WO2021047525A1 - Sel d'un composé de benzothiopyrone, son procédé de préparation et son utilisation - Google Patents

Sel d'un composé de benzothiopyrone, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2021047525A1
WO2021047525A1 PCT/CN2020/114126 CN2020114126W WO2021047525A1 WO 2021047525 A1 WO2021047525 A1 WO 2021047525A1 CN 2020114126 W CN2020114126 W CN 2020114126W WO 2021047525 A1 WO2021047525 A1 WO 2021047525A1
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Prior art keywords
cyclohexylmethyl
piperazin
nitro
benzothiopyran
trifluoromethyl
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PCT/CN2020/114126
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English (en)
Chinese (zh)
Inventor
李刚
黄海洪
李鹏
马辰
张婷婷
王宝莲
李燕
Original Assignee
中国医学科学院药物研究所
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Priority to CN202080070377.8A priority Critical patent/CN114929682B/zh
Publication of WO2021047525A1 publication Critical patent/WO2021047525A1/fr
Priority to ZA2022/03673A priority patent/ZA202203673B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis

Definitions

  • the invention belongs to the field of medical technology.
  • it relates to salts of benzothiopyrone compounds: 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8 represented by formula (I) -Nitro-benzothiopyran-4-one salt, its preparation method, pharmaceutical composition using the salt as an active ingredient, and their preparation for the treatment and/or prevention of infectivity caused by Mycobacterium tuberculosis Application of disease drugs.
  • Tuberculosis (Tuberculosis, TB) is a chronic fatal disease caused by Mycobacterium tuberculosis. It is a major infectious disease that endangers human health and causes human death. According to WHO estimates, there were approximately 1.7 billion people latently infected with tuberculosis worldwide in 2017, and the latent infection rate was 23%. There are about 10 million new cases of tuberculosis in the world, and about 1.4 million deaths. The incidence of tuberculosis is 133 per 100,000. Among them, children younger than 15 years old and HIV-infected people account for 10% and 9% of the new cases, respectively.
  • the unique cell wall of Mycobacterium tuberculosis has a multi-layered structure.
  • the biosynthetic pathways of these unique components are a rich source of potential drug targets.
  • the first-line drugs isoniazid and ethambutol act on mycolic acid and arabinan layers, respectively. Synthesis, interferes with the formation of the cell wall of Mycobacterium tuberculosis.
  • the main component of the arabinogalactan layer and arabinomannan layer of the outer membrane of Mycobacterium tuberculosis cell wall is a kind of arabinose with DPA as an important precursor. Studies have shown that DPA is mainly composed of DPR in DprE1 and DprE2.
  • Epimerization is obtained under the joint action, so inhibiting the activity of DprE1 can hinder the synthesis of cell wall and ultimately achieve the purpose of killing Mycobacterium tuberculosis two-step epimerization of decaprenylphosphoryl ribose. Journal of bacteriology 2005,187(23),8020-8025).
  • the benzothiopyrone core structure has been determined as the dominant skeleton and applied for Patent (Patent No.: 201810092333.X and PCT/CN2018/080787), through systematic and in-depth research, obtained the benzothiopyrone compound 6b(2) with significant anti-tuberculosis and drug-resistant tuberculosis activity and low toxicity -(4-(Cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one)(Identification of novel benzothiopyranone compounds against against Mycobacterium tuberculosis through scaffold morphing from benzothiazinones[J].Eur.J.Med.Chem.,2018,160,157-170).
  • Patent 201810092333.X and PCT/CN2018/080787 disclose 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyridine Examples of pyran-4-one and its hydrochloride salt, but no specific examples and experimental results of other pharmaceutically acceptable salts are disclosed.
  • the technical problem to be solved by the present invention is to provide a 2-(4-(cyclohexylmethyl)piperazin-1-yl) which has significantly improved pharmacokinetic properties and physical and chemical properties and has strong activity against Mycobacterium tuberculosis in vivo and in vitro.
  • Salt of 6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one The present invention found that the salt of 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one has Strong anti-Mycobacterium tuberculosis effect in vivo and in vitro.
  • the present invention provides the following technical solutions:
  • the first aspect of the technical scheme of the present invention provides 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzo represented by formula (I)
  • salt of 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one does not include salt Acid salt.
  • the salt of any one of the first aspect of the present invention is characterized in that it is 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-
  • the maleate, fumarate, citrate and L-malate of benzothiopyran-4-one is 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro- The maleate, fumarate, citrate and L-malate of benzothiopyran-4-one.
  • the salt of any one of the first aspect of the present invention is characterized in that it is 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro- Benzothiopyran-4-one ⁇ 1 maleate, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro- Benzothiopyran-4-one 1/2 maleate, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro -Benzothiopyran-4-one ⁇ 3/2 maleate; 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8 -Nitro-benzothiopyran-4-one ⁇ 1 fumarate, 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8 -N
  • the second aspect of the technical solution of the present invention provides a method for preparing the salt according to the first aspect of the present invention, which comprises the following steps:
  • the third aspect of the technical solution of the present invention provides a pharmaceutical composition, which comprises a therapeutically and/or preventively effective amount of a pharmaceutically acceptable salt of the compound according to the first aspect of the present invention, and optionally one or A variety of pharmaceutically acceptable carriers, excipients, diluents, excipients and vehicles.
  • the fourth aspect of the technical solution of the present invention provides a pharmaceutically acceptable salt of the compound of the first aspect of the present invention, or the pharmaceutical composition of the third aspect of the present invention is used in the preparation of treatment and/or prevention caused by Mycobacterium tuberculosis Application of medicines for infectious diseases.
  • room temperature refers to a temperature from 10°C to 40°C. In some embodiments, “room temperature” refers to a temperature from 20°C to 30°C; in other embodiments, room temperature refers to 25°C.
  • the term "effective amount” refers to the amount of a drug that can achieve the desired treatment of the disease or condition of the present invention in a subject.
  • the term "pharmaceutically acceptable”, for example, when describing “pharmaceutically acceptable salt”, means that the salt is not only physiologically acceptable to the subject, but also refers to a synthetic material that is of pharmaceutically useful value. substance.
  • composition can also refer to a “composition”, which can be used to achieve the treatment of the disease or condition of the present invention in a subject, especially a mammal.
  • the "treatment” of the disease includes:
  • a “therapeutically effective amount” refers to an amount of a compound that is sufficient to achieve treatment of the disease when administered to a mammal for the treatment of the disease.
  • the therapeutically effective amount will vary depending on the compound, the disease to be treated and its severity, and the mammal's age, weight, sex and other factors.
  • a therapeutically effective amount can also refer to any amount of the compound sufficient to achieve the desired beneficial effect, including the prevention, suppression or alleviation of diseases as described in (1)-(3) above.
  • the amount of compound may be between 0.1-250 mg/kg, or preferably, 0.5-100 mg/kg, or more preferably, 1-50 mg/kg, or even more preferably, 2-20 mg/kg.
  • the amount of the compound is administered to the mammal twice a day. More preferably, the amount of the compound is administered to the mammal once a day.
  • the term "disease and/or disorder” refers to a physical state of the subject, which physical state is related to the disease and/or disorder described in the present invention.
  • the diseases and/or conditions described in the present invention refer to infectious diseases of Mycobacterium tuberculosis.
  • the term "subject” may refer to a patient or other animal, particularly a mammal, that receives a salt of the compound of formula (I) of the present invention or a pharmaceutical composition thereof to treat the disease or condition of the present invention, for example People, dogs, monkeys, cows, horses, etc.
  • Another aspect of the present invention also relates to a pharmaceutical composition using the compound of the present invention as an active ingredient.
  • the pharmaceutical composition can be prepared according to methods known in the art.
  • the compound of the present invention can be combined with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants to prepare any dosage form suitable for human or animal use.
  • the compound of the present invention or the pharmaceutical composition containing it can be administered in unit dosage form, and the route of administration can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous injection, nasal cavity, oral mucosa, eye, Lung and respiratory tract, skin, vagina, rectum, etc.
  • the dosage form for administration may be a liquid dosage form, a solid dosage form or a semi-solid dosage form.
  • Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including water injections, powder injections and infusions), eye drops
  • the solid dosage form can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, aerosols, sprays, etc.; semi-solid dosage forms can be ointments, Gels, pastes, etc.
  • the compound of the present invention can be made into ordinary preparations, and can also be made into sustained-release preparations, controlled-release preparations, targeted preparations and various particulate drug delivery systems.
  • diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • wetting agent can be water, ethanol, Isopropanol, etc.
  • the binder can be starch syrup, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia syrup, gelatin syrup, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl Methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.
  • the disintegrant can be dry starch, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • the wetting agent can be water, ethanol, Isopropanol, etc.
  • the binder can be starch syrup, de
  • the tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.
  • the active ingredient of the compound of the present invention can be mixed with a diluent and a co-solvent, and the mixture can be directly placed in a hard or soft capsule.
  • the active ingredient of the compound of the present invention can also be prepared into granules or pellets with diluents, binders, and disintegrants, and then placed in hard or soft capsules.
  • the various diluents, binders, wetting agents, disintegrants, and cosolvents used to prepare the compound tablets of the present invention can also be used to prepare the compound capsules of the present invention.
  • solubilizers, cosolvents, pH regulators, and osmotic pressure regulators commonly used in this field can be added.
  • the solubilizer or co-solvent can be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.
  • the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.
  • the osmotic pressure regulator can be It is sodium chloride, mannitol, glucose, phosphate, acetate, etc.
  • mannitol, glucose, etc. can also be added as proppants.
  • coloring agents can also be added to the pharmaceutical preparations.
  • the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
  • the compound or composition of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs.
  • the compound of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.
  • the inventor of the present invention synthesized the salt of the compound represented by formula (I), and performed the minimum inhibitory concentration (MIC ) with M. tuberculosis H 37 Rv strain by the MABA (Microplate alamar blue assay) method.
  • the test showed strong anti-Mycobacterium tuberculosis activity.
  • 5 salts with MIC ⁇ 0.016 ⁇ g/mL were obtained, which was significantly stronger than isoniazid, the first-line anti-tuberculosis drug.
  • the maleate, fumarate, citrate and L-malate of the compound of formula (I) of the present invention are superior to the hydrochloride of the compound of formula (I) in cell permeability, indicating that the present invention Salt has better absorption properties.
  • mice showed that the bioavailability of the maleate and L-malate of the compound of formula (I) was significantly improved compared to that of the compound (I).
  • the results of rat pharmacokinetic experiments showed that compared with the compound of formula (I) and its hydrochloride, the maleate of the compound of formula (I) has significantly increased in vivo exposure (AUC) and bioavailability, which indicates that the present invention
  • the salt has better pharmacokinetic properties than the free base and hydrochloride.
  • In vivo pharmacodynamic experiments in mice showed that the maleate of the compound of formula (I) has stronger anti-tuberculosis activity in vivo than the compound of formula (I) at the same dose.
  • the test results of influencing factors show that the maleate of the compound of formula (I) is very stable when placed under light, high temperature and high humidity conditions for ten days, especially under light conditions, the stability is significantly better than that of compound (I), which indicates
  • the salt of the invention has a significant improvement in light stability.
  • the present invention provides a class of salts of benzothiopyrone compounds with strong anti-tuberculosis activity, significantly improved pharmacokinetic properties and physical and chemical properties, which can be used for infectious diseases caused by bacteria, especially tuberculosis branches.
  • the treatment or preventive treatment of tuberculosis caused by bacilli can also be used to overcome the problems related to drug resistance.
  • the structure of the compound was determined by proton nuclear magnetic resonance spectroscopy ( 1 H NMR).
  • the chemical shift ( ⁇ ) of the proton nuclear magnetic resonance spectrum is given in units of parts per million (ppm).
  • the coupling constant (J) is in Hertz (Hz).
  • the NMR spectrum was measured with a Mercury-400 nuclear magnetic resonance instrument, deuterated methanol (CD 3 OD) and deuterated dimethyl sulfoxide (DMSO-d 6 ) were used as solvents, and tetramethylsilane (TMS) was used as an internal standard.
  • the electronic balance adopts the Japanese Yanaco LY-300 electronic balance.
  • Anhydrous solvents are processed by standard methods.
  • Other reagents are commercially available analytical grade.
  • CFU is the colony forming unit
  • MIC is the minimum inhibitory concentration
  • iv is intravenous administration
  • AUC is the area under the drug concentration-time curve
  • T max is the peak time
  • MABA Microplate Alamar Blue Assay
  • Alamar Blue added to the culture medium can be used as a redox indicator, and the color changes from blue to red, reflecting the consumption of oxygen molecules by the studied microorganisms.
  • the color change of Alamar Blue can be measured with a photometer, and its emission wavelength is 590nm.
  • Caco-2 cells are human cloned colon adenocarcinoma cells, similar in structure and function to differentiated epithelial cells, with microvilli and other structures, and are widely used in vitro to simulate the penetration and absorption of drugs in the intestinal tract.
  • the apparent permeability coefficient (Papp) of the compound is calculated by the following formula:
  • dQ/dt is the permeation rate of drug molecules across the membrane
  • C 0 is the initial concentration of the drug
  • A is the area of the monolayer.
  • mice Male weighing 23-25 grams were used in each group for the pharmacokinetic study of compounds 1, 2, 3 and 5.
  • Compounds 1, 2, 3 and 5 were prepared as 5 mg/mL suspensions with 0.5% carboxymethyl cellulose, respectively, and were administered orally at a dose of 50 mg/kg.
  • Compounds 1, 2, 3 and 5 were prepared as 1 mg/mL solutions with 20% HP- ⁇ -CD and 1N hydrochloric acid, respectively, and were given a dose of 5 mg/kg intravenously.
  • Plasma samples were collected at 5, 15, 30 minutes, and 1, 2, 4, 7, and 24 hours after oral and intravenous administration. The collected plasma samples are stored at -80°C until used for analysis. Plasma samples were extracted with acetonitrile containing terfenadine internal standard, and the ratio of extractant to plasma was 20:1.
  • the analyte was quantified by LC/TSQ Quantum Access mass spectrometer (AB Sciex5500). Chromatographic conditions: Column: Kinetex C18 100A (30mm ⁇ 3.0mm, 2.6 ⁇ m); column temperature: room temperature, mobile phase: acetonitrile/water (80:20, v/v) (containing 0.1% formic acid); flow rate: 0.8mL /min.
  • the compound detection on the mass spectrometer is carried out in electrospray positive ionization mode.
  • the WinNonlin software (6.3Pharsight Corporation, Mountain View, USA) was used to calculate the pharmacokinetic parameters.
  • the bioavailability (F) of the compounds 1, 2, 3 and 5 of the present invention is 18.9-28.0%.
  • the bioavailability of the free base 6b (compound (I)) of compounds 1, 2, 3 and 5 reported in the comparative document (Eur. J. Med. Chem., 2018, 160, 157-170) is 13.1%.
  • the bioavailability of compounds 1, 2, 3 and 5 is improved, among which compounds 1 and 5 are increased by about 1 times, indicating that the compound of the present invention has better pharmacokinetic properties.
  • Compound 1 Compound (I) and its hydrochloride were prepared into a 5 mg/mL suspension with 0.5% carboxymethyl cellulose, respectively, and were administered orally at a dose of 50 mg/kg.
  • HP- ⁇ -CD hydroxypropyl- ⁇ -cyclodextrin
  • Plasma samples were collected 5, 15, 30 minutes after oral and intravenous administration, and 1, 2, 4, 7, 12, and 24 hours. The collected plasma samples are stored at -80°C until used for analysis. The WinNonlin software (6.3Pharsight Corporation, Mountain View, USA) was used to calculate the pharmacokinetic parameters.
  • Balb/c mice were infected with Mycobacterium tuberculosis H37Rv by aerosol, and were given drug treatment (25, 50, 100 mg/kg) 10 days after infection, once a day, 5 times a week, three weeks after the administration, Anatomy, with the lung CFU as the main evaluation index, a blank control group was set up to give 0.5% CMC, and the first-line clinical drug isoniazid was used as the positive control drug to investigate the anti-tuberculosis activity of compound (I) and compound 1 in vivo.
  • the CMC group is a blank control group, given 0.5% CMC.
  • test results show that compound (I) has strong anti-tuberculosis activity at doses of 25, 50 and 100 mg/kg, and the number of viable lung tissues in mice decreased by 2.28, 3.58 and 3.73 log 10 CFU respectively compared with the blank control group.
  • the CMC group is a blank control group, given 0.5% CMC.
  • test results show that compound 1 has strong anti-tuberculosis activity at doses of 25, 50 and 100 mg/kg, and shows a significant dose-effect relationship.
  • the number of viable lung tissues in mice decreased by 3.01, respectively, compared with the blank control group. 3.99 and 4.68 log 10 CFU.
  • compound 1 of the present invention can reduce Log 10 CFU values more than compound (I) at doses of 25, 50 and 100 mg/kg, especially at doses of 100 mg/kg. Compared with the blank control group, compound 1 can reduce 4.68 Log 10 CFU, which is significantly better than compound (I) (reducing 3.73 Log 10 CFU), indicating that compound 1 has stronger anti-tuberculosis activity in vivo.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
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  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention relève du domaine technique de la médecine, et concerne un sel d'un composé de benzothiopyrone, son procédé de préparation et son utilisation, en particulier, un sel de 2-(4-(cyclohexylméthyl)pipérazin-1-yl)-6-(trifluorométhyl)-8-nitro-benzothiopyran-4-one tel que représenté par la formule (I), son procédé de préparation, une composition pharmaceutique de celui-ci, et une utilisation associée dans la préparation d'un médicament pour le traitement et/ou la prévention d'une maladie infectieuse provoquée par Mycobacterium tuberculosis. La présente invention vise à préparer un sel de 2-(4-(cyclohexylméthyl)pipérazin-1-yl)-6-(trifluorométhyl)-8-nitro-benzothiopyran-4-one ayant des propriétés pharmacocinétiques et physico-chimiques significativement améliorées et ayant une forte activité contre Mycobacterium tuberculosis in vivo et in vitro ; en tant que nouveau médicament potentiel, le sel peut être utilisé pour le traitement ou le traitement préventif d'une maladie infectieuse provoquée par des bactéries, en particulier la tuberculose (TB) provoquée par Mycobacterium tuberculosis, et peut également être utilisé pour surmonter un problème lié à la résistance aux médicaments de Mycobacterium tuberculosis.
PCT/CN2020/114126 2019-09-09 2020-09-09 Sel d'un composé de benzothiopyrone, son procédé de préparation et son utilisation WO2021047525A1 (fr)

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CN202080070377.8A CN114929682B (zh) 2019-09-09 2020-09-09 苯并硫代吡喃酮类化合物的盐及其制备方法和用途
ZA2022/03673A ZA202203673B (en) 2019-09-09 2022-03-30 Salt of benzothiopyrone compound, and preparation method therefor and application thereof

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CN201910849215.3A CN112457291B (zh) 2019-09-09 2019-09-09 苯并硫代吡喃酮类化合物的盐及其制备方法和用途
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Cited By (1)

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Publication number Priority date Publication date Assignee Title
EP4296674A1 (fr) 2022-06-20 2023-12-27 Université Toulouse III - Paul Sabatier Molécules innovantes réduisant la virulence des mycobactéries pour le traitement de la tuberculose

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Publication number Priority date Publication date Assignee Title
EP4296674A1 (fr) 2022-06-20 2023-12-27 Université Toulouse III - Paul Sabatier Molécules innovantes réduisant la virulence des mycobactéries pour le traitement de la tuberculose

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