the following compounds of structural formula:

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

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

[0011] Preferably, in the above use, the nitroimidazole derivative is a compound of formula I;

[0012] Preferably, in the above use, the salt is a benzenesulfonate.

[0013] Preferably, in the above use, the effective component dose of the benzenesulfonate of the compound of formula I is 20 mg / day to 400 mg / day.

[0014] More preferably, in the above use, the effective component dose of the benzenesulfonate of the compound of formula I is 200 mg / day to 400 mg / day.

[0015] In the above use, the administration scheme of the benzenesulfonate of the compound of formula I is once a day, twice a day or three times a day.

[0016] Most preferably, in the above use, the effective component dose and mode of administration of the benzenesulfonate of the compound of formula I are 100 mg BID or 200 mg BID.

[0017] The present application also provides a use of a combination drug of a nitroimidazole derivative, a pharmaceutically acceptable form thereof or a pharmaceutical composition thereof in the preparation of a drug for resisting drug-sensitive pulmonary tuberculosis; wherein the nitroimidazole derivative is selected from the following compounds of structural formula:

[0018] The pharmaceutically acceptable form is a pharmaceutically acceptable salt or an optical isomer;

[0019] The effective component dose of the nitroimidazole derivative, the pharmaceutically acceptable form thereof or the pharmaceutical composition thereof is 20 mg / day to 480 mg / day.

[0020] The combination drug is a nitroimidazole derivative, a pharmaceutically acceptable form thereof, or a pharmaceutical composition thereof, and another drug for drug-susceptible pulmonary tuberculosis.

[0021] Preferably, in the use of the combination drug, the nitroimidazole derivative is a compound of Formula I.

[0022] Preferably, in the use of the combination drug, the salt is a besylate salt.

[0023] Preferably, in the use of the combination drug, the effective ingredient dose of the besylate salt of the compound of Formula I is 20 mg / day to 400 mg / day.

[0024] More preferably, in the use of the combination drug, the effective ingredient dose of the besylate salt of the compound of Formula I is 200 mg / day to 400 mg / day.

[0025] Preferably, in the use of the combination drug, the administration schedule of the besylate salt of the compound of Formula I is once a day, twice a day, or three times a day.

[0026] Most preferably, in the use of the combination drug, the effective ingredient administration dose and method of the besylate salt of the compound of Formula I is 100 mg BID or 200 mg BID.

[0027] Preferably, in the use of the combination drug, the other drug for drug-susceptible pulmonary tuberculosis includes at least one of bedaquiline, linezolid, moxifloxacin / levofloxacin, clofazimine, cycloserine, isoniazid, rifampicin, pyrazinamide, or ethambutol.

[0028] In the present application, pharmaceutically acceptable salts include acid addition salts and base addition salts. Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. A review of suitable salts can be found in, for example, "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 pharmaceutical acceptable salts of the compounds of the present application are known to those skilled in the art.

[0029] "Pharmaceutically acceptable acid addition salt" refers to salts of the free base which retain the biological effectiveness and non-toxicity of the free base and which are formed with inorganic acids or organic acids. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like. Organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, pimelate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalene- disulfonate, and the like. These salts can be prepared by methods known to those skilled in the art.

[0030] "Pharmaceutically acceptable base addition salt" refers to salts of the free acid which retain the biological effectiveness and non-toxicity of the free acid and which are formed with inorganic or organic bases. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary 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, dimethyl ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known to those skilled in the art.

[0031] In the present application, the pharmaceutical composition is one which contains the nitroimidazole derivative or a pharmaceutically acceptable form thereof described in the present application as an active ingredient, together with a pharmaceutically acceptable carrier.

[0032] In the present application, the effective ingredient dose is based on the compound, such as the compound of formula I. Advantages:

[0033] The animal long-term toxicity test of the nitroimidazole derivative of formula I and the benzene sulfonate thereof is verified by animal experiments, and no obvious abnormality is found in the histological dissection, no obvious drug accumulation, no obvious reproductive toxicity, and no obvious cardiotoxicity. The nitroimidazole derivative of formula I and the benzene sulfonate thereof are verified by the phase I clinical test, and no QT interval prolongation is found, and the heart safety is obviously better than that of delamanid. The half-life of the parent drug and the main metabolite of the nitroimidazole derivative of formula I and the benzene sulfonate thereof is shorter than that of delamanid and its metabolite, and it is safer. In particular, the nitroimidazole derivative of formula I and the benzene sulfonate thereof are verified by the phase II clinical test and the optimized drug dosage and mode, and the treatment time is shorter, and the curative effect is remarkable, the cavity of the patient is obviously reduced or the lesion is obviously absorbed, and the absorption rate of the lesion / cavity is obviously higher than that of the standard anti-tuberculosis treatment. The nitroimidazole derivative of formula I and the benzene sulfonate thereof are extremely safe, and are the anti-tuberculosis drugs with extremely high safety at present, and have an excellent curative effect on drug-sensitive pulmonary tuberculosis, and are expected to be used as a new drug or a combined drug for preventing and treating drug-sensitive pulmonary tuberculosis. BRIEF DESCRIPTION OF DRAWINGS

[0034] Fig. 1 is a graph of the cardiotoxicity results of the benzene sulfonate of the compound of formula I in animal experiments.

[0035] Fig. 2 is a graph of the blood drug concentration of the benzene sulfonate of the compound of formula I after multiple drug administrations.

[0036] Fig. 3 is a graph of the change of the logarithm of the colony forming units in the solid culture of Mycobacterium tuberculosis in sputum with time within 0-14 days.

[0037] Fig. 4 is a comparison graph of the early bactericidal activity of the 200mg BID group of the benzene sulfonate of the compound of formula I and the delamanid group.

[0038] Fig. 5 is a comparison graph of the early bactericidal activity of the 100mg BID group of the benzene sulfonate of the compound of formula I and the delamanid group.

[0039] Fig. 6 is a graph of the analysis of the lung cavity imaging of the benzene sulfonate of the compound of formula I before and after the 200mg BID drug administration of case 1.

[0040] Fig. 7 is a graph of the analysis of the lung cavity imaging of the benzene sulfonate of the compound of formula I before and after the 200mg BID drug administration of case 2.

[0041] Fig. 8 is a graph of the analysis of the lung cavity imaging of the benzene sulfonate of the compound of formula I before and after the 100mg BID drug administration of case 3.

[0042] Fig. 9 is a graph of the analysis of the lung cavity imaging of the benzene sulfonate of the compound of formula I before and after the 100mg BID drug administration of case 4.

[0043] Fig. 10 is a graph of the analysis of the lung cavity imaging of the benzene sulfonate of the compound of formula I before and after the 200mg QD drug administration of case 5.

[0044] Figure 11 is a lung cavity imaging analysis chart of the compound of formula I benzenesulfonate 200 mg QD before and after administration of case 6.

[0045] Figure 12 is a lung cavity imaging analysis chart of FDC before and after administration of case 7.

[0046] Figure 13 is a lung cavity imaging analysis chart of delamanid before and after administration of case 8.

[0047] Figure 14 is a chart of the average blood drug concentration of the compound of formula I benzenesulfonate prototype drug in different dose groups.

[0048] Figure 15 is a chart of the blood drug concentration of the main metabolite of the compound of formula I benzenesulfonate in different dose groups. DETAILED DESCRIPTION

[0049] The following specific examples will be listed to explain the scheme of the present application. Those skilled in the art will understand that the following examples are only used to illustrate the present application, and should not be regarded as limiting the scope of the present application. The specific techniques or conditions not mentioned in the examples are carried out according to the techniques or conditions described in the literature in the art or according to the product instructions. The reagents or instruments not marked with the manufacturer are all conventional products that can be obtained by market purchase.

[0050] Drugs and reagents:

[0051] The compound of formula I benzenesulfonate disclosed in CN201780045398.2;

[0052] Chemical structure:

[0053] Delamanid: nitroimidazole antituberculosis drug of Otsuka Pharmaceutical Co., Ltd.;

[0054] Chemical structure:

[0055] FDC: antituberculosis drug compound preparation (containing standard dose of isoniazid, rifampicin, ethambutol, pyrazinamide four drug compound preparation).

[0056] In the examples of the present application, the administration dose of the compound of formula I benzenesulfonate is calculated based on the compound of formula I.

[0057] Example 1: animal experiment

[0058] (1) SD rats were orally administered with 30, 120, 480 mg / kg (calculated as the compound of Formula I) of the compound of Formula I benzenesulfonate salt for 4 consecutive weeks and then stopped for 4 weeks. No abnormal changes were observed in the general state, body weight, food intake, ophthalmic examination, hematology and blood biochemistry examination, urine examination, organ weight and coefficient, gross anatomical observation and histopathological examination of the rats in each group.

[0059] Within the dose range of 30-480 mg / kg, no significant gender difference was observed in the plasma exposure of the compound of Formula I benzenesulfonate salt and its metabolites in female and male rats after the first and last administration, the exposure increased at a lower rate than the dose, and no accumulation was observed after 4 consecutive administrations. The non-observed adverse effect level (NOAEL) of SD rats orally administered with the compound of Formula I benzenesulfonate salt for 4 consecutive weeks was 480 mg / kg.

[0060] As can be seen, no obvious abnormalities were observed in the histological examination of the animals in the long-term toxicity test of the compound of Formula I benzenesulfonate salt, and no obvious drug accumulation was observed.

[0061] (2) SD male rats were orally administered with the solvent control and 30, 120, 480 mg / kg (calculated as the compound of Formula I) of the compound of Formula I benzenesulfonate salt once a day from 4 weeks before mating to the end of mating, and SD female rats were orally administered with the solvent control and 30, 120, 480 mg / kg (calculated as the compound of Formula I) of the compound of Formula I benzenesulfonate salt once a day from 2 weeks before mating to the 7th day of pregnancy. The percentage of absorbed pregnant rats increased in the 480 mg / kg group. Except for this, no obvious abnormal changes were observed in the body weight, food intake, fertility and other indicators of the male rats and female / pregnant rats in each group of the compound of Formula I benzenesulfonate salt, and no obvious abnormal changes were observed in the early embryonic development indicators in the 30 and 120 mg / kg groups. The non-observed adverse effect level (NOAEL) of the compound of Formula I benzenesulfonate salt on the parental female and male rats and fertility was 480 mg / kg, and the NOAEL of the early embryonic development was 120 mg / kg.

[0062] As can be seen, the compound of Formula I benzenesulfonate salt showed no obvious reproductive toxicity in the animal test.

[0063] (3) The compound of Formula I benzenesulfonate salt was orally administered to conscious non-restrained Beagle dogs at a dose of 15, 60, 300 mg / kg (calculated as the compound of Formula I) once, and the compound of Formula I benzenesulfonate salt showed no effect on the indicators of lead II electrocardiogram and blood pressure of the dogs.

[0064] (4) In order to compare the cardiotoxicity of the compound of Formula I benzenesulfonate salt and dramanil, a 4-week parallel control QD oral administration toxicology test was conducted. In the first to fourth weeks, the doses of the compound of Formula I benzenesulfonate salt were 15 mg / kg / day, 30 mg / kg / day and 100 mg / kg / day (calculated as the compound of Formula I), and the doses of dramanil were 50 mg / kg / day and 100 mg / kg / day.

[0065] Results: As shown in Figure 1, after 4 weeks of continuous administration, the Q-T interval of the delamanil administration group was significantly prolonged compared with that before administration, and the prolongation was dose-dependent; while the Q-T interval of all administration groups of the compound of formula I benzenesulfonate salt tended to be stable from the 14th day.

[0066] Therefore, the compound of formula I benzenesulfonate salt has no obvious cardiotoxicity in animal tests.

[0067] Example 2: Phase I clinical study

[0068] Objective: To evaluate the safety, tolerability and the effect of food on the pharmacokinetics of the compound of formula I benzenesulfonate salt tablets in Chinese healthy adult subjects after single and multiple oral administration under fasting and fed conditions.

[0069] Study method:

[0070] The first part is a single-dose escalation trial (SAD trial): the compound of formula I benzenesulfonate salt has 6 dose groups, namely 20 mg, 50 mg, 100 mg, 200 mg, 300 mg and 400 mg dose groups (based on the compound of formula I), the first dose group (20 mg) has 4 cases (including 1 placebo), the rest has 10 cases (8 cases of the compound of formula I benzenesulfonate salt tablets, 2 cases of placebo), a total of 54 cases are enrolled. Under fasting conditions, D1 takes the compound of formula I benzenesulfonate salt tablets or placebo once, and completes the PK sample collection and safety evaluation on the 5th day (D5) and is discharged.

[0071] The second part is the effect of food on the pharmacokinetics of the compound of formula I benzenesulfonate salt tablets: 12 subjects are enrolled, and a randomized, open, single-dose, two-period, double-crossover trial design is used. According to the randomization results, the compound of formula I benzenesulfonate salt is taken under fasting or postprandial conditions on the first day, and after a 14-day washout period, the compound of formula I benzenesulfonate salt tablets are taken under postprandial or fasting conditions on the 15th day.

[0072] The third part is a multiple-dose trial: the multiple-dose part has 2 dose groups: the first dose group is the compound of formula I benzenesulfonate salt tablets 100 mg BID group, and the second dose group is the compound of formula I benzenesulfonate salt tablets 200 mg BID group. 20 healthy subjects are enrolled for a 14-day postprandial multiple-dose study.

[0073] Table 1 Main pharmacokinetic parameters of the compound of formula I benzenesulfonate salt

[0074] In Table 1, the half-life of the main metabolite of compound I benzyl sulfonate is 37.89 hours, and it is expected to reach steady state around day 8. The 14-day safety assessment is sufficient. As shown in Table 1 and Figure 2 (blood drug concentration graph of compound I benzyl sulfonate after multiple dosings), the half-life of the parent drug and the main metabolite of compound I benzyl sulfonate are shorter than those of delamani and its metabolites, making it safer. In the Phase I clinical trial of compound I benzyl sulfonate, the blood drug concentrations in both dosage groups after multiple dosings far exceeded its minimum inhibitory concentration against drug-resistant tuberculosis in vitro, ensuring efficacy.

[0075] Table 2. Compounds of Formula I, benzenesulfonate, delamane, and their corresponding major metabolites C max IC with hERG inhibition 50 Compare

[0076] 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.

[0077] Example 3: Phase II Clinical Study

[0078] 1. Phase II clinical dosing regimen:

[0079] 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.

[0080] Primary efficacy endpoint: Logarithmic change in colony-forming units (CFU) in sputum Mycobacterium tuberculosis solid culture (log10 CFU, 0–2 days; 2–14 days; 0–14 days). Secondary efficacy endpoint: Change in time to positive report (TTP) in sputum Mycobacterium tuberculosis liquid culture (0–14 days; 2–14 days; 0–14 days).

[0081] 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:

[0082] (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.

[0083] (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.

[0084] (3) Safety: Treatment-associated 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-associated 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.

[0085] (4) PK: AUC at the same dose in Phase II 0-24Slightly higher than the Phase I trial 200 mg BID group and 100 mg BID group exposure (Phase I: 200 mg BID group prototype drug: 9754 ± 2056; 5935 ± 1315 ng / ml*h; metabolite: 4536 ± 922; 2603 ± 530 ng / ml*h; Phase II: 200 mg BID group prototype drug: 13858 ± 3606, metabolite: 6100 ± 1747 ng / ml*h).

[0086] 3. Phase II clinical efficacy

[0087] (1) Bactericidal activity.

[0088] Table 3 Change in logarithm of colony forming units (log CFU / ml) of M. tuberculosis in sputum in solid culture 10

[0089] Table 4 Early bactericidal activity EBA (log CFU / ml / day) 10

[0090] Note: CFU: colony forming unit.

[0091] As shown in Tables 3-4 and Figures 3-5 (results of comparison of early bactericidal activity of the benzenesulfonate salt of the compound of Formula I with delamanid, FDC, and CFU count), the benzenesulfonate salt of the compound of Formula I has good bactericidal activity against drug-sensitive tuberculosis during the period of 0-14 days, and the 100 mg BID group shows bactericidal activity comparable to that of delamanid, and the 200 mg BID group has better bactericidal activity than delamanid.

[0092] (2) Evaluation of TTP as an efficacy indicator.

[0093] Table 5 Change in positive reporting time of M. tuberculosis in sputum in liquid culture medium

[0094] Table 6 Early bactericidal activity EBA of the benzenesulfonate salt of the compound of Formula I TTP

[0095] ​​The time to positive (TTP) in sputum M. tuberculosis liquid culture for each treatment group is shown in Table 5 (0-14 days, 0-2 days, 2-14 days). The median change in TTP from baseline for the five treatment groups over 14 days was -29.00, -3.50, -27.50, -2.00, -121.75 hours, respectively. The median EBA (TTP) 0-14 was -2.070, -0.250, -1.960, -0.140, -8.700 hours, respectively, as shown in Table 6. A negative change in TTP indicates a longer time to positive (i.e., a lower bacterial load and a longer time to culture positivity) compared to baseline, while a positive change indicates a shorter time to positive (i.e., a higher bacterial load and a shorter time to culture positivity). The 100 mg BID and 200 mg BID groups showed comparable TTP prolongation, with a trend toward better performance than the 200 mg QD and delamanid groups. Thus, the change in TTP 0-14 days suggests that each of the doses of the compound of Formula I benzenesulfonate salt prolongs TTP and has good early bactericidal activity against M. tuberculosis.

[0096] (3) Radiographic analysis.

[0097] The formation of cavities in pulmonary tuberculosis is related to the bacterial load, virulence of the tubercle bacillus, and immune function of the body. Cavity pulmonary tuberculosis is a more severe form of pulmonary tuberculosis, and the cavity destroys lung tissue and blood vessels, affecting the concentration of drugs in the lesion tissue, making it difficult for the drugs in the cavity to reach an effective bacteriostatic concentration. Pulmonary cavities are an important factor known to affect the efficacy of anti-tuberculosis treatment. About 5%-22% of patients with cavity pulmonary tuberculosis have a significant reduction in cavities or significant lesion absorption after 2 months of standard anti-tuberculosis treatment (at least 4 effective anti-tuberculosis drugs), and it takes a longer time for the cavity to completely close, and even some patients still have residual tuberculous cavities when the drug is stopped.

[0098] Comparing the CT results of 50 subjects who completed the trial drug administration with those after 14 days of screening, 2 subjects in each of the dose groups of the compound of Formula I benzenesulfonate salt had a significant radiographic efficacy, with a significant reduction in the diameter of the cavity (more than 50% reduction in the diameter of the cavity), and some subjects also had lesion absorption; 1 subject in the delamanid group had a slight absorption of the pulmonary cavity (about 10%-20% reduction in the diameter of the cavity); and 1 subject in the FDC group had a significant absorption of the cavity. The lung distribution concentration of the compound of Formula I benzenesulfonate salt is much higher than that in the plasma (45 times that in the plasma at 0.5 h after administration) and other tissues, which is the basis for the breakthrough in lung efficacy, and the compound of Formula I benzenesulfonate salt shows excellent therapeutic effect, as shown in Table 7. Typical cases are shown in Figures 6-13.

[0099] Table 7. Therapeutic effect of the compound of Formula I benzenesulfonate salt on drug-sensitive pulmonary tuberculosis

[0100] (4) Safety evaluation.

[0101] Table 8 Summary of adverse events

[0102] Note: a fatigue grade 1; QT interval prolongation grade 1. b pruritic rash grade 1. c abnormal liver function grade 1. d rash SAE; rash grade 1; 1 person with uric acid elevation, grade 1; white blood cell count increased grade 1. e hyperuricemia 7 people, grade 1-2; bilirubin increased grade 1; rash grade 1; nausea grade 1; sinus tachycardia grade 1; constipation grade 1; fibrinogen increased.

[0103] As can be seen from Table 8, the incidence of adverse reactions in all dose groups of the compound of formula I benzenesulfonate is lower than that in the delamanid group and the FDC group, thus indicating that the compound of formula I benzenesulfonate has high clinical safety.

[0104] (5) Pharmacokinetics.

[0105] Table 9 Pharmacokinetic results of the compound of formula I benzenesulfonate in phase II clinical study

[0106] As shown in Table 9 and Figures 14-15, the compound of formula I benzenesulfonate has a short half-life and low drug accumulation risk. In the phase II clinical trial, the drug exposure of the compound of formula I benzenesulfonate in the 200 mg BID group is higher than that in the 100 mg BID group and the 200 mg QD group, and the drug exposure has a certain correlation with the dose.

[0107] The lung distribution concentration of the compound of formula I benzenesulfonate is much higher than that in the blood plasma (0.5 h after taking the drug, the lung is 45 times that of the blood plasma) and other tissues, which is the basis for the breakthrough of lung efficacy. The compound of formula I benzenesulfonate shows excellent therapeutic effect, as shown in Table 10.

[0108] Table 10 Therapeutic effect of the compound of formula I benzenesulfonate on drug-sensitive pulmonary tuberculosis

Claims

1. Use of a nitroimidazole derivative, a pharmaceutically acceptable form thereof or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of drug sensitive tuberculosis; wherein, The nitroimidazole derivative is selected from the group consisting of compounds of the following structural formula: said pharmaceutically acceptable form is a pharmaceutically acceptable salt or an optical isomer; said nitroimidazole derivative, pharmaceutically acceptable form thereof or pharmaceutical composition thereof is in an effective ingredient dose of 20mg / day~480mg / day.

2. Use according to claim 1, characterized in that: The nitroimidazole derivative is a compound of formula I; said salt is a besylate salt.

3. Use according to claim 2, characterized in that: said effective ingredient dose of the besylate salt of the compound of formula I is 20mg / day~400mg / day; preferably 200mg / day~400mg / day.

4. Use according to claim 2, characterized in that: said besylate salt of the compound of formula I is administered once a day, twice a day or three times a day.

5. Use according to any one of claims 2 to 4, characterized in that: said effective ingredient dose and mode of administration of the besylate salt of the compound of formula I is 100mg BID or 200mg BID.

6. The use of a combination of a nitroimidazole derivative, a pharmaceutically acceptable form thereof or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of drug sensitive tuberculosis; wherein, The nitroimidazole derivative is selected from the group consisting of compounds of the following structural formula: said pharmaceutically acceptable form is a pharmaceutically acceptable salt or an optical isomer; said nitroimidazole derivative, pharmaceutically acceptable form thereof or pharmaceutical composition thereof is in an effective ingredient dose of 20mg / day~480mg / day. said combination drug is a nitroimidazole derivative, pharmaceutically acceptable form thereof or pharmaceutical composition thereof, and other anti-drug sensitive tuberculosis drugs administered separately or simultaneously.

7. Use according to claim 6, characterized in that: The nitroimidazole derivative is a compound of formula I; said salt is a besylate salt.

8. Use according to claim 7, characterized in that: said effective ingredient dose of the besylate salt of the compound of formula I is 20mg / day~400mg / day; preferably 200mg / day~400mg / day; said besylate salt of the compound of formula I is administered once a day, twice a day or three times a day.

9. Use according to claim 7 or 8, characterized in that: said effective ingredient dose and mode of administration of the besylate salt of the compound of formula I is 100mg BID or 200mg BID.

10. Use according to any one of claims 6 to 9, characterized in that: said other anti-drug sensitive tuberculosis drugs are at least one selected from the group consisting of bedaquiline, linezolid, moxifloxacin / levofloxacin, clofazimine, cycloserine, isoniazid, rifampicin, pyrazinamide or ethambutol.

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