36 results about "Bedaquiline" patented technology

A method for preparing bedaquiline using a low-temperature continuous flow, and a product prepared. The preparation method comprises the following steps: step S1, carrying out first continuous flow reaction on a feed liquid A and a feed liquid B by using a continuous flow to obtain a reaction liquid D; step S2, carrying out second continuous flow reaction on the reaction liquid D and a feed liquid C by using a continuous flow, wherein the reaction residence time of the first continuous flow reaction is 30-600 s, and the reaction residence time of the second continuous flow reaction is 30-200 s; and step S3, carrying out quenching. The preparation method achieves a good yield, and by using the method for preparation of bedaquiline, a crude product obtained requires only simple post-treatment to achieve a purity of pure bedaquiline of up to 99.8%.

This invention concerns pharmaceutical compositions for administration via intramuscular or subcutaneous injection, comprising micro- or nanoparticles of the anti-TB compound bedaquiline, suspended in an aqueous pharmaceutically acceptable carrier, and the use of such pharmaceutical compositions in the treatment and prophylaxis of a pathogenic mycobacterial infection.

FIELD: pharmacology.SUBSTANCE invention can be used to determine the concentration of an anti-tuberculosis drug in blood serum. The method for determining the concentration of bedaquiline in the blood serum in patients with tuberculosis or mycobacteriosis is that whole blood samples are centrifuged at 3000 rpm for 20 minutes, then the blood plasma is collected in sterile 1.5 mL Eppendorf tubes, then 900 mcL of acetonitrile are added to 300 mcL of plasma and centrifuged at 13500g for 15 minutes, then 1 mL of the supernatant is transferred to a chromatographic vial and make the assay by UHPLC MS / MS using an Athena UHPLC C18, 1.8 mcM, 120A, 2.1×100 mm chromatography column, when using an aqueous solution containing 5 g / L of ammonium acetate, 25 ml / L of concentrated acetic acid, 2 ml / L trifluoroacetic acid as mobile phase A and 100% acetonitrile as mobile phase B, the concentration of bedaquiline is determined using a pre-plotted calibration curve.EFFECT: determination of bedaquiline in human blood plasma in a time not exceeding 6 minutes.1 cl, 9 dwg, 6 tbl

The invention provides a mycobacterium tuberculosis drug sensitivity kit and a method and application thereof, the drug sensitivity condition of mycobacterium tuberculosis to 12 drugs such as bedaquiline is detected based on a liquid method, the kit comprises a drug freeze-drying agent and an additive, the drug freeze-drying agent contains drugs, glucan, glycerol and valine, and the additive is a mixture of the drugs, the glucan, the glycerol and the valine. The additive is used for culturing mycobacterium tuberculosis, acetic acid is added to a non-water-soluble drug as a solvent, a cosolvent or a disintegrating agent is added to an indissolvable drug, and the prepared drug freeze-drying agent can be stored for a long time, can be redissolved only with water, and is good in redissolution stability, free of solvent residual toxicity and higher in drug stability and drug sensitivity detection accuracy. And meanwhile, the method also has better universality.

The present invention relates to pharmaceutical compositions for intramuscular or subcutaneous injection administration comprising microparticles of the anti-TB compound bedaquiline suspended in a pharmaceutically acceptable aqueous carrier, and to the use of such pharmaceutical compositions in the treatment and prevention of pathogenic mycobacterial infections.

The invention concerns a compound of formula (Ia) or (Ib) wherein R1 is hydrogen or a methyl group; R2 is an unsubsti- tuted or substituted alkyl group; R3 is an aryl group or a heteroaryl group, optionally substituted by one or more groups selected from halogen, alkyl or alkoxy; and, in Formula (Ia), X is CH or N and Y is NH, S or O, or, in Formula (Ib), X is NH, S or O and Y is CH or N. The invention further concerns a method of synthesiz- ing the inventive compound, a composition comprising the inven- tive compound or a pharmaceutically acceptable salt thereof and bedaquiline (BDQ), an analogue of bedaquiline (BDQ) or a mix- ture thereof, and the use of said composition or compound for the treatment of tuberculosis.

The present invention relates to a compound having the formula (Ia) or (Ib) wherein R1 is hydrogen or methyl; R2 is unsubstituted or substituted alkyl; R3 is aryl or heteroaryl, which is optionally substituted by one or more groups selected from halogen, alkyl or alkoxy; and, in formula (Ia), X is CH or N and Y is NH, S or O, or in formula (Ib), X is NH, S or O and Y is CH or N. The present invention further relates to a method for synthesizing the compounds of the present invention, a composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and bedaquiline (BDQ), an analogue of bedaquiline (BDQ) or a mixture thereof, and the use of said composition or compound for the treatment of tuberculosis.

The invention belongs to the technical field of biological medicines, and particularly relates to a group of synergists for anti-tuberculosis infection medicines and application of the synergists. In the invention, Vortioxetine (Vor) shows obvious activity for enhancing mycobacterium infection resistance: under the concentration of 2 mu g / mL, the MIC (minimal inhibitory concentration) of Bedaquiline to H37Rv can be reduced by about 64 times (from 0.06 mu g / mL to 0.0009375 mu g / mL), and the MIC of Bedaquiline to an Rv0678 mutant strain can be reduced by about 64 times (from 1 mu g / mL to 0.0156 mu g / mL). And the content of sertraline hydrochloride (STL) can be reduced by about 16 times and 8 times respectively. The synergistic effect of fluoxetine (FXT) is weakest and is only reduced by two times. The synergist disclosed by the invention is a drug which has been sold on the market, so that the synergist has safety and complete medication guidance. The preparation process and the production process are both perfect, the product can be quickly sold on the market, the selling price is reasonable, the market acceptability is good, and the patient compliance is high. The votioxetine or the sertraline can be used as a synergist of a medicine for resisting mycobacterium tuberculosis infection.

The application discloses a pyridine derivative, an intermediate, a preparation method and application. Specifically disclosed is a compound as shown in formula I or a pharmaceutically acceptable salt thereof. The pyridine derivative of the application can inhibit the growth of sensitive Mycobacterium tuberculosis, drug-resistant Mycobacterium tuberculosis, and in particular, bedaquiline drug-resistant strains, and has the advantages of longer elimination half-life in pharmacokinetics and higher safety.

The present invention relates to a co-administered formulation for alleviating anti-tuberculosis drug-induced toxicity comprising dead cells, and a pharmaceutical composition for preventing or treating tuberculosis comprising same. By co-administering Lactobacillus sakei CVL-001 or Lactobacillus reuteri NCHBL-005 as the dead cells with the anti-tuberculosis drug, the present invention exhibits excellent effects in alleviating drug toxicity (hepatotoxicity and nephrotoxicity) caused by the anti-tuberculosis drug, thereby increasing drug adherence of the anti-tuberculosis drug to obtain the effect of inhibiting the emergence of multidrug-resistant tuberculosis and recurrence of tuberculosis. In addition, the present invention can be used as an adjuvant for co-administration with drugs that have high efficacy despite significant side effects, such as bedaquiline or linezolid, with the expected effect of reducing the treatment period of tuberculosis, thereby being effectively used in the treatment process of tuberculosis.

The present invention belongs to the technical field of biopharmaceuticals and specifically relates to use of a pharmaceutical composition in combating mycobacterial infection. The use of zuclopenthixol in combination with bedaquiline exhibits significantly enhanced anti-mycobacterial infection activity. Compared to the use of bedaquiline alone, the use of 2 μg / ml zuclopenthixol in combination with bedaquiline results in varying reductions in colony counts of the MmpL5-MmpS5 strain when the concentration of bedaquiline ranges from 1 / 16 MIC to 2 MIC. As an enhancer of bedaquiline, zuclopenthixol can enhance the anti-mycobacterial infection activity of bedaquiline. The minimum inhibitory concentration of zuclopenthixol against the Rv0678 mutant strain in vitro is 16 μg / ml, and the minimum inhibitory concentration of BDQ against the Rv0678 mutant strain in vitro is 1 μg / mL. The use of 1 μg / ml zuclopenthixol in combination with BDQ reduces the MIC of BDQ against the Rv0678 mutant strain from 1 μg / ml to 0.03 μg / ml (a 32-fold increase in efficacy), which is lower than the MIC against the wild strain H37Rv (0.06 μg / ml), reversing resistance to BDQ and further enhancing the anti-mycobacterial infection activity.

The invention discloses a method for synthesizing (1R, 2S)-bedaquiline, belongs to the technical field of drug synthesis, and discloses a method for synthesizing (1R, 2S)-bedaquiline by using a chiral reagent (I) in a key reaction for synthesizing bedaquiline, the chiral reagent asymmetrically induces a reaction between 6-bromo-3-benzyl-2-methoxyquinoline (1) and 3-dimethylamino-1-naphthyl-1-acetone (2) to obtain a product (3), and the (1R, 2S)-bedaquiline is synthesized by using the product (3). The enantioselectivity of the reaction is improved, and the purpose of improving the overall yield is finally achieved. Reaction formula as follows: # imgabs0 #

The application discloses a kind of bichiral metal synergistic catalytic system and its application in asymmetric synthesis bedaquiline;Specifically: metal lithium, sodium or potassium salt and another metal salt form bichiral metal synergistic catalytic system under the action of suitable ligand and additive, promote 6-bromo-3-benzyl-2-methoxyquinoline (I) and 3-dimethylamino-1-naphthyl-1-propanone (II) addition reaction and regulate its selectivity, first with high yield and high selectivity to obtain target product (1R,2S)-bedaquiline.

The invention belongs to the technical field of biological medicine, and particularly relates to application of a combined synergistic pharmaceutical composition in resisting mycobacterial infection. The pimozide (PMZ) provided by the invention can be used as an active component and applied to the medicines for combined anti-mycobacterium tuberculosis, a new application of the PMZ is developed, the PMZ is combined with the anti-tuberculosis medicines (Bedaquiline BDQ, clofazimine CFZ and the like) to improve the anti-tuberculosis activity, the PMZ can be used as a synergist, the treatment course is expected to be shortened, the drug resistance is reduced, and a new treatment strategy is provided. The MIC (Minimum Inhibitory Concentration) of the mycobacterium tuberculosis sensitive bacterium H37Rv to the BDQ is reduced from 0.06 g / ml to 0.0038 g / ml (the synergy is 16 times) by combining the PMZ with the concentration of 0.5 g / ml with the BDQ; 0.5 g / ml of pimozide is combined with BDQ, so that the MIC (minimal inhibitory concentration) of the Rv0678 mutant strain on the BDQ is reduced from 1g / ml to 0.0313 g / ml (synergistic effect is 32 times) and is lower than that of a wild strain H37Rv MIC (0.06 g / ml), the drug resistance of the BDQ is reversed, and the activity of resisting mycobacterium infection is further enhanced. And the mycobacterium tuberculosis can be completely killed after the combination of 1.5 mu g / ml of PMZ and 0.03 mu g / ml of BDQ for 14 days.

The invention discloses a chiral catalysis method for synthesis of (1R, 2S)-bedaquiline, and belongs to the technical field of drug synthesis, in a key reaction for synthesis of bedaquiline, (I) a metal lithium salt and a chiral reagent are combined for use, and the catalyst catalyzes a reaction of 6-bromo-3-benzyl-2-methoxyquinoline (1) and 3-dimethylamino-1-naphthyl-1-acetone (2) to obtain a product (3). Therefore, the conversion rate and diastereoselectivity of the reaction are improved, and the purpose of improving the overall yield is finally achieved. Reaction formula as follows: # imgabs0 #

The present invention discloses a bimetallic synergistic catalytic system containing a chelating ligand and its application in the asymmetric synthesis of bedaquiline. Specifically, in the bimetallic synergistic catalytic system, a chelating ligand formed by a non-chiral secondary amine and lithium chiral amino alcohol increases the equilibrium constant of the reaction, promoting the addition reaction of 6-bromo-3-benzyl-2-methoxyquinoline (I) and 3-dimethylamino-1-naphthalen-1-yl-propan-1-one (II) to proceed in the forward direction, and this bimetallic synergistic catalytic system significantly improves the yield of the target product (1R,2S)-bedaquiline.

The invention provides a purification process for selectively removing (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline, which comprises the following steps: providing an organic solvent; the method comprises the following steps: adding a Bedaquiline isomer mixture into an organic solvent, the Bedaquiline isomer mixture comprising (1S, 2R)-Bedaquiline, (1R, 2S)-Bedaquiline, (1R, 2R)-Bedaquiline and (1S, 2S)-Bedaquiline, pulping the Bedaquiline isomer mixture at a preset temperature, and enriching (1R, 2R)-Bedaquiline and (1S, 2S)-Bedaquiline in a mother solution; (1R, 2R)-bedaquiline and (1S, 2S)-bedaquiline contained in the mother liquor are filtered out, (1S, 2R)-bedaquiline and (1R, 2S)-bedaquiline contained in a filter cake are recovered, and a target product is obtained. The process is simple, convenient and efficient, effectively improves the dr value of the product, and is suitable for industrial production.

The application discloses a method for preparing bedaquiline in a low-temperature continuous flow and a prepared product. The preparation method comprises the following steps: step S1: feeding liquid A and feeding liquid B to perform a first continuous flow reaction in a continuous flow to obtain reaction liquid D; step S2: feeding the reaction liquid D and feeding liquid C to perform a second continuous flow reaction in a continuous flow; the reaction residence time of the first continuous flow reaction is 30s-600s; the reaction residence time of the second continuous flow reaction is 30s-200s; and step S3: quenching. The preparation method has high yield, and through the method, the purity of the pure bedaquiline can be up to 99.8% or more after simple post-treatment of the crude product obtained by preparing bedaquiline.

This invention belongs to the field of biomedicine and specifically relates to the use of a combined synergistic pharmaceutical composition for the treatment of mycobacterial infections. Pimozide (PMZ) described in this invention can be used as an active ingredient in a combined anti-Mycobacterium tuberculosis drug, opening up new applications for PMZ. Combining PMZ with anti-tuberculosis drugs (such as bedaquiline (BDQ) and clofazimine (CFZ)) can enhance anti-tuberculosis activity. PMZ's use as a synergist is expected to shorten treatment courses and reduce drug resistance, representing a novel therapeutic strategy. The combination of PMZ (0.5µg / ml) and BDQ reduced the MIC of susceptible Mycobacterium tuberculosis strain H37Rv to BDQ from 0.06µg / ml to 0.0038µg / ml (a 16-fold increase in efficacy). The combination of pimozide (0.5µg / ml) and BDQ reduced the MIC of the Rv0678 mutant to BDQ from 1µg / ml to 0.0313µg / ml (a 32-fold increase in efficacy), which is lower than the MIC of wild-type H37Rv (0.06µg / ml). This reversed BDQ resistance and further enhanced anti-mycobacterial activity. A 1.5µg / ml PMZ combined with 0.03µg / ml BDQ treatment for 14 days completely killed Mycobacterium tuberculosis.

The invention provides application of bedaquiline in preparation of a medicine for preventing and / or treating leukemia, and belongs to the technical field of medicines. The invention provides an application of bedaquiline in preparation of a medicine for preventing and / or treating leukemia. In-vitro leukemia cell experiments show that the bedaquiline has an obvious inhibition effect on the proliferation of leukemia cells, the EC50 of the bedaquiline to human chronic myelogenous leukemia cells is 10.06 mu M, and the EC50 of the bedaquiline to human acute lymphoblastic leukemia cells is 11.15 mu M. Besides, the BDQ has no obvious influence on the survival rate of normal cells, and the BDQ is a marketed medicine and can be quickly applied to a clinical stage, so that unnecessary time waste is reduced, and a patient can be treated in time. The invention provides a new scheme for treatment of leukemia.

The invention belongs to the field of biological medicines, and particularly relates to application of dapinustat in preparation of a medicine for preventing and / or treating mycobacterium tuberculosis infection. In-vitro experiments prove that dapunostat has remarkable inhibitory activity on a mycobacterium tuberculosis standard strain, the minimum inhibitory concentration (MIC) is 1 mu g / mL, and the bactericidal effect of dapunostat under high bacterial load is superior to that of rifampicin. The dapinustat and the rifampicin have a synergistic effect. When dapunostat is combined with first-line antituberculosis drugs such as isoniazide, bedaquiline and ethambutol for use, drug effects are added. In addition, the dapunostat has no obvious toxicity to THP-1 human macrophages under an effective concentration. According to the invention, the new application of dapinustat in resisting mycobacterium tuberculosis is found for the first time, a brand new candidate drug and a drug combination scheme with known safety are provided for treatment of tuberculosis, especially drug-resistant tuberculosis, and the dapinustat has important clinical application value and development prospect.

The present invention provides a Mycobacterium tuberculosis drug susceptibility kit, a method, and an application thereof. The kit detects the drug susceptibility of Mycobacterium tuberculosis to 12 drugs, such as bedaquiline, based on a liquid method. The kit comprises a drug lyophilized agent and an additive. The drug lyophilized agent contains a drug, dextran, glycerol, and valine. The additive is used to culture Mycobacterium tuberculosis. Acetic acid is added as a solvent for water-insoluble drugs, and a cosolvent or disintegrant is added for poorly soluble drugs. The prepared drug lyophilized agent can be stored for a long time and can be re-dissolved with water only. The re-dissolution stability is good, there is no residual solvent toxicity, the drug stability and drug susceptibility detection accuracy are higher, and the kit also has better universality.

This invention relates to combinations for treating nontuberculous mycobacterial diseases. Specifically, it relates to combinations of bedaquiline, macrolides (e.g., clarithromycin), and optionally ethambutol for use in the treatment of diseases associated with nontuberculous mycobacteria (NTM).

The invention provides an application of (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-ketone in preparation of a medicine for treating or preventing drug-resistant mycobacterium tuberculosis infection, the MIC (minimal inhibitory concentration) of the (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-ketone to mycobacterium tuberculosis H37Rv, rifampicin drug-resistant strains, levofloxacin drug-resistant strains and bedaquiline drug-resistant strains is 2g / mL, and the MIC (minimal inhibitory concentration) of the (5R, 6E)-5-hydroxy-17-diphenyl-6-heptene-3-ketone to mycobacterium tuberculosis H37Rv, rifampicin drug-resistant strains, levofloxacin drug-resistant strains and bedaquiline drug-resistant strains is The core problem of tuberculosis with multiple drug resistance and wide drug resistance is solved, and an alternative treatment approach is provided.

This invention belongs to the field of biomedical technology, specifically relating to the application of a pharmaceutical composition in the fight against mycobacterial infections. The combination of juglottisol and bedaquiline significantly enhances the activity against mycobacterial infections. Compared to bedaquiline alone, 2 μg / ml of juglottisol combined with bedaquiline reduced the colony count of MmpL5-MmpS5 strains to varying degrees, from 1 / 16 MIC to 2 MIC of bedaquiline. Juglottisol, as an synergist of bedaquiline, enhances the anti-mycobacterial activity of bedaquiline. The minimum inhibitory concentration (MIC) of juglottisol against the Rv0678 mutant strain in vitro is 16 μg / ml, and the MIC of BDQ against the Rv0678 mutant strain in vitro is 1 μg / mL. The combination of 1 μg / ml zirconia thiazide and BDQ reduced the MIC of the Rv0678 mutant strain against BDQ from 1 μg / ml to 0.03 μg / ml (32-fold increase), which was lower than the MIC of the wild-type strain H37Rv (0.06 μg / ml), reversing BDQ resistance and further enhancing its activity against mycobacterial infections.

The invention discloses a method for selectively synthesizing Bedaquiline, belongs to the technical field of medicine synthesis, and relates to a method for selectively synthesizing Bedaquiline, in a key reaction for synthesizing Bedaquiline, (I) an alkaline metal lithium salt catalyst is used, and 6-bromo-3-benzyl-2-methoxyquinoline (1) and 3-dimethylamino-1-naphthyl-1-acetone (2) are catalyzed by the catalyst to react to obtain a product (3). Therefore, the conversion rate and diastereoselectivity of the reaction are improved, and the purpose of improving the overall yield is finally achieved. Reaction formula as follows: # imgabs0 #

The present invention relates to novel combinations, which are useful in the treatment of tuberculosis.

The invention provides a mycobacterium tuberculosis drug sensitivity kit and a preparation method and application thereof.The drug sensitivity condition of mycobacterium tuberculosis to 12 drugs such as bedaquiline is detected on the basis of an MGIT liquid method.The kit comprises a drug freeze-drying agent and an additive, the drug freeze-drying agent contains drugs, raffinose and glycerol, and the additive is a mixture of the drugs, the raffinose and the glycerol. The additive is used for culturing mycobacterium tuberculosis, acetic acid is added to a non-water-soluble drug as a solvent, a cosolvent or a disintegrating agent is added to an indissolvable drug, and the prepared drug freeze-drying agent can be stored for a long time, can be redissolved only with water, and is good in redissolution stability, free of solvent residual toxicity and higher in drug stability and drug sensitivity detection accuracy. And meanwhile, the method also has better universality.

The invention provides a purification process for selectively enriching (1R, 2S)-bedaquiline from a bedaquiline optical isomer mixture, which comprises the following steps: providing the bedaquiline optical isomer mixture; adding a mixed solvent formed by an organic solvent into the Bedaquiline optical isomer mixture, pulping at a preset temperature, and enriching (1R, 2S)-Bedaquiline in the mixed solvent. The process is simple, convenient and efficient, effectively improves the purity and yield of the target product, and is suitable for industrial production.

This invention discloses a bedaquiline hapten, antigen, antibody, and their preparation methods and applications, belonging to the field of small molecule immunoassay technology. This invention introduces a linker arm to the tertiary amine nitrogen atom in the N,N-dimethylpiperidinamine structure of the bedaquiline molecule's side chain via the Menschutkin reaction to form a quaternary ammonium salt. This chemical modification does not involve the core aromatic bicyclic system of bedaquiline, ensuring the preservation of the pharmacophore conformation, thus solving the technical bottleneck of the drug's inability to be detected immunoassay. The prepared antibody possesses high affinity and excellent specificity. Its application scenarios cover the entire monitoring system from central laboratories to bedside, home, and mobile follow-up, significantly improving the accessibility and adherence to precision treatment for tuberculosis.