Application of nitroimidazole derivative and combined drug in preparation of drug for resisting drug-sensitive tuberculosis

Abstract

The invention discloses application of a nitroimidazole derivative and a combined drug in preparation of a drug for resisting drug-sensitive tuberculosis, and belongs to the technical field of biological medicine. The invention provides application of a nitroimidazole derivative and a combined drug in preparation of a drug for resisting drug-sensitive tuberculosis in order to solve the clinical research blank of the nitroimidazole derivative in prevention and treatment of drug-sensitive tuberculosis. Animal experiments, I-stage clinic, II-stage clinic and medication dosage and mode optimization prove that the nitroimidazole derivative has no obvious drug accumulation, no obvious reproductive toxicity, no obvious cardiotoxicity and no QT interval extension, and compared with existing drugs such as deramanib, the nitroimidazole derivative is shorter in treatment time, more remarkable in curative effect, higher in safety and suitable for clinical application. Especially in lung iconography, voids of a patient are obviously reduced or focuses are obviously absorbed, so that the compound is expected to be used as a new medicine for preventing and treating drug-sensitive pulmonary tuberculosis.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine, and specifically relates to the use of nitroimidazole derivatives and combined drugs in preparing drugs for resisting drug-sensitive pulmonary tuberculosis. Background Art

[0002] Tuberculosis (TB) is a contagious disease that poses a serious threat to human health worldwide. The causative agent is Mycobacterium tuberculosis. The currently recommended treatment is a combination chemotherapy regimen that includes rifampicin, isoniazid, pyrazinamide, and ethambutol. However, this treatment is both lengthy and toxic.

[0003] Tuberculosis, especially drug-sensitive tuberculosis (DS-TB), has always had the problem of few drug options, which directly affects the treatment effect of tuberculosis patients, and usually follows, either new (3-4%) or due to treatment failure (18-21%). For decades, only a few new drugs against drug-sensitive tuberculosis have been launched on the market worldwide, such as bedaquiline, delamanid, and pretomanid. However, the tuberculosis drugs that have been marketed have a considerable degree of side effects, including hepatotoxicity, cardiotoxicity, reproductive toxicity, bone marrow suppression, nephrotoxicity, etc., and there are problems of poor water solubility and nonlinear dose effect. There is also a potential risk of QT interval prolongation, which may lead to fatal side effects in clinical practice. There are also existing treatments for tuberculosis that use a combination of multiple agents recommended by the U.S. Public Health Service, including first using a combination of isoniazid, rifampicin, pyrazinamide and ethambutol for two months, and then using a combination of isoniazid and rifampicin alone for four months. It has been used for more than 50 years, and the problem of drug resistance is extremely serious. Moreover, these drugs have two major problems: poor safety and high price.

[0004] Nitroimidazole derivatives of formula I and the like are new anti-tuberculosis drugs developed in recent years. According to the existing in vitro activity, pharmacokinetics and in vivo efficacy results, the drug has an in vitro anti-mycobacterial activity comparable to that of delamanid, and has excellent in vivo efficacy, lung tissue distribution and good safety. However, the randomized, open, multicenter study results on the early bactericidal activity, safety, tolerability and pharmacokinetic characteristics of this type of nitroimidazole derivatives in clinical studies of patients with drug-sensitive pulmonary tuberculosis need further study. Summary of the invention

[0005] In order to address the clinical research gap in the use of nitroimidazole derivatives (such as compounds of formula I) to prevent or treat drug-sensitive pulmonary tuberculosis patients, the present invention provides the use of nitroimidazole derivatives and combined drugs in the preparation of drugs against drug-sensitive pulmonary tuberculosis.

[0006] In order to achieve the above application purpose, the technical solution adopted in this application is as follows:

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

[0008]

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

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

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

[0012]

[0013] Preferably, in the above use, the salt is benzenesulfonate.

[0014] Preferably, in the above use, the dosage of the active ingredient of the benzenesulfonate salt of the compound of formula I is 20 mg / day to 400 mg / day.

[0015] More preferably, in the above use, the dosage of the active ingredient of the benzenesulfonate salt of the compound of formula I is 200 mg / day to 400 mg / day.

[0016] Among them, in the above use, the administration regimen of the benzenesulfonate salt of the compound of formula I is once a day, twice a day or three times a day.

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

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

[0019]

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

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

[0022] The combined drug is a nitroimidazole derivative, a pharmaceutically acceptable form thereof or a pharmaceutical composition thereof, and other drugs for preventing drug-sensitive pulmonary tuberculosis, which are administered separately or simultaneously.

[0023] Preferably, in the use of the above-mentioned combination drug, the nitroimidazole derivative is a compound represented by formula I;

[0024]

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

[0026] Preferably, in the above-mentioned combined use, the dosage of the active ingredient of the benzenesulfonate salt of the compound of formula I is 20 mg / day to 400 mg / day.

[0027] More preferably, in the above-mentioned combined use, the dosage of the active ingredient of the benzenesulfonate salt of the compound of formula I is 200 mg / day to 400 mg / day.

[0028] Among them, in the use of the above-mentioned combined drug, the administration regimen of the benzenesulfonate salt of the compound of formula I is once a day, twice a day or three times a day.

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

[0030] Among them, in the use of the above-mentioned combination drug, the other drugs against drug-sensitive pulmonary tuberculosis include at least one of bedaquiline, linezolid, moxifloxacin / levofloxacin, clofazimine, cycloserine, isoniazid, rifampicin, pyrazinamide or ethambutol.

[0031] In the present invention, pharmaceutically acceptable salts include acid addition salts and base addition salts thereof. 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. For a review of suitable salts, see, 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 pharmaceutically acceptable salts of the compounds of the present 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 biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, etc.; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetates, trifluoroacetates, propionates, caproates, caprylates, decanoates, undecylenates, glycolates, gluconates, lactates, sebacates, adipates, glutarates, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamate, pyroglutamate, aspartate, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginate, ascorbate, salicylates, 4-aminosalicylates, naphthalene disulfonates, etc. These salts can be prepared by methods known in the present patent.

[0033] "Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects. 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 salts, sodium salts, calcium salts, and magnesium salts. The salt derived from organic base includes but is not limited to the following salt: primary amines, secondary amines and tertiary amines, substituted amines, including natural 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 hexyl caffeine. These salts can be prepared by known methods.

[0034] In the present invention, the pharmaceutical composition is a pharmaceutical composition comprising the nitroimidazole derivatives of the present invention or a pharmaceutically acceptable form thereof as an active ingredient, supplemented with a pharmaceutically acceptable carrier.

[0035] In the present invention, the dosage of the active ingredient is based on the compound, such as the compound of formula I.

[0036] Beneficial effects:

[0037] The present invention verifies through animal experiments that the animal long-term toxicity test tissue dissection of nitroimidazole derivatives such as Formula I and their benzenesulfonates has no obvious abnormalities, no obvious drug accumulation, no obvious reproductive toxicity, and no obvious cardiac toxicity; through Phase I clinical trials, it is verified that nitroimidazole derivatives such as Formula I and their benzenesulfonates have no QT interval prolongation, and their cardiac safety is significantly better than delamanid. The half-life of the parent drug and the main metabolites of nitroimidazole derivatives such as Formula I and their benzenesulfonates are shorter than that of delamanid and its metabolites, and they are safer; in particular, through Phase II clinical trials, as well as optimized dosage and method of medication, it is verified that nitroimidazole derivatives such as Formula I and their benzenesulfonates have a shorter treatment time and significant efficacy compared with drugs such as delamanid or combined drugs, and the patient's cavity is significantly reduced or the lesion is significantly absorbed, and the lesion / cavity absorption rate is significantly higher than the standard anti-tuberculosis treatment. Nitroimidazole derivatives such as Formula I and their benzenesulfonates are extremely safe, are currently highly safe anti-tuberculosis drugs, and have excellent efficacy on drug-sensitive pulmonary tuberculosis, and are expected to be used as new drugs or combined drugs for the prevention and treatment of drug-sensitive pulmonary tuberculosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 This is a diagram showing the cardiac toxicity results of the benzenesulfonate salt of the compound of formula I in animal experiments.

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

[0040] Figure 3 The graph shows the change in the logarithm of colony forming units of Mycobacterium tuberculosis in sputum solid culture over time from day 0 to day 14.

[0041] Figure 4 This is a comparison chart of the early bactericidal activity of the benzenesulfonate salt of the compound of formula I 200 mg BID group and the delamanid group.

[0042] Figure 5 This is a comparison chart of the early bactericidal activity of the benzenesulfonate salt of the compound of formula I 100 mg BID group and the delamanid group.

[0043] Figure 6 The following are imaging analysis images of lung cavities in Case 1 before and after administration of 200 mg BID of benzenesulfonate salt of the compound of Formula I.

[0044] Figure 7 This is an imaging analysis of lung cavitation in Case 2 before and after administration of 200 mg BID of benzenesulfonate salt of the compound of Formula I.

[0045] Figure 8 The following are imaging analysis images of lung cavities in Case 3 before and after administration of 100 mg BID of benzenesulfonate salt of the compound of Formula I.

[0046] Fig. 9The following are imaging analysis images of lung cavities in Case 4 before and after administration of 100 mg BID of benzenesulfonate salt of the compound of Formula I.

[0047] Fig.10 This is an imaging analysis of lung cavities in Case 5 before and after taking 200 mg QD of benzenesulfonate salt of Formula I.

[0048] Fig.11 This is an imaging analysis of lung cavities in Case 6 before and after taking 200 mg QD of benzenesulfonate salt of Formula I.

[0049] Fig.12 This is the imaging analysis of lung cavities in Case 7 before and after taking FDC.

[0050] Fig.13 This is the imaging analysis of lung cavities in Case 8 before and after taking Delamanid.

[0051] Fig.14 The figure is the average blood drug concentration of the prototype drug of the benzenesulfonate salt of the compound of formula I in different dosage groups.

[0052] Fig.15 The graphs show the blood concentrations of the main metabolites of the benzenesulfonate salt of the compound of formula I in different dosage groups. DETAILED DESCRIPTION

[0053] Specific examples will be listed below to explain the scheme of the present invention. It will be appreciated by those skilled in the art that the following examples are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. Where specific techniques or conditions are not indicated in the examples, the techniques or conditions described in the literature in this area or the product instructions are used. Reagents or instruments used that do not indicate manufacturers are all conventional products that can be obtained commercially.

[0054] Drugs and reagents:

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

[0056] Chemical structure:

[0057] Delamanid: A nitroimidazole anti-tuberculosis drug from Otsuka Pharmaceutical Co., Ltd.

[0058] Chemical structure:

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

[0060] In the embodiments of the present invention, the dosage of the benzenesulfonate salt of the compound of formula I is calculated based on the compound of formula I.

[0061] Example 1: Animal Experiment

[0062] (1) SD rats were orally gavaged with 30, 120, and 480 mg / kg (based on the compound of formula I) of the benzenesulfonate salt of the compound of formula I for 4 consecutive weeks and then stopped for 4 weeks. No abnormal changes were found in the general condition, body weight and food intake, ophthalmological examination, hematological and blood biochemical examination, urine examination, organ weight and coefficient, gross anatomical observation, and histopathological examination of the rats in each group.

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

[0064] It can be seen that there is no obvious abnormality in the tissue dissection of the animal long-term toxicity test of the benzenesulfonate salt of the formula I compound, and there is no obvious drug accumulation.

[0065] (2) From 4 weeks before mating to the end of mating, and from 2 weeks before mating to the 7th day of pregnancy, SD male mice were given solvent control and 30, 120, and 480 mg / kg (calculated as the compound of formula I) benzenesulfonate salt of the compound of formula I by oral gavage once a day. The percentage of pregnant mice with absorbed fetuses increased in the 480 mg / kg group. In addition, no significant abnormal changes were observed in the body weight, food intake, fertility and other indicators of male and female / pregnant mice in each group of the benzenesulfonate salt of the compound of formula I, and no significant abnormal changes were observed in the various indicators of early embryonic development in the 30 and 120 mg / kg groups. The no toxic effect level (NOAEL) of the benzenesulfonate salt of the compound of formula I on parental female and male mice and fertility was 480 mg / kg, and the NOAEL for early embryonic development was 120 mg / kg.

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

[0067] (3) The benzenesulfonate salt of the compound of formula I was administered orally to conscious, unrestrained Beagle dogs at a dose of 15, 60, or 300 mg / kg (based on the compound of formula I) once. The benzenesulfonate salt of the compound of formula I had no effect on the canine lead II electrocardiogram and blood pressure indicators.

[0068] (4) A 4-week parallel controlled QD oral toxicology study was conducted in dogs to compare the cardiotoxicity of the besylate salt of the compound of formula I and delamanid. In weeks 1 to 4, the doses of the besylate salt of the compound of formula I 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 delamanid 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 delamanid administration group was significantly prolonged compared with that before administration, and was dose-related; while the QT interval of all administration groups of the benzenesulfonate salt of the compound of formula I began to stabilize from the 14th day.

[0070] It can be seen that the benzenesulfonate salt of the 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 effect of food intake on the pharmacokinetics of single and multiple oral administrations of besylate tablets of the compound of formula I on an empty stomach in healthy Chinese adult subjects.

[0073] Research Methodology:

[0074] The first part is a single-dose ascending dose trial (SAD trial): There are 6 dose groups of benzenesulfonate of Formula I, namely 20mg, 50mg, 100mg, 200mg, 300mg, and 400mg dose groups (calculated as Formula I compound), 4 cases in the first dose group (20mg) (including 1 case taking placebo), and 10 cases in each of the remaining groups (8 cases receiving benzenesulfonate tablets of Formula I compound and 2 cases receiving placebo), for a total of 54 cases. Take benzenesulfonate tablets of Formula I compound or placebo once on D1 under fasting conditions, and be discharged after completing PK sample collection and safety assessment on Day 5 (D5).

[0075] The second part is the test on the effect of food intake on the pharmacokinetics of benzenesulfonate tablets of compound of formula I: 12 subjects were enrolled in a randomized, open, single-dose, two-period, double-crossover trial design. According to the random results, benzenesulfonate tablets of compound of formula I were taken on an empty stomach or after a meal on the first day, and after a 14-day washout period, benzenesulfonate tablets of compound of formula I were taken on an empty stomach or after a meal on the 15th day.

[0076] The third part is a multiple-dose test: the multiple-dose part has two dose groups: the first dose group is the benzenesulfonate tablets of the compound of formula I 100 mg BID group, and the second dose group is the benzenesulfonate tablets of the compound of formula I 200 mg BID group. 20 healthy subjects were enrolled in the study of multiple postprandial dosing for 14 consecutive days.

[0077] Table 1 Main pharmacokinetic parameters of benzenesulfonate salt of compound of formula I

[0078]

[0079] In Table 1, the half-life of the main metabolite of the benzenesulfonate salt of the compound of Formula I is 37.89 hours, and it is expected to reach steady state around the 8th day. The 14-day safety assessment is sufficient. Figure 2 (Chart of blood drug concentration of benzenesulfonate salt of compound of formula I after multiple dosing) It can be seen that the half-life of the parent drug and main metabolites of benzenesulfonate salt of compound of formula I are shorter than that of delamanid and its metabolites, and are safer; the blood drug concentrations of the two dosage groups of multiple dosing of benzenesulfonate salt of compound of formula I in Phase I clinical trial far exceeded its minimum inhibitory concentration against drug-resistant tuberculosis in vitro, and the efficacy is guaranteed.

[0080] Table 2 Benzenesulfonate of Formula I, Delamanid and corresponding major metabolites C max IC with hERG inhibition 50 Compare

[0081]

[0082] As shown in Table 2, the parent drug of the benzenesulfonate salt of the compound of formula I and its main metabolite C max Much lower than the IC for hERG inhibition 50 , the main metabolite C max Approximately IC for hERG inhibition 50 The relevant data of Delamanid come from the published review report of Delamanid. max Below IC for hERG inhibition 50 ; The Cmax of the main metabolite DM6705 is approximately higher than the hERG inhibition IC 50 Clinical results suggest that the prolongation of the QT interval is correlated with the concentration of DM6705, and DM6705 is related to the adverse reaction of QT prolongation of delamanid. The benzenesulfonate salt of the compound of formula I of the present invention has significantly better cardiac safety than delamanid.

[0083] Example 3: Phase II clinical study

[0084] 1. Phase II clinical dosing regimen:

[0085] 52 patients with drug-sensitive pulmonary tuberculosis were enrolled and randomly divided into 5 groups: Group 1: 100 mg BID of benzenesulfonate of compound of formula I (calculated as compound of formula I); Group 2: 200 mg BID of benzenesulfonate of compound of formula I (calculated as compound of formula I); Group 3: 200 mg QD of benzenesulfonate of compound of formula I (calculated as compound of formula I); Group 4: delamanid (100 mg BID); Group 5: FDC (standard anti-tuberculosis drug dose selected according to body weight), 8 cases in each control group, 12 cases in each of the 3 dose groups of benzenesulfonate of compound of formula I. The patients took the drug for 14 consecutive days, collected overnight sputum to measure the tuberculosis CFU count in the sputum, and evaluated the bactericidal activity of the test drug.

[0086] The main efficacy index: the logarithmic change of colony forming units in solid culture of sputum tuberculosis (log10CFU, 0-2 days; 2-14 days; 0-14 days). The secondary efficacy index: the change of positive reporting time in liquid culture medium of sputum tuberculosis (TTP, 0-14 days, 2-14 days, 0-14 days).

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

[0088] (1) Enrollment: A total of 54 subjects with drug-sensitive pulmonary tuberculosis were screened and enrolled, of whom 52 subjects took the trial drug and were included in the safety analysis, and 50 subjects completed the administration of the trial drug.

[0089] (2) Efficacy: 31 patients were enrolled in the besylate of Formula I (10 patients in the 200 mg BID group, 10 patients in the 100 mg BID group, and 11 patients in the 200 mg QD group); 8 patients were enrolled in the delamanid group; and 7 patients were enrolled in the FDC group for CFU data analysis. The EBA cfu of the target treatment group of the besylate of Formula I was superior to that of delamanid. The TTP results of 35 patients were enrolled for analysis (9 patients in the 200 mg QD group, 8 patients in the 100 mg BID group, 9 patients in the 200 mg BID group, 5 patients in the delamanid group, and 4 patients in the FDC group). TTP Better than delamanid. In the group of benzenesulfonate of Formula I 100mg BID, sputum culture of one patient turned negative after 15 days of treatment. Of the 52 CT images received, 6 patients in the group of benzenesulfonate of Formula I showed significant imaging efficacy, with significant reduction of cavities or significant absorption of lesions.

[0090] (3) Safety: TEAEs related to study drugs occurred in all groups: 1 case (8.33%) in the Formula I compound besylate 100 mg BID group, 1 case (8.33%) in the Formula I compound besylate 200 mg QD group, 1 case (9.09%) in the Formula I compound besylate 200 mg BID group, 4 cases (44.44%) in the Delamanid group, and 7 cases (87.50%) in the FDC group. One subject (11.11%) in the Delamanid group experienced a treatment-related SAE during the study period. None of the 35 subjects taking the Formula I compound besylate tablet group experienced AEs of grade 3 or higher, no SAEs, no AEs leading to discontinuation of study medication, and no AEs leading to trial termination.

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

[0092] 3. Phase II clinical efficacy

[0093] (1) Bactericidal activity.

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

[0095]

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

[0097]

[0098] Note: CFU: colony forming unit.

[0099] Through Table 3-Table 4 and Figure 3 to Figure 5 (Comparison of the early bactericidal activity of the benzenesulfonate of the compound of formula I with delamanid and FDC and CFU counts) It can be seen that during the 0-14 day period, the benzenesulfonate of the compound of formula I has good bactericidal activity against drug-sensitive tuberculosis, the 100 mg BID group showed bactericidal activity comparable to that of delamanid, and the bactericidal activity of the 200 mg BID group was better than that of delamanid.

[0100] (2) Evaluation of efficacy indicator TTP.

[0101] Table 5 Changes in the time of positive reporting of Mycobacterium tuberculosis in sputum liquid culture medium

[0102]

[0103] Table 6 Early bactericidal activity of benzenesulfonate salt of formula 1 EBA TTP

[0104]

[0105] The changes in the positive reporting time of sputum tuberculosis Mycobacterium liquid culture medium (TTP, 0-14 days, 0-2 days, 2-14 days) are shown in Table 5. The five treatment groups were treated for 14 days, and the median values ​​of TTP changes compared with the baseline were: -29.00, -3.50, -27.50, -2.00, -121.75 hours. The median values ​​of EBA (TTP) 0-14 were: -2.070, -0.250, -1.960, -0.140, -8.700 hours, see Table 6. A negative change in TTP indicates that the TTP time is prolonged compared with the baseline (that is, the amount of viable bacteria is reduced, and a longer culture time is required to report a positive result), and a positive change indicates that the TTP time is prolonged compared with the baseline (that is, the amount of viable bacteria is increased, and a shorter culture time can report a positive result). The extent of TTP extension in the 100 mg BID group and the 200 mg BID group was comparable, showing a trend superior to the 200 mg QD group and the delamanid group. Therefore, the changes in TTP from day 0 to day 14 indicated that each dose group of the benzenesulfonate salt of the compound of formula I could prolong TTP and had good early bactericidal activity against Mycobacterium tuberculosis.

[0106] (3) Imaging analysis.

[0107] The formation of pulmonary tuberculosis cavities is related to the bacterial load, virulence of tuberculosis bacteria, and the body's immune function. Cavitary pulmonary tuberculosis is a more severe form of pulmonary tuberculosis. The cavities will damage the blood vessels of the lung tissue and affect the concentration of drugs in the diseased tissue, making it difficult for the drugs in the cavities to reach an effective antibacterial concentration. Pulmonary cavities are known to be an important factor affecting the efficacy of anti-tuberculosis treatment. After 2 months of standardized anti-tuberculosis treatment (at least 4 effective anti-tuberculosis drugs) in patients with cavitary pulmonary tuberculosis, approximately 5%-22% of patients will have significantly reduced cavities or significant lesion absorption. It will take a longer time for the cavities to close completely, and some patients will even still have residual tuberculosis cavities when they stop taking the drugs.

[0108] Comparison of the CT examination results of the screening period and 14 days after taking the drug for 50 subjects who completed the trial administration showed that 2 subjects in each dose group of the benzenesulfonate of Formula I compound had significant imaging efficacy, with significant reduction of cavities (cavity diameter reduced by more than 50%), and some subjects also had lesion absorption; 1 subject in the Delamanid group had slight absorption of lung cavities (cavity diameter reduced by about 10%-20%); 1 subject in the FDC group had significant absorption of cavities. The concentration of the benzenesulfonate of Formula I compound in the lungs is much higher than that in plasma (the lungs are 45 times that of plasma 0.5 hours after taking the drug) and other tissues, which is the basis for the breakthrough in lung efficacy. The benzenesulfonate of Formula I compound showed excellent therapeutic effects, as shown in Table 7. Typical cases include Figures 6 to 13 shown.

[0109] Table 7 The therapeutic effect of benzenesulfonate of compound of formula I on drug-sensitive pulmonary tuberculosis

[0110]

[0111] (4) Safety evaluation.

[0112] Table 8 Summary of AEs and adverse events

[0113]

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

[0115] As shown in Table 8, the incidence of adverse reactions in all dosage groups of the besylate of the compound of formula I was lower than that in the delamanid group and the FDC group, which shows that the besylate of the compound of formula I has high clinical safety.

[0116] (5) Pharmacokinetics.

[0117] Table 9 Pharmacokinetic results of Phase II clinical study of benzenesulfonate salt of Formula I compound

[0118]

[0119] Table 9 and Figure 14-15 As shown, the benzenesulfonate salt of the 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 benzenesulfonate salt of the compound of formula I in the 200 mg BID group was higher than that in the 100 mg BID group and the 200 mg QD group, and the drug exposure was correlated to a certain extent with the dose.

[0120] The concentration of benzenesulfonate salt of Formula I in lungs is much higher than that in plasma (45 times that in lungs at 0.5 hours after taking the drug) and other tissues, which is the basis for the breakthrough in lung efficacy. The benzenesulfonate salt of Formula I shows excellent therapeutic effects, as shown in Table 10.

[0121] Table 10 The therapeutic effect of benzenesulfonate of compound of formula I on drug-sensitive pulmonary tuberculosis

[0122]

Claims

1. Use of nitroimidazole derivatives, pharmaceutically acceptable forms thereof or pharmaceutical compositions thereof in the preparation of drugs for treating drug-sensitive pulmonary tuberculosis; wherein: The nitroimidazole derivative is selected from the following compounds: The pharmaceutically acceptable form is a pharmaceutically acceptable salt or optical isomer; The dosage of the active ingredient of the nitroimidazole derivative, its pharmaceutically acceptable form or its pharmaceutical composition is 20 mg / day to 480 mg / day.

2. The use according to claim 1, characterized in that: The nitroimidazole derivative is a compound represented by formula I; The salt is benzenesulfonate.

3. The use according to claim 2, characterized in that: The dosage of the active ingredient of the benzenesulfonate salt of the compound of formula I is 20 mg / day to 400 mg / day, preferably 200 mg / day to 400 mg / day.

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

5. The use according to any one of claims 2 to 4, characterized in that: The dosage and administration method of the active ingredient benzenesulfonate of the compound of formula I is 100 mg BID or 200 mg BID.

6. Use of nitroimidazole derivatives, pharmaceutically acceptable forms thereof or combination drugs thereof in the preparation of drugs for treating drug-sensitive pulmonary tuberculosis; wherein: The nitroimidazole derivative is selected from the following compounds: The pharmaceutically acceptable form is a pharmaceutically acceptable salt or optical isomer; The dosage of the active ingredient of the nitroimidazole derivative, its pharmaceutically acceptable form or its pharmaceutical composition is 20 mg / day to 480 mg / day; The combined drug is a nitroimidazole derivative, a pharmaceutically acceptable form thereof or a pharmaceutical composition thereof, and other drugs for preventing drug-sensitive pulmonary tuberculosis, which are administered separately or simultaneously.

7. The use according to claim 6, characterized in that: The nitroimidazole derivative is a compound represented by formula I; The salt is benzenesulfonate.

8. The use according to claim 7, characterized in that: The dosage of the active ingredient of the benzenesulfonate of the compound of formula I is 20 mg / day to 400 mg / day, preferably 200 mg / day to 400 mg / day. The dosage regimen of the benzenesulfonate of the compound of formula I is once a day, twice a day or three times a day.

9. The use according to claim 7 or 8, characterized in that: The dosage and administration method of the active ingredient benzenesulfonate of the compound of formula I is 100 mg BID or 200 mg BID.

10. The use according to any one of claims 6 to 9, characterized in that: The other drugs against drug-sensitive pulmonary tuberculosis are selected from at least one of bedaquiline, linezolid, moxifloxacin / levofloxacin, clofazimine, cycloserine, isoniazid, rifampicin, pyrazinamide or ethambutol.

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