WO2016187521A1 - Composés de 1h-tétrazole substitué en position 5, procédés de synthèse et utilisation thérapeutique - Google Patents

Composés de 1h-tétrazole substitué en position 5, procédés de synthèse et utilisation thérapeutique Download PDF

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Publication number
WO2016187521A1
WO2016187521A1 PCT/US2016/033493 US2016033493W WO2016187521A1 WO 2016187521 A1 WO2016187521 A1 WO 2016187521A1 US 2016033493 W US2016033493 W US 2016033493W WO 2016187521 A1 WO2016187521 A1 WO 2016187521A1
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tetrazole
antibiotic
tetrazole compound
substituted
tetrazol
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PCT/US2016/033493
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English (en)
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Adiel COCA
Elizabeth Lewis ROBERTS
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South Connecticut State University
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/713—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with four or more nitrogen atoms as the only ring hetero atoms
    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates generally to 5-substituted 1 H-tetrazole compounds and, more specifically, to 5-substituted 1 H-tetrazole compounds with antimicrobial properties, methods of synthesizing same, and therapeutic uses of same.
  • An embodiment of the present invention provides a pharmaceutical formulation that includes an antibiotic tetrazole 5-substituted 1 /-/-tetrazole compound in an amount sufficient to treat a bacterial infection, the antibiotic tetrazole compound being selected from the group consisting of: an aryl compound, a heteroaryl tetrazole compound, a vinyl tetrazole compound, and a benzylic tetrazole compound.
  • An embodiment of the present invention provides a method of treating a bacterial infection in a subject.
  • the method includes administering an antibiotic 5- substituted 1 /-/-tetrazole compound in an amount sufficient to treat a bacterial infection, the antibiotic tetrazole compound being selected from the group consisting of: an aryl compound, a heteroaryl tetrazole compound, a vinyl tetrazole compound, and a benzylic tetrazole compound.
  • An embodiment of the present invention provides a method of synthesizing an antibiotic tetrazole compound.
  • the method includes forming a mixture of an azide, an organonitrile, a catalyst, and a solvent and heating the mixture at a temperature of about 100-160 °C for about 30 minutes to 4 hours to synthesize the antibiotic tetrazole compound.
  • aspects of the invention are directed to pharmaceutical formulations of one or more tetrazole compounds described herein having antibiotic activity.
  • Tetrazoles are a class of heterocycles and have the ability to hold large amounts of energy. Compared to carboxylic acids, tetrazole compounds are more lipophilic (i.e., increased biological absorption), more metabolically stable, and bind anions better. Tetrazole compounds are more suitable for cell penetrance than carboxylates due to their higher pKa.
  • Embodiments of the present invention are directed to a method of synthesizing 5-substituted 1 /-/-tetrazole compounds.
  • Tetrazole compounds may be synthesized through a [2 + 3] cycloaddition of an azide and a nitrile.
  • Equation 1 cycloaddition of an organonitrile with sodium azide is shown below in Equation 1.
  • sodium azide e.g., 1 -3 equivalent
  • an organonitrile e.g., 2 mmol, 1 equivalent
  • a rare-earth or post-transitional metal catalyst e.g., 0.1 -0.5 equivalent
  • a solvent e.g. 8 ml_
  • the reaction may occur in a microwave reactor.
  • the reaction may be heated at about 100- 160 °C for about 30 minutes to 4 hours.
  • the product may be extracted by addition of a saturated aqueous sodium bicarbonate solution (e.g., 15 ml_).
  • the aqueous layers may be washed twice with ethyl acetate (e.g. , 15 ml_) and subsequently acidified with a concentrated hydrochloric acid solution.
  • An extraction may be performed twice using ethyl acetate (e.g., 15 ml_ x 2).
  • the organic layers may be combined and dried with anhydrous sodium sulfate.
  • the tetrazole compound may then be concentrated by rotary evaporation using reduced pressure.
  • the azide and nitrile used in the synthesis of the 5-substituted 1 /-/-tetrazole compounds may vary based on the intended application. Both organic and inorganic azides can violently decompose with little input of energy making them heat and shock sensitive. These considerations may be minimized through the use of azides wherein the total number of nitrogen atoms does not exceed the number of carbon atoms.
  • the azide may include, without limitation, sodium, tin, silicon, and organoaluminum azides.
  • Exemplary nitriles include, without limitation, para-substituted aryl nitriles, heteroaryl nitriles, vinyl nitriles, benzylic nitriles, and aliphatic nitriles.
  • the solvent may be an aprotic polar solvent, such as dioxane, dichloromethane (DCM), tetrahydrofuran (THF), or dimethylformamide (DMF), or a protic polar solvent, such as an isopropanol/water mixture.
  • the catalyst may include, for example, rare earth metal catalysts and post-transitional metal catalysts.
  • Exemplary catalysts include, without limitation, zinc salts, ytterbium triflate (Yb(OTf) 3 ), indium chloride (lnCI 3 ), indium triflate (ln(OTf) 3 ), cerium chloride (CeCI 3 ), scandium triflate (Sc(OTf) 3 ), bismuth chloride (BiCI 3 ), bismuth triflate (Bi(OTf) 3 ), and iron trichloride (FeCI 3 ).
  • Yb(OTf) 3 ytterbium triflate
  • indium chloride lnCI 3
  • indium triflate ln(OTf) 3
  • cerium chloride CeCI 3
  • Sc(OTf) 3 scandium triflate
  • BiCI 3 bismuth chloride
  • Bi(OTf) 3 bismuth triflate
  • FeCI 3 iron trichloride
  • the yield percentage for a given synthesis reaction may vary depending on the catalyst used.
  • compositions may vary based on the intended application.
  • Exemplary 5-substituted 1 H-tetrazole compounds include, without limitation, aryl, heteroaryl, vinyl, benzylic, and aliphatic tetrazole compounds.
  • Exemplary tetrazole compounds include, but are not limited to: 5-(4-nitrobenzo)-1 H-tetrazole (1 a), 1 - (4(1 H-tetrazol-5-yl)phenyl)ethan-1 -one (1 b), 5-(4-bromobenzo)-1 H-tetrazole (1 c), 1 ,4-di(1 H-tetrazol-5-yl)benzene (1 d), 3-(1 H-tetrazol-5-yl)pyrrole (1 e), 4-(1 H-tetrazol- 5-yl)isoquinoline (1f), (E)-1 ,2-di(1 H-tetrazol-5-yl)ethene (1 g), and phenyl(1 H-tetrazol
  • Additional exemplary tetrazole compounds include: 5-(4-chlorophenyl)- 1 H-tetrazole (1 i), 5-(4-methoxyphenyl)-1 H-tetrazole (1j), 5-phenyl-1 H-tetrazole (1 k), phenyl(1 H-tetrazol-5-yl)methanone (1 1), 5-(thiophen-3-yl)-1 H-tetrazole (1 m), and 5- (furan-2-yl)-1 H-tetrazole (1 n).
  • the structural formulas for these compounds are shown below.
  • a pharmaceutical formulation includes, in addition to the one or more tetrazole compounds, one or more additional antibiotic compounds.
  • the combination of the one or more tetrazole compounds with one or more additional antibiotic compounds may result in a synergistic effect on the antimicrobial properties of the combination.
  • additional antibiotic compounds include, without limitation, amoxicillin trihydrate, sulfamethoxazole, and trimethoprim.
  • the mass ratio of the tetrazole compound to the antibiotic compound may be about 1 : 1 , 2: 1 , or 1 :2, although other ratios may be used.
  • aspects of the invention are directed to methods of treating a subject for a bacterial infection with pharmaceutical formulations that include one or more antibiotic tetrazole compounds.
  • the antibiotic tetrazole compound may be a 5- substituted 1 H tetrazole compound as described herein.
  • aspects of the invention are directed to methods of treating a subject for a bacterial infection with pharmaceutical formulations that include one or more antibiotic tetrazole compounds in combination with one or more additional antibiotic compounds.
  • the one or more antibiotic 5- substituted 1 H tetrazole compounds are administered in a dose that achieves levels of the one or more antibiotic tetrazole compounds and/or their active metabolites at the sight of the infection to levels sufficient to have an antibiotic effect to treat and prevent bacterial infections.
  • An antibiotic effect means that the growth of the microorganisms is inhibited.
  • the method includes
  • tetrazole/antibiotic combination may range from 0.1 mg/kg per day to 1 g/kg per day or from 1 -100 mg/kg per day.
  • the pharmaceutical formulations may be administered by standard routes, such as by injection, orally, topically, and transdermally. Accordingly, pharmaceutical formulations may be in a form suitable for the desired route of administration. For example, the pharmaceutical formulations may be dissolved in a liquid for injection, formed into pills or filled into capsules for oral administration, or suspended in an ointment for topical or transdermal administration.
  • pharmaceutical formulation may include additional additives pharmaceutically acceptable for the desired route of administration.
  • the reaction was monitored by TLC using an ether/hexane mixture (typically 50/50) for development. After cooling, the reaction mixture was diluted with saturated aqueous sodium bicarbonate (20 mL) and washed with ethyl acetate (2 x 15 mL). The aqueous sodium bicarbonate layer was cooled to 0 °C and acidified to a pH of 2 or less with concentrated hydrochloric acid, which was added drop-wise. The precipitate formed was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried with anhydrous sodium sulfate and decanted into a tared round bottom flask. The organic layer was concentrated under reduced pressure. The tetrazole product was recrystallized from ethyl acetate and hexane. All reagents mentioned above were used unpurified.
  • NMR Spectra NMR Spectra. NMR spectra were acquired on a spectrometer at 300 MHz for 1 H and 75 MHz for 13 C acquisitions. All 1 H NMR spectra were taken in DMSO-d6 using DMSO as a standard at 2.52 ppm. All 13 C NMR spectra were taken in DMSO-d6 using DMSO as a standard at 40.45 ppm. An IR spectrum was obtained using an FTIR spectrophotometer. A melting point was also obtained for the solid products. 1 -(4(1 /-/-Tetrazol-5-yl)phenyl)ethan-1 -one (1 b) is a white solid.
  • 1 -(4(1 /-/-tetrazol-5-yl)phenyl)ethan-1-one (1 b) were investigated against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa.
  • Compound 1 b was screened for antimicrobial activity by a modified Kirby-Bauer assay.
  • Compound 1 b was dissolved in DMSO at concentration of 0.1 mg/mL.
  • 10 ⁇ _ of the solution was placed on a nutrient agar plate streaked with a lawn of bacteria of S. aureus (ATTC 27661 ), E. coli (ATCC 14948), or P.
  • aeruginosa ATCC 27853
  • Bioactivity was determined after incubating each plate at 37 °C for 24 hours. A lack of bacterial growth where a tetrazole solution was placed was taken as a sign of bioactivity. Because 1 -(4(1 /-/-tetrazol-5-yl)phenyl)ethan-1 -one (1 b) was found to be active, it was dissolved in a 20% DMSO in nutrient broth at an initial concentration of 10 mg/mL. The tetrazole standard solution was serially diluted with nutrient broth in glass tubes to make solutions with concentrations of 1000, 500, 250, 125, 62.5, 31 .3, 15.6, 7.81 , and 3.91 ⁇ g/mL.
  • a solution without any tetrazole present was also prepared. Each solution was inoculated with 10 ⁇ _ of an overnight culture of one of the previously mentioned strains of bacteria. After 24 h of incubation at 37 °C, the minimum inhibitory concentration (MIC) for the 1 b compound was determined as the concentration of the test substance, which completely inhibited the growth of the microorganism (solution was 100% transparent).
  • MIC minimum inhibitory concentration
  • Heteroaryl tetrazole compounds i.e., tetrazole compounds attached to heteroaromatic rings
  • several vinyl, benzylic, and aliphatic tetrazole compounds were prepared using the same method. Vinyl, benzylic, and aliphatic tetrazoles are generally slower reacting than aryl tetrazoles.
  • tetrazole compounds gave relatively high yields, while others were obtained in yields of less than 50%.
  • tetrazole products corresponding to 4- bromothiopene-2-carbonitrile, 3-bromobenzonitrile, 5-bromo-3-cyanopyridine and 4- cyanobenzaldehyde afforded yields of 84%, 82%, 84% and 79%, respectively.
  • MIC Minimum Inhibitory Concentration
  • Table 1 shows the MIC ⁇ g/mL) values for the 5-substituted 1/-/- tetrazole compounds: 5-(4-nitrobenzo)-1/-/-tetrazole (1a), 1-(4(1/-/-tetrazol-5- yl)phenyl)ethan-1-one (1b), 5-(4-bromobenzo)-1/-/-tetrazole (1c), 1 ,4-di(1 --tetrazol- 5-yl)benzene (1d), 3-(1 /-/-tetrazol-5-yl)pyrrole (1e), 4-(1/-/-tetrazol-5-yl)isoquinoline (1f), (E)-1,2-di(1H-tetrazol-5-yl)ethene (1g), phenyl(1H-tetrazol-5-yl)methanol (1h), 5- (4-chlorophenyl)-1/-/-tetrazole (1i), 5-(
  • MIC Minimum Inhibitory Concentration
  • Tetrazole/ Antibiotic Combinations The eight most active tetrazole compounds from Example 2 were tested in 1 : 1 by weight combinations with one of trimethoprim, amoxicillin trihydrate, or sulfamethoxazole.
  • the eight tetrazole compounds include: 5-(4-nitrobenzo)-1 /-/-tetrazole (1 a), 1 -(4(1 /-/-tetrazol-5-yl)phenyl)ethan-1 -one (1 b), 5- (4-bromobenzo)-1 H-tetrazole (1 c), 1 ,4-di(1 H-tetrazol-5-yl)benzene (1 d), 3-(1 H- tetrazol-5-yl)pyrrole (1 e), 4-(1 /-/-tetrazol-5-yl)isoquinoline (1f), (E)-1 ,2-di(1 /-/-tetrazol- 5-yl)eth
  • trimethoprim combinations with compounds 1 b, 1 c, and 1 d also seemed to show a synergistic effect against Gram-positive S. aureus with MIC values as low as 3.91 ⁇ g/mL, which was similar to the MIC value obtained for the
  • trimethoprim (1 /-/-tetrazol-5-yl)isoquinoline (1f) and trimethoprim showed MIC values of 7.81 ⁇ g/mL against S. aureus and E. coli.
  • Trimethoprim with 1 ,2-di-1 /-/-tetrazole ethene (1 g) performed well against E. coli showing a MIC value of 0.98 ⁇ g/mL against E. coli and moderately against S. aureus with a MIC value of 125 ⁇ g/mL.
  • Phenyl(1 /-/-tetrazol-5-yl)methanol (1 h) was active against E coli at a concentration of 62.5 ⁇ g/mL when used with trimethoprim.
  • a combination of phenyl (1 /-/-tetrazol-5- yl)methanol (1 h) and amoxicillin trihydrate showed inhibition of E. coli with a MIC value of 31 .3 ⁇ g/mL but was not very active when evaluated in conjunction with sulfamethoxazole. None of the tetrazoles tested, whether or not in combination with trimethoprim, significantly inhibited the growth of Gram-negative P. aeruginosa.
  • Sulfonamide drugs such as sulfamethoxazole, possess antibacterial activity because they compete with p-aminobenzoic acid for the enzyme dihydropteroate synthase and, therefore, interrupt the biosynthesis of tetrahydrofolate in bacteria.
  • 5-substituted aryl 1 /-/-tetrazoles without a p-amino group could potentially serve as structural analogs of sulfonamides.

Abstract

L'invention concerne une formulation pharmaceutique comprenant un composé de 1H-tétrazole substitué en position 5 antibiotique en une quantité suffisante pour traiter une infection bactérienne, le composé de 1H-tétrazole substitué en position 5 antibiotique étant choisi dans le groupe constitué de : un composé d'aryltétrazole, un composé d'hétéroaryltétrazole, un composé de vinyltétrazole et un composé de tétrazole benzylique. L'invention concerne un procédé de synthèse d'un composé 1H-tétrazole substitué en position 5 antibiotique, qui comprend la formation d'un mélange d'un azoture, d'un organonitrile, d'un catalyseur et d'un solvant et le chauffage du mélange à une température d'environ 100 à 160 °C pendant environ 30 minutes à 4 heures pour synthétiser le 1H-tétrazole substitué en position 5 antibiotique.
PCT/US2016/033493 2015-05-21 2016-05-20 Composés de 1h-tétrazole substitué en position 5, procédés de synthèse et utilisation thérapeutique WO2016187521A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112047896A (zh) * 2020-10-12 2020-12-08 上海麦克林生化科技有限公司 芳环基或芳杂环基四氮唑的合成方法
US11459296B2 (en) 2018-05-16 2022-10-04 Infex Therapeutics Limited Antibacterial compounds
US11634391B2 (en) 2018-08-31 2023-04-25 Ucl Business Ltd Compounds which are inhibitors of Notum

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US4647572A (en) * 1982-10-29 1987-03-03 Meiji Seika Kaisha, Ltd. Iodoallyl and iodopropargyl substituted tetrazoles and anti-microbial compositions thereof
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Title
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11459296B2 (en) 2018-05-16 2022-10-04 Infex Therapeutics Limited Antibacterial compounds
US11845725B2 (en) 2018-05-16 2023-12-19 Infex Therapeutics Limited Antibacterial compounds
US11634391B2 (en) 2018-08-31 2023-04-25 Ucl Business Ltd Compounds which are inhibitors of Notum
CN112047896A (zh) * 2020-10-12 2020-12-08 上海麦克林生化科技有限公司 芳环基或芳杂环基四氮唑的合成方法
CN112047896B (zh) * 2020-10-12 2022-06-17 上海麦克林生化科技有限公司 芳环基或芳杂环基四氮唑的合成方法

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