A pyruvate composition for the prevention and treatment of pulmonary tuberculosis and its application.

Abstract

The present invention belongs to the field of biomedicine technology, and in particular, relates to a pyruvate composition for preventing and treating pulmonary tuberculosis and its application. The above-mentioned pyruvate composition is made of pyruvate, curcumin derivatives and other pharmaceutically acceptable excipients, and the curcumin derivatives are modified by chemical means to synergize with pyruvate. The pyruvate composition of the present invention has a therapeutic effect on pulmonary tuberculosis and increases lung capacity, and the curcumin derivatives can synergize with pyruvate, and the effect is better than the combined use of curcumin and pyruvate and the single effect of pyruvate.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and in particular relates to a pyruvate composition for preventing and treating pulmonary tuberculosis and an application thereof. Background Art

[0002] Pulmonary tuberculosis is a very common clinical disease. Most tuberculosis infections are transmitted through the respiratory tract. Droplets containing tuberculosis bacteria are sprayed out of the body through coughing, sneezing, and loud noises. Healthy people are infected after inhaling them. Pulmonary tuberculosis is usually treated with anti-tuberculosis drugs, which usually takes a long time. Various drugs must be taken from the early stage of the disease, and they must be taken continuously for at least 6 months. Some patients may experience various adverse reactions during treatment, such as liver and kidney damage, gastrointestinal reactions, optic nerve damage, blood system damage, peripheral neuritis, allergic reactions, bone and joint damage, etc.

[0003] Drug-induced liver injury (DILI) refers to liver damage caused by the toxic effects of drugs or their metabolites or allergic reactions when using drugs. It is one of the common adverse drug reactions in clinical practice. Since the liver in the human body is the site of drug metabolism, many anti-tuberculosis drugs for the treatment of pulmonary tuberculosis usually cause liver damage after long-term use, which in turn causes excessive levels of transaminase in the body and may even increase total bilirubin. During the treatment of pulmonary tuberculosis patients by taking medicine, some middle-aged and elderly patients are affected by age and their immune function declines, making it difficult for them to quickly repair the lesions through their own functions. In addition, the liver and kidney functions of patients will also be abnormal, making it impossible to completely clear the drugs, which will also lead to a prolonged half-life of the drugs and cause drug accumulation. In addition, since the anti-tuberculosis treatment cycle is mostly long, overdose may cause serious damage to the patient's liver, especially for patients with underlying diseases, the damage of DILI will be aggravated.

[0004] At present, how to ensure the effectiveness of anti-tuberculosis drugs while alleviating the problem of drug-induced liver damage in anti-tuberculosis treatment is a key issue. If a pulmonary tuberculosis patient causes kidney damage due to medication, the medication should be stopped immediately. Therefore, in the process of treating pulmonary tuberculosis patients, it is necessary not only to choose the appropriate type of medicine, but also to closely observe the liver and kidney damage, adjust the dosage and medicine in time, ensure the complete liver and kidney functions, and improve the treatment effect.

[0005] Pyruvate is a pyruvic acid derivative and plays an important role in glycolysis or sugar metabolism. In addition to the human body being able to synthesize this compound naturally from glucose, it can also be found in red wine, dark beer, red apples and other foods. In recent years, studies have found that pyruvate, especially sodium pyruvate, has a certain role in the treatment of tuberculosis.

[0006] Curcumin, also known as curcumin and acid yellow, can be extracted from the rhizomes of turmeric, zedoary, mustard, curry, turmeric and other plants of the ginger family. The main chain is unsaturated aliphatic and aromatic groups and belongs to the diketone class of compounds. Curcumin is a natural compound with good anti-inflammatory and anti-cancer properties. Many studies have been done on curcumin derivatives, such as patent CN117860912A (a curcumin derivative nanotherapeutic agent) discloses a curcumin derivative as an anti-tumor drug. At present, there is no research on curcumin derivatives in the field of tuberculosis treatment. Summary of the invention

[0007] In order to overcome the deficiencies of the prior art, one of the objects of the present invention is to provide a pyruvate composition for preventing and treating pulmonary tuberculosis, which enhances the efficacy of anti-tuberculosis drugs while reducing hepatotoxicity and other side effects caused by long-term use of the drugs.

[0008] In order to achieve the above object, the technical solution adopted by the present invention is: a pyruvate composition for preventing and treating pulmonary tuberculosis, comprising pyruvate and a curcumin derivative; the mass ratio of the pyruvate to the curcumin derivative is: 1:(1.2-1.6); the structural formula of the curcumin derivative is:

[0009] .

[0010] Furthermore, the preparation of the curcumin derivative comprises the following steps:

[0011]

[0012] (1) In the presence of potassium carbonate and iodine salt, curcumin and bromopropionamide are reacted at 80-90°C for 12-16 hours, and then a strong base is added to the reaction solution, and the reaction is carried out at 80-90°C for 3-4 hours. The reaction solution is post-treated to obtain compound 1;

[0013] (2) in the presence of magnesium sulfate, reacting the compound 1 with aldehyde phenylboronic acid for 8 to 12 hours, and post-treating the reaction solution to obtain compound 2;

[0014] (3) in the presence of magnesium sulfate, reacting the compound 2 with 3,4-dihydroxybenzaldehyde for 12 to 16 hours, and post-treating the reaction solution to obtain compound 3;

[0015] (4) Under the condition of pH 8-9, 1,3-indanedione and p-aminoacetophenone were reacted at 50-60°C for 4-6 hours, and the reaction solution was post-treated to obtain compound 3A;

[0016] (5) in the presence of iodine, reacting the compound 3A with thiourea at 85-95° C. for 12-18 h, and post-treating the reaction solution to obtain compound 3B;

[0017] (6) In the presence of magnesium sulfate, compound 3B is reacted with compound 3 for 8-12 hours, and the reaction solution is post-treated to obtain a curcumin derivative.

[0018] The invention firstly carries out a substitution reaction between 1,3-indandione and p-aminoacetophenone to obtain compound 3A; compound 3A is then condensed with thiourea to obtain compound 3B; curcumin and 2-bromopropionamide are then subjected to an amination reaction in the presence of potassium carbonate and potassium iodide to obtain compound 1; compound 1 is subjected to a Schiff base reaction with aldehyde phenylboronic acid to obtain compound 2; compound 2 is subjected to an esterification reaction with 3,4-dihydroxybenzaldehyde to generate compound 3; then, compound 3 is subjected to a Schiff base reaction with compound 3B to finally obtain a curcumin derivative.

[0019] Furthermore, in step (1), the molar ratio of curcumin, bromopropionamide, potassium carbonate, iodine salt and strong base is 1: (2-2.5): (3-3.5): (0.2-0.5): (2.2-3); the iodine salt is potassium iodide, and the strong base is potassium hydroxide.

[0020] Furthermore, in step (2), the molar ratio of compound 1, formaldehyde phenylboronic acid and magnesium sulfate is 1:(2-2.2):(0.02-0.04).

[0021] Furthermore, in step (3), the molar ratio of the compound 2,3,4-dihydroxybenzaldehyde to magnesium sulfate is 1:(2-2.2):(2.5-3).

[0022] Furthermore, the molar ratio of 1,3-indanedione to p-aminoacetophenone in step (4) is 1:(1-1.2), and the molar ratio of compound 3A, thiourea and iodine in step (5) is 1:(1.5-1.7):(1-1.5).

[0023] Furthermore, in step (6), the molar ratio of compound 3, compound 3B and magnesium sulfate is 1:(2-2.5):(0.04-0.06).

[0024] Furthermore, the pyruvate is sodium pyruvate.

[0025] The second object of the present invention is to provide an application of a pyruvate composition for preventing and treating pulmonary tuberculosis.

[0026] In order to achieve the above object, the technical solution adopted by the present invention is:

[0027] Application of the pyruvate composition for preventing and treating pulmonary tuberculosis in the preparation of a drug for treating pulmonary tuberculosis.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] 1. The pyruvate composition of the present invention can effectively alleviate lung damage caused by pulmonary tuberculosis and increase lung capacity, and the curcumin derivative can synergize with pyruvate, and the effect is better than the combined use of curcumin and pyruvate and the effect of pyruvate alone.

[0030] 2. The pyruvate composition of the present invention hardly causes drug-induced liver damage during anti-tuberculosis treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 Schematic diagram of the synthesis route of the curcumin derivatives of the present invention;

[0032] Figure 2 Schematic diagram of hydrogen spectrum of curcumin derivative intermediate 1 of the present invention;

[0033] Figure 3 Schematic diagram of mass spectrum of curcumin derivative intermediate 1 of the present invention;

[0034] Figure 4 Schematic diagram of hydrogen spectrum of curcumin derivative intermediate 2 of the present invention;

[0035] Figure 5 Schematic diagram of mass spectrum of curcumin derivative intermediate 2 of the present invention;

[0036] Figure 6 Schematic diagram of hydrogen spectrum of curcumin derivative intermediate 3 of the present invention;

[0037] Figure 7 Schematic diagram of mass spectrum of curcumin derivative intermediate 3 of the present invention;

[0038] Figure 8 Schematic diagram of the hydrogen spectrum of the curcumin derivative intermediate 3A of the present invention;

[0039] Fig. 9 Schematic diagram of mass spectrum of curcumin derivative intermediate 3A of the present invention;

[0040] Fig.10 Schematic diagram of hydrogen spectrum of curcumin derivative intermediate 3B of the present invention;

[0041] Fig.11 Schematic diagram of mass spectrum of curcumin derivative intermediate 3B of the present invention;

[0042] Fig.12 Schematic diagram of the hydrogen spectrum of the curcumin derivative of the present invention;

[0043] Fig.13 Schematic diagram of mass spectrum of curcumin derivatives of the present invention;

[0044] Fig.14 The figure is a schematic diagram of the effect of the pyruvate composition of the present invention on the blood biochemical indexes of mice; wherein (a) is the level of ALT in the plasma sample, and (b) is the level of AST in the plasma sample. DETAILED DESCRIPTION

[0045] Below, in conjunction with the accompanying drawings and specific embodiments, the present invention is further described. It should be noted that, under the premise of no conflict, the embodiments described below or the technical features can be arbitrarily combined to form new embodiments. The specific conditions not specified in the embodiments are carried out under normal conditions. The reagents or instruments used, unless otherwise specified, are conventional products obtained through commercial channels.

[0046] Example 1

[0047] A pyruvate composition for preventing and treating pulmonary tuberculosis, wherein the pyruvate is sodium pyruvate, and the mass ratio of sodium pyruvate to a curcumin derivative is 1:1.5; and the preparation method thereof comprises the following preparation steps:

[0048] The specific preparation process of curcumin derivatives includes the following steps, and the route diagram is as follows: Figure 1 As shown,

[0049] (1) 1 g of curcumin (2.7 mmol, 1 eq) was added to 8 mL of acetonitrile, and potassium carbonate (3 eq), potassium iodide (0.2 eq), and 2-bromopropionamide (2 eq) were added in sequence, and stirred evenly at room temperature, and then heated to 80 °C for 16 h; the reaction solution was cooled to room temperature, potassium hydroxide (2.2 eq) was added to the reaction solution, and the temperature was raised to 80 °C, and stirring was continued for 2 h; 8 mL of water was added to the reaction system, and the reaction solution was stirred for 2 h under reflux; 16 mL of water was added to stop heating, and the reaction solution was gradually cooled to room temperature, the reaction solution was filtered, and the filter cake was collected and dried to obtain compound 1.

[0050] The above compound 1 1 HNMR Figure 2 As shown, MS Figure 3 As shown, specifically 1 HNMR (C 21 H 22 N2O4, 400MHz, DMSO- d6 ) δ: 7.65 (d, 2H), 7.34 (d, 2H), 6.91-6.73 (m, 6H), 4.59 (s, 4H), 4.61 (s, 2H), 3.89 (s, 6H); [M+H]+ m / z: 367.16, ESI-MS (m / z): 367.16. 1 The results of HNMR and MS confirmed that it was the target product.

[0051] (2) 1 g of compound 1 (2.7 mmol, 1 eq), formaldehyde phenylboronic acid (2 eq) and magnesium sulfate (0.02 eq) were added to 10 mL of dichloromethane in sequence, stirred evenly at room temperature, reacted for 12 h, concentrated, and recrystallized to obtain compound 2.

[0052] The above compound 2 1 HNMR Figure 4 As shown, MS Figure 5 As shown, specifically 1 HNMR (C 35 H 32 B2N2O8, 400MHz, DMSO- d6 ) δ: 8.64 (s, 2H), 7.81 (d, 4H), 7.65 (d, 2H), 7.47-7.45 (m, 6H), 7.10-7.09 (d, 2H), 6.92-6.85 (t, 4H), 4.61 (s, 2H), 4.02 (s, 6H); [M+H] + m / z: 631.23, ESI-MS (m / z): 631.23. 1 The results of HNMR and MS confirmed that it was the target product.

[0053] (3) 1 g of compound 2 (3.2 mmol, 1 eq) and 3,4-dihydroxybenzaldehyde (2 eq) were added to a mixed solvent of 10 mL THF and 0.2 mL water. After stirring for 20 min, magnesium sulfate (2.5 eq) was added and stirred at room temperature for 16 h. The reaction solution was dried, concentrated, and filtered through a column (eluent, petroleum ether:ethyl acetate = 9:1) to obtain compound 3.

[0054] The above compound 3 1 HNMR Figure 6 As shown, MS Figure 7 As shown, specifically 1 HNMR (C 49 H 36 B2N2O 10 , 400MHz, DMSO- d6) δ: 9.61 (s, 2H), 8.64 (s, 2H), 7.81 (d, 4H), 7.65 (d, 2H), 7.47-7.45 (m, 6H), 7.2 7 (d, 2H), 7.10-7.06 (t, 2H), 6.93-6.85 (m, 8H), 4.61 (s, 2H), 4.02 (s, 6H); [M+H] + m / z: 835.26, ESI-MS (m / z): 835.27. 1 The results of HNMR and MS confirmed that it was the target product.

[0055] (4) 1 g of 1,3-indanedione (6.8 mmol, 1 eq) and p-aminoacetophenone (1 eq) were added to 50 mL of deionized water, the pH was adjusted to 9, the temperature was raised to 50 °C, and the reaction was carried out for 6 h. The reaction solution was cooled to room temperature, diluted with deionized water, and then extracted with ethyl acetate. The ethyl acetate phase was dried, concentrated, and filtered through a column (eluent, petroleum ether: ethyl acetate = 15:1) to obtain compound 3A.

[0056] The above compound 3A 1 HNMR Figure 8 As shown, MS Fig. 9 As shown, specifically 1 HNMR (C 17 H 12 O3, 400MHz, DMSO- d6 ) δ: 8.12 (s, 4H), 7.57 (d, 2H), 6.81 (d, 2H), 5.80 (s, 1H), 2.53 (s, 3H); [M+H] + m / z: 265.08, ESI-MS (m / z): 265.08. 1 The results of HNMR and MS confirmed that it was the target product.

[0057] (5) 1 g of compound 3A (3.8 mmol, 1 eq), thiourea (1.5 eq) and I2 (1 eq) were added to 10 mL of DMSO in sequence, the temperature was raised to 85 °C, and the reaction was carried out for 18 h. The reaction solution was filtered and concentrated to obtain a crude product. The crude product was diluted with methyl tert-butyl ether and water, and the pH was adjusted to 10 with ammonia. After separation, the aqueous phase was extracted with methyl tert-butyl ether, and the methyl tert-butyl ether phases were combined and dried, concentrated, and filtered through a column (eluent, petroleum ether: ethyl acetate = 5:1) to obtain compound 3B.

[0058] The above compound 3B 1 HNMR Fig.10 As shown, MS Fig.11 As shown, specifically 1 HNMR (C 18 H12 N2O2S, 400MHz, DMSO- d6 ) δ: 8.12 (s, 4H), 7.65 (d, 2H), 7.20 (d, 2H), 7.02-6.95 (m, 3H), 5.80 (s, 1H); [M+H] + m / z: 321.06, ESI-MS (m / z): 321.09. 1 The results of HNMR and MS confirmed that it was the target product.

[0059] (6) 1 g of compound 3 (1.2 mmol, 1 eq), 3B (2 eq) and magnesium sulfate (0.04 eq) were added to 10 mL of dichloromethane in sequence, stirred evenly at room temperature, reacted for 12 h, concentrated, and recrystallized to obtain a curcumin derivative.

[0060] The above-mentioned curcumin derivatives 1 HNMR Fig.12 As shown, MS Fig.13 As shown, specifically 1 HNMR (C 85 H 56 B2N6O 12 S2, 400MHz, DMSO- d6 ) δ: 8.99 (d, 2H), 8.64 (s, 2H), 8.12 (s, 8H), 7.96 (s, 2H), 7.81 (d, 4H), 7.68-7.60 (m, 6H) ), 7.48-7.45 (m, 6H), 7.22-6.75 (m, 16H), 5.80 (s, 2H) 4.61 (s, 2H), 4.02 (s, 6H); [M+H] + m / z: 1439.36, ESI-MS (m / z): 1439.41. 1 The results of HNMR and MS confirmed that it was the target product.

[0061] Example 2

[0062] A pyruvate composition for preventing and treating pulmonary tuberculosis, wherein the pyruvate is sodium pyruvate, and the mass ratio of sodium pyruvate to a curcumin derivative is 1:1.2; the preparation steps are as follows:

[0063] The specific preparation process of curcumin derivatives includes the following steps:

[0064] (1) Add 1g of curcumin (2.7mmol, 1eq) to 8mL of acetonitrile, then add potassium carbonate (3.2eq), potassium iodide (0.3eq), and 2-bromopropionamide (2.2eq) in sequence, stir evenly at room temperature, and then heat to 90°C for 12h; cool the reaction solution to room temperature, add potassium hydroxide (2.5eq) to the reaction solution, and heat to 90°C at the same time, and continue stirring for 1.5h; then add 8mL of water to the reaction system, and continue stirring the reaction solution under reflux for 1.5h; add 16mL of water to stop heating, and gradually cool the reaction solution to room temperature, filter the reaction solution, collect the filter cake and dry it to obtain compound 1. 1 The structure was consistent with that in Example 1 as determined by HNMR and MS.

[0065] (2) 1 g of compound 1 (2.7 mmol, 1 eq), formaldehyde phenylboronic acid (2.2 eq), and magnesium sulfate (0.03 eq) were added to 8 mL of dichloromethane in sequence, stirred evenly at room temperature, reacted for 10 h, concentrated, and recrystallized to obtain compound 2. 1 The structure was consistent with that in Example 1 as determined by HNMR and MS.

[0066] (3) Add 1 g of compound 2 (3.2 mmol, 1 eq) and 3,4-dihydroxybenzaldehyde (2.1 eq) to a mixed solvent of 10 mL of THF and 0.5 mL of water, stir for 20 min, then add magnesium sulfate (3 eq), and stir at room temperature for 14 h; the reaction solution is dried, concentrated, and filtered through a column (eluent, petroleum ether: ethyl acetate = 9:1) to obtain compound 3. 1 The structure was consistent with that in Example 1 as determined by HNMR and MS.

[0067] (4) Add 1 g of 1,3-indanedione (6.8 mmol, 1 eq) and p-aminoacetophenone (1.2 eq) to 70 mL of deionized water, adjust the pH to 8, heat to 60 °C, and react for 4 h; cool the reaction solution to room temperature, dilute with deionized water, and extract with ethyl acetate. The ethyl acetate phase is dried, concentrated, and column-filtered (eluent: petroleum ether: ethyl acetate = 15:1) to obtain compound 3A. 1 The structure was consistent with that in Example 1 as determined by HNMR and MS.

[0068] (5) 1g of compound 3A (3.8mmol, 1eq), thiourea (1.6eq) and I2 (1.2eq) were added to 10mL DMSO in sequence, the temperature was raised to 90°C, and the reaction was carried out for 16h; the reaction solution was filtered and concentrated to obtain a crude product, the crude product was diluted with methyl tert-butyl ether and water, the pH was adjusted to 9 with ammonia, the aqueous phase was extracted with methyl tert-butyl ether after separation, the methyl tert-butyl ether phases were combined and dried, concentrated, and passed through a column (eluent, petroleum ether: ethyl acetate = 5:1) to obtain 3B. 1 The structure was consistent with that in Example 1 as determined by HNMR and MS.

[0069] (6) 1 g of compound 3 (1.2 mmol, 1 eq), 3B (2.5 eq) and magnesium sulfate (0.05 eq) were added to 10 mL of dichloromethane in sequence, stirred evenly at room temperature, reacted for 8 h, concentrated, and recrystallized to obtain compound 2. A curcumin derivative was obtained. 1 The structure was consistent with that in Example 1 as determined by HNMR and MS.

[0070] Example 3

[0071] A pyruvate composition for preventing and treating pulmonary tuberculosis, wherein the pyruvate is sodium pyruvate, and the mass ratio of sodium pyruvate to a curcumin derivative is 1:1.6; the preparation steps are as follows:

[0072] The specific preparation process of curcumin derivatives includes the following steps: (1) Add 1g curcumin (2.7mmol, 1eq) to 8mL acetonitrile, then add potassium carbonate (3.5eq), potassium iodide (0.5eq), and 2-bromopropionamide (2.5eq) in sequence, stir evenly at room temperature, and then heat to 85°C for reaction for 15h; cool the reaction solution to room temperature, add potassium hydroxide (3eq) to the reaction solution, and heat to 85°C at the same time, and continue stirring for 1.5h; then add 8mL water to the reaction system, and continue stirring the reaction solution under reflux for 1.5h; add 16mL water to stop heating, and gradually cool the reaction solution to room temperature, filter the reaction solution, collect the filter cake and dry it to obtain compound 1. 1 The structure was consistent with that in Example 1 as determined by HNMR and MS.

[0073] (2) 1 g of compound 1 (2.7 mmol, 1 eq), formaldehyde phenylboronic acid (2.1 eq), and magnesium sulfate (0.04 eq) were added to 8 mL of dichloromethane in sequence, stirred evenly at room temperature, reacted for 8 h, concentrated, and recrystallized to obtain compound 2. 1 The structure was consistent with that in Example 1 as determined by HNMR and MS.

[0074] (3) Add 1 g of compound 2 (3.2 mmol, 1 eq) and 3,4-dihydroxybenzaldehyde (2.2 eq) to a mixed solvent of 10 mL of THF and 0.8 mL of water, stir for 20 min, then add magnesium sulfate (2.8 eq) and stir at room temperature for 12 h; the reaction solution is dried, concentrated, and filtered through a column (eluent, petroleum ether: ethyl acetate = 9:1) to obtain compound 3. 1 The structure was consistent with that in Example 1 as determined by HNMR and MS.

[0075] (4) Add 1 g of 1,3-indanedione (6.8 mmol, 1 eq) and p-aminoacetophenone (1.1 eq) to 60 mL of deionized water, adjust the pH to 9, heat to 55 °C, and react for 5 h; cool the reaction solution to room temperature, dilute with deionized water, and extract with ethyl acetate. The ethyl acetate phase is dried, concentrated, and column-filtered (eluent: petroleum ether: ethyl acetate = 15:1) to obtain compound 3A. 1 The structure was consistent with that in Example 1 as determined by HNMR and MS.

[0076] (5) 1 g of compound 3A (3.8 mmol, 1 eq), thiourea (1.7 eq) and I2 (1.5 eq) were added to 8 mL of DMSO in sequence, the temperature was raised to 95 °C, the reaction was allowed to react for 12 h, the reaction solution was filtered and concentrated to obtain a crude product, the crude product was diluted with methyl tert-butyl ether and water, the pH was adjusted to 10 with ammonia, the aqueous phase was extracted with methyl tert-butyl ether after separation, the methyl tert-butyl ether phases were combined and dried, concentrated and column-filtered (eluent, petroleum ether: ethyl acetate = 5:1) to obtain 3B. 1 The structure was consistent with that in Example 1 as determined by HNMR and MS.

[0077] (6) 1 g of compound 3 (1.2 mmol, 1 eq), 3B (2.2 eq) and magnesium sulfate (0.06 eq) were added to 8 mL of dichloromethane in sequence, stirred evenly at room temperature, reacted for 10 h, concentrated, and recrystallized to obtain compound 2. A curcumin derivative was obtained. 1 The structure was consistent with that in Example 1 as determined by HNMR and MS.

[0078] Comparative Example 1

[0079] A pyruvate composition, the difference being that the curcumin derivative is replaced with an equal amount of curcumin.

[0080] Test Example 1

[0081] Effects of the pyruvate composition of the present invention on blood biochemical indicators of mice (testing the therapeutic effect of tuberculosis and the safety of the drug on the liver)

[0082] ①Test materials: Mycobacterium tuberculosis H37 R v ; 90 male mice, weighing 20g±2g; 80 mice were randomly selected to establish the tuberculosis virus model, and the remaining 10 mice were set up as a blank control group.

[0083] ②Establishment of tuberculosis virus model:

[0084] Take Mycobacterium tuberculosis (H 37 R v ) was weighed, ground and used to prepare a bacterial solution containing 1-5 mg / mL (wet weight) in normal saline; 0.2 mL of the bacterial solution was injected into the tail vein of mice, and the mice were observed for 3 days. The occurrence of fever, cough, and increased wheezing indicated that the model was successfully established.

[0085] ③ Experimental groups and dosing regimen:

[0086] 70 mice with successful tuberculosis virus model were selected and randomly divided into model group, Example 1 group, Example 2 group, Example 3 group, Comparative Example 1 group, sodium pyruvate group, and curcumin derivative group (prepared in Example 1), with 10 mice in each group. The pyruvate composition, sodium pyruvate, and curcumin derivative prepared in Examples 1-3 and Comparative Example 1 were gavaged into mice at a dose of 0.8 mg / kg for 28 days; the blank control group and the model group were gavaged with an equal volume of normal saline every day.

[0087] ④Test method:

[0088] After 28 days of continuous treatment, 8 groups of mice (blank control group, model group, Example 1-3 groups and Comparative Example 1-3 groups) were intraperitoneally anesthetized with 50 mg / kg of Shutai 12 hours after the last administration, and tracheal intubation and ventilator-assisted breathing were performed. The following pulmonary function indicators were detected using a pulmonary function meter: 50% forced expiratory flow (FEF50), 75% forced expiratory flow (FEF75), and peak expiratory flow rate (PEF) as shown in Table 1; then about 0.8 mL of blood was collected from the abdominal aorta, placed in a 1.5 mL centrifuge tube (with heparin anticoagulation), and centrifuged at 6000 rpm for 5 min at 4°C. The supernatant was transferred to a new centrifuge tube to obtain a plasma sample, and the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined by enzyme-linked immunosorbent assay (ELISA). Fig.14 All data were expressed as mean ± standard deviation (x ± s), quantitative data were analyzed by variance analysis, and differences among groups were analyzed by Student T test.

[0089] Table 1 Comparison of lung function indicators of mice in each group ( )

[0090]

[0091] ⑤Experimental conclusion:

[0092] As shown in Table 1, the FEF50, FEF75 and PEF of the model group were significantly lower than those of the blank control group; the values ​​of the Example 1-3 groups and the Comparative Example 1, the sodium pyruvate group and the curcumin derivative group were significantly higher than those of the model group; there was no significant difference between the Comparative Example 1 group and the sodium pyruvate group, and the various lung function indicators were lower than those of the Example 1-3 groups, indicating that the present invention can effectively alleviate the lung damage caused by pulmonary tuberculosis and increase the vital capacity, and the curcumin derivatives can synergize with pyruvate, and the effect is better than the combined use of curcumin and pyruvate and the effect of pyruvate alone; the various lung function indicators of the curcumin derivative group were significantly lower than those of the Example 1-3 groups, but significantly higher than those of the model group, indicating that the curcumin derivatives can alleviate the lung damage caused by pulmonary tuberculosis, and the effect is slightly weaker than that of the Example 1-3 groups.

[0093] Fig.14 (a) is the level of ALT in plasma samples of each group, Fig.14 (b) is the level of AST in plasma samples of each group. Fig.14 It can be seen that the ALT and AST levels of the Examples 1 to 3 groups are almost consistent with those of the blank control group, which indicates that the pyruvate composition of the present invention will not cause drug-induced liver injury.

[0094] The above-mentioned embodiments are only preferred embodiments of the present invention and cannot be used to limit the scope of protection of the present invention. Any non-substantial changes and substitutions made by technicians in this field on the basis of the present invention shall fall within the scope of protection required by the present invention.

Claims

1. A pyruvate composition for preventing and treating pulmonary tuberculosis, characterized in that: It includes pyruvate and curcumin derivatives; the mass ratio of the pyruvate to the curcumin derivative is 1: (1.2-1.6); the pyruvate is sodium pyruvate; the structural formula of the curcumin derivative is: 。 2. The pyruvate composition for preventing and treating pulmonary tuberculosis according to claim 1, characterized in that: The preparation of the curcumin derivative comprises the following steps: (1) In the presence of potassium carbonate and iodine salt, curcumin and bromopropionamide are reacted at 80-90°C for 12-16 hours, and then a strong base is added to the reaction solution, and the reaction is carried out at 80-90°C for 3-4 hours. The reaction solution is post-treated to obtain compound 1; (2) in the presence of magnesium sulfate, reacting the compound 1 with aldehyde phenylboronic acid for 8 to 12 hours, and post-treating the reaction solution to obtain compound 2; (3) in the presence of magnesium sulfate, reacting the compound 2 with 3,4-dihydroxybenzaldehyde for 12 to 16 hours, and post-treating the reaction solution to obtain compound 3; (4) Under the condition of pH 8-9, 1,3-indanedione and p-aminoacetophenone were reacted at 50-60°C for 4-6 hours, and the reaction solution was post-treated to obtain compound 3A; (5) in the presence of iodine, reacting the compound 3A with thiourea at 85-95° C. for 12-18 h, and post-treating the reaction solution to obtain compound 3B; (6) In the presence of magnesium sulfate, the compound 3B is reacted with the compound 3 for 8-12 hours, and the reaction solution is post-treated to obtain a curcumin derivative.

3. The pyruvate composition for preventing and treating pulmonary tuberculosis according to claim 2, characterized in that: The molar ratio of curcumin, bromopropionamide, potassium carbonate, iodine salt and strong base in step (1) is 1: (2-2.5): (3-3.5): (0.2-0.5): (2.2-3); the iodine salt is potassium iodide, and the strong base is potassium hydroxide.

4. The pyruvate composition for preventing and treating pulmonary tuberculosis according to claim 2, characterized in that: The molar ratio of compound 1, formaldehyde phenylboronic acid and magnesium sulfate in step (2) is 1: (2-2.2): (0.02-0.04).

5. The pyruvate composition for preventing and treating pulmonary tuberculosis according to claim 2, characterized in that: The molar ratio of the compound 2,3,4-dihydroxybenzaldehyde to magnesium sulfate in step (3) is 1:(2-2.2):(2.5-3).

6. The pyruvate composition for preventing and treating pulmonary tuberculosis according to claim 2, characterized in that: The molar ratio of 1,3-indanedione to p-aminoacetophenone in step (4) is 1:(1-1.2), and the molar ratio of compound 3A, thiourea and iodine in step (5) is 1:(1.5-1.7):(1-1.5).

7. The pyruvate composition for preventing and treating pulmonary tuberculosis according to claim 2, characterized in that: The molar ratio of compound 3, compound 3B and magnesium sulfate in step (6) is 1:(2-2.5):(0.04-0.06).

8. Use of the pyruvate composition for preventing and treating pulmonary tuberculosis according to any one of claims 1 to 7 in the preparation of a drug for treating pulmonary tuberculosis.

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