17 results about "Bedaquiline" patented technology

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 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 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 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 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 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 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).

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 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.

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.

The invention discloses a method for recovering chiral phosphoric acid from bedaquiline waste liquid, which belongs to the technical field of waste liquid recovery, and comprises the following steps: (1) separating enantiomers and chiral phosphate: recovering bedaquiline resolution mother liquid under reduced pressure, and separating the liquid to obtain an organic phase containing the enantiomers and a water phase containing the chiral phosphate; (2) enantiomer recovery: recovering the organic phase in the step (1) under reduced pressure, crystallizing, filtering and drying to obtain the enantiomer; (3) dissociating chiral phosphoric acid: combining the water phase obtained in the step (1) with a water phase generated in the dissociation process of bedaquiline, adjusting the pH value to be acidic, adding diatomite for adsorption, and filtering to obtain a filter cake; and (4) recovering the chiral phosphoric acid: adding tetrahydrofuran and water into the filter cake, stirring, dispersing, crystallizing, filtering and drying to obtain the chiral phosphoric acid. According to the method, chiral phosphoric acid contained in the bedaquiline waste liquid can be effectively recovered, the production cost is greatly reduced, and high economic benefits are achieved.

The invention discloses a synthesis method of a Bedaquiline enantiomer impurity, and relates to the technical field of drug synthesis, the enantiomer impurity (1S, 3S) with chiral purity up to 99% or more and related substance purity up to 99% or more is obtained by using four configurations of mixed rotation Bedaquiline (SS / RR / SR / RS) as a raw material through resolution and purification. The preparation method comprises the following steps: preparing (2R, 2R)-1-(6-bromo-2-methoxyquinoline-3-yl)-4-(dimethylamino)-2-(naphthalene-1-yl)-1-phenylbutyl-2-ol; the method is convenient to operate, extremely low in experiment danger coefficient and low in environmental pollution, and the obtained sample is high in purity and low in cost.

The invention concerns a compound of formula (Ia) or (Ib) wherein R1 is hydrogen or a methyl group; R2 is an unsubstituted 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 synthesizing the inventive compound, a composition comprising the inventive compound 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.