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WO2017177828A1 - Nouveau dérivé d'oxazolidinone-fluoroquinolone et ses utilisations - Google Patents

Nouveau dérivé d'oxazolidinone-fluoroquinolone et ses utilisations Download PDF

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WO2017177828A1
WO2017177828A1 PCT/CN2017/078798 CN2017078798W WO2017177828A1 WO 2017177828 A1 WO2017177828 A1 WO 2017177828A1 CN 2017078798 W CN2017078798 W CN 2017078798W WO 2017177828 A1 WO2017177828 A1 WO 2017177828A1
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methyl
oxo
fluoro
hydroxymethyl
carboxylic acid
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李靖
崔海峰
吕鹏月
戴宝华
裴玉宁
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    • 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
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/06—Peri-condensed 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines having two or more nitrogen atoms in the same ring, e.g. oxadiazines
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/14—Ortho-condensed systems

Definitions

  • the present invention relates to the use of a novel class of oxazolidinone-fluoroquinolone derivatives and pharmaceutical compositions thereof for preventing or treating infections, such as bacterial infections.
  • the compounds of the present invention are effective antimicrobial agents which are effective against a variety of human and animal pathogens, including Gram-positive bacteria, Gram-negative bacteria, Anaerobic microorganisms and acid-resistant microorganisms.
  • MRSA methicillin-resistant Staphylococcus aureus
  • VRE vancomycin-resistant enterococci
  • antibiotic-associated diarrhea AAD
  • PMC pseudomembranous colitis
  • Clostridium difficile is the most important infectious agent in antibiotic-associated diarrhea.
  • the diarrhea caused by it is collectively called C. difficile-associated diarrhea (CDAD), which accounts for 20-30% of antibiotic-associated diarrhea. 90% of pseudomembranous colitis.
  • CDAD C. difficile-associated diarrhea
  • the compound disclosed in the present invention not only exhibits high inhibitory activity against common pathogenic bacteria, but also has unexpected inhibition on super-resistant bacteria resistant to methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Activity, and more importantly, this compound also has a high inhibitory effect on C. difficile, which is of great significance for patients with CDAD, especially patients with MRSA or VRE in the hospital, providing a very effective treatment. .
  • the invention relates to a compound of formula I or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof:
  • n 0, 1, 2, 3;
  • C is phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, which is independently substituted by one or more groups, wherein the substituent is selected from the group consisting of F, Cl, Br, C 1-8 alkyl;
  • X is O, S, SO, SO 2 , NR 3 , -CH(R 4 )CH 2 -, -CH(R 4 )-;
  • Y is NR 5 , -CH 2 -, -CH(R 6 )CH 2 -, -CH(R 6 )-;
  • R 1 is H or NH 2 ;
  • R 3 is H, C 1-8 alkyl
  • R 4 is H, F, Cl, Br, OR 7 , S R 7 , NR 7 R 8 , C 1-8 alkyl;
  • R 5 is H, C 1-8 alkyl
  • R 6 is H, F, Cl, Br, OR 9 , S R 9 , NR 9 R 10 , C 1-8 alkyl;
  • R 7 is H, C 1-8 alkyl
  • R 8 is H, C 1-8 alkyl
  • R 9 is H, C 1-8 alkyl
  • R 10 is H, C 1-8 alkyl
  • n 0, 1, 2, 3;
  • A is O, S, SO, SO 2 , NR 3 , -CH(R 4 )CH 2 -, -CH(R 4 )-;
  • B is O, S, SO, SO 2 , NR 5 , -CH(R 6 )CH 2 -, -CH(R 6 )-;
  • C is phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, which is independently substituted by one or more groups, wherein the substituent is selected from the group consisting of F, Cl, Br, C 1-8 alkyl;
  • Z is N, CR 11 ;
  • R 2 is H or NH 2 ;
  • R 3 is H, C 1-8 alkyl
  • R 4 is H, F, Cl, Br, OR 7 , S R 7 , NR 7 R 8 , C 1-8 alkyl;
  • R 5 is H, C 1-8 alkyl
  • R 6 is H, F, Cl, Br, OR 9 , S R 9 , NR 9 R 10 , C 1-8 alkyl;
  • R 7 is H, C 1-8 alkyl
  • R 8 is H, C 1-8 alkyl
  • R 9 is H, C 1-8 alkyl
  • R 10 is H, C 1-8 alkyl
  • R 11 is H, C 1-8 alkyl.
  • the compounds of formula I may contain one or more stereosymmetric centers or asymmetric centers, such as one or more asymmetric carbon atoms.
  • the compounds of the formula I can therefore be present in the form of a mixture of stereoisomers or preferably in the form of pure stereoisomers. Stereoisomeric mixtures can be isolated in a manner known in the art.
  • the number of carbon atoms in the hydrocarbon moiety referred to herein is named by a prefix containing the smallest number and the largest number of carbon atoms.
  • an alkyl group prefixed with Cab exhibits an alkyl group having from a to b carbon atoms.
  • C 1-8 represents an alkyl group having 1-8 carbon atoms.
  • alkyl refers to a saturated straight or branched alkyl group containing from 1 to 10 carbon atoms and preferably from 1 to 8 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl Base, n-hexyl and iso-hexyl.
  • Any alkyl group as defined herein may be substituted with one or more substituents, for example 2 substituents F, Cl, Br, I, NH 2, OH, SH or NO.
  • “Pharmaceutically acceptable” as used in the present invention means that a carrier, carrier, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients which constitute a pharmaceutical dosage form. And is physiologically compatible.
  • salts and “pharmaceutically acceptable salt” refer to a compound of the formula I or II or a stereoisomer thereof, or an organic or inorganic salt thereof. These salts may be obtained directly in the final isolation and purification of the compound, or by reacting a compound represented by I or II or a stereoisomer thereof, or a prodrug thereof, respectively, using a suitable organic or inorganic acid or base. The salt is then isolated.
  • Commonly used salts include, for example, hydrobromide, hydrochloride, sulfate, hydrogen sulfate, nitrate, acetate, oxalate, besylate, palmitate, hard acid, monthly silicate , borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthate, methanesulfonate, Gluconate, lactobionate, dodecyl sulfonate and other similar salts.
  • salts may also include salts formed by reaction with alkali or alkaline earth metals, such as lithium, sodium, potassium, magnesium or calcium salts, or ammonium salts, or organic base salts such as methylamine, dimethylamine, trimethylamine, triethylamine. a salt of ethylenediamine, ethanolamine, meglumine, tris-(2-hydroxyethyl)amine, choline hydroxide, piperidine, morpholine, lysine or arginine. Further examples are found in the references of this patent, Berge, et al., J. Pharm. Sci., 66, 1-19 (1977).
  • a salt of the compound of the formula I or II can be obtained by suitably mixing a solution of the compound of the formula I or II with a desired acid or base. These salts may form a precipitate in the solution, may be collected by filtration, or may be recovered after evaporation of the solvent.
  • the compound of formula I or II may exist in unsolvated as well as solvated forms of a pharmaceutically acceptable solvent such as water, ethanol, and the like, and it is contemplated that the invention encompasses all solvated and unsolvated forms.
  • Prodrug means a compound that is a prodrug that releases the active drug in vivo by a chemical or physiological process (eg, by placement at physiological pH or by enzymatic action) after administration to the subject.
  • a chemical or physiological process e.g. by placement at physiological pH or by enzymatic action
  • Prodrugs may also include metabolic precursors of the compounds of the invention, which may not be active when administered to a subject, but may be converted in vivo to a compound of the invention. Prodrugs can also be naturally occurring or chemically synthesized compounds.
  • One embodiment of the invention comprises a group of compounds of formula I or II, the compounds of which are structurally characterized by:
  • C is phenyl or pyridyl optionally substituted by one or more groups, wherein the substituent is selected from the group consisting of F, Cl, Br, C 1-8 alkyl;
  • X is O, S, SO, SO 2 , NR 3 , -CH(R 4 )CH 2 -, -CH(R 4 )-;
  • Y is NR 5 , -CH(R 6 )CH 2 -, -CH(R 6 )-;
  • R 1 is H or NH 2 ;
  • R 3 is H, C 1-8 alkyl
  • R 4 is H, F, Cl, Br, OR 7 , S R 7 , NR 7 R 8 , C 1-8 alkyl;
  • R 5 is H, C 1-8 alkyl
  • R 6 is H, F, Cl, Br, OR 9 , S R 9 , NR 9 R 10 , C 1-8 alkyl;
  • R 7 is H, C 1-8 alkyl
  • R 8 is H, C 1-8 alkyl
  • R 9 is H, C 1-8 alkyl
  • R 10 is H, C 1-8 alkyl
  • A is O, S, SO, SO 2 , NR 3 , -CH(R 4 )CH 2 -, -CH(R 4 )-;
  • B is O, S, SO, SO 2 , NR 5 , -CH(R 6 )CH 2 -, -CH(R 6 )-;
  • C is phenyl or pyridyl optionally substituted by one or more groups, wherein the substituent is selected from the group consisting of F, Cl, Br, C 1-8 alkyl;
  • Z is N, CH;
  • R 2 is H or NH 2 ;
  • R 3 is H, C 1-8 alkyl
  • R 4 is H, F, Cl, Br, OR 7 , S R 7 , NR 7 R 8 , C 1-8 alkyl;
  • R 5 is H, C 1-8 alkyl
  • R 6 is H, F, Cl, Br, OR 9 , S R 9 , NR 9 R 10 , C 1-8 alkyl;
  • R 7 is H, C 1-8 alkyl
  • R 8 is H, C 1-8 alkyl
  • R 9 is H, C 1-8 alkyl
  • R 10 is H, C 1-8 alkyl.
  • One embodiment of the invention comprises a group of compounds of formula I or II, the compounds of which are structurally characterized by:
  • C is a phenyl group substituted by one or more fluorine atoms
  • X is O, S, NR 3 , -CH(R 4 )-;
  • Y is NR 5 , -CH(R 6 )CH 2 -, -CH(R 6 )-;
  • R 1 is H or NH 2 ;
  • R 3 is H, C 1-8 alkyl
  • R 4 is H, C 1-8 alkyl
  • R 5 is H, C 1-8 alkyl
  • R 6 is H, C 1-8 alkyl
  • A is S, NR 3 , -CH(R 4 )CH 2 -, -CH(R 4 )-;
  • B is S, NR 5 , -CH(R 6 )CH 2 -, -CH(R 6 )-;
  • C is a phenyl group substituted by one or more fluorine atoms
  • Z is N, CH;
  • R 2 is H or NH 2 ;
  • R 3 is H, C 1-8 alkyl
  • R 4 is H, C 1-8 alkyl
  • R 5 is H, C 1-8 alkyl
  • R 6 is H, C 1-8 alkyl.
  • One embodiment of the invention comprises a group of compounds of formula I or II, the compounds of which are structurally characterized by:
  • C is a phenyl group substituted by a fluorine atom
  • X is O, S, NH, -CH 2 -;
  • Y is NCH 3 , -CH(CH 3 )-;
  • R 1 is H or NH 2 ;
  • A is S
  • B is -CH(CH 3 )-
  • C is a phenyl group substituted by a fluorine atom
  • R 2 is H or NH 2 .
  • One embodiment of the invention comprises a group of compounds of formula I or II, the compounds of which are structurally characterized by:
  • C is a phenyl group substituted by a fluorine atom
  • X is O, S, NH, -CH 2 -;
  • Y is NCH 3 , -CH(CH 3 )-;
  • R 1 is H
  • A is S
  • B is -CH(CH 3 )-
  • C is a phenyl group substituted by a fluorine atom
  • R 2 is H
  • One embodiment of the invention comprises a group of compounds of formula I or II, the compounds of which are structurally characterized by:
  • One embodiment of the invention comprises a group of compounds of formula I, the compounds of which are structurally characterized by:
  • One embodiment of the invention comprises a group of compounds of formula I or II, the compounds of which are structurally characterized by:
  • the invention further comprises a compound of formula I or II, or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof, for the treatment and prevention of human or animal diseases Aspect of the application.
  • Treatment when referring to a disease means treating the disease in a patient or animal, or although the animal or patient is affected by the disease, some or all of the symptoms of the disease are alleviated or eliminated.
  • preventing a reference to a disease means that the patient or animal does not develop the disease, or that although the animal or patient is affected by the disease, some or all of the symptoms of the disease are alleviated or absent.
  • Animals include canines, felines, equines, bovidae, pigs, etc., such as dogs, cats, horses, cows, pigs, and the like.
  • the invention further comprises a compound of formula I or II or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof for use in the treatment and prevention of bacterial infections Application in human or animal diseases.
  • the present invention also includes a compound of Formula I or II or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof for treating and preventing brain and heart
  • a compound of Formula I or II or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof for treating and preventing brain and heart
  • the present invention also includes a compound of Formula I or II or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof for treating and preventing skin, gastrointestinal Use of human or animal diseases caused by bacterial infections in the tract, breast, and urinary tract.
  • the invention further comprises a compound of formula I or II or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof for the treatment and prevention of gastrointestinal sites.
  • a compound of formula I or II or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof for the treatment and prevention of gastrointestinal sites.
  • the invention further comprises an infectious bacterium preferably comprising a compound of formula I or II or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof for prevention and treatment But not limited to: Staphylococcus, Streptococcus, Enterococcus, Polymorpha spp., Clostridium spp., Clostridium difficile, Clostridium perfringens, Mycobacterium tuberculosis, Mycobacterium tuberculosis or tuberculosis Mycobacteria.
  • the invention further comprises an infectious bacterium preferably comprising a compound of formula I or II or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof for prevention and treatment
  • infectious bacterium preferably comprising a compound of formula I or II or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug or formulation thereof for prevention and treatment
  • it is not limited to: Staphylococcus, Streptococcus, Enterococcus, Polymorpha spp., Clostridium spp., Clostridium difficile, Clostridium perfringens.
  • the present invention includes a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound of Formula I or II or a pharmaceutically acceptable optical racemate, stereoisomer, salt, solvate, hydrate, prodrug thereof , and one or more pharmaceutically acceptable excipients.
  • MRSA methicillin-resistant Staphylococcus aureus
  • PE petroleum ether
  • VRE vancomycin-resistant enterococci
  • the solvent should be stable under the reaction conditions and not participate in the reaction, and should be able to completely dissolve S1 and S2 (or S4), preferably the solvent is DMSO.
  • R 12 is a hydrogen atom
  • S3 or S5 is the final product I or II.
  • R 12 is an ethyl group
  • the nucleophilic substitution yield of S1 and S2 is not high, so the reaction of S2 with boron triacetate to form S6 can improve the yield (S6 preparation method such as Chem. Pharm. Bull. (1996), 44(4), 642-645)).
  • S1 and S6 are dissolved in DMF (N,N-dimethylformamide), heated to 50 ° C for 12 hours, the reaction solution is cooled to room temperature, poured into ice water, solid is precipitated, filtered, and the obtained solid is added to hydrogen.
  • Figure 1 is a chemical structural formula for the synthesis of Compound I.
  • Figure 3 is a schematic diagram of a synthetic compound of Formula I.
  • Figure 4 is a schematic diagram of a synthetic compound of Formula II.
  • Figure 5 is another path diagram of the synthetic compound Formula I.
  • Example 1 9-Fluoro-10-(4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxymethyl -4-hydroxy-piperidine -1-yl)-3-methyl-7-oxo-3,7-dihydro-2H-[1,3,4]oxaxazine [6,5,4-ij]quinoline-6- carboxylic acid
  • Step 1 6-Fluoro-7-((4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxymethyl) -4-hydroxy-piperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline-3-carboxylic acid Ethyl ester
  • Step 2 6-Fluoro-7-((4-(2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxymethyl) -4-hydroxy-piperidin-1-yl)-1-methyl-4-oxo-14-dihydro-[1,3]thiazepine[3,2-a]quinoline-3-carboxylic acid
  • step 1 The white solid obtained in step 1 (1.58 g, 2.5 mmol, 1 eq.) was dissolved in a mixture of methanol (20mL) and THF (20mL). The mixture was stirred at room temperature for 2 hours. After adjusting the pH ⁇ 6 with 50% sulfuric acid, the solid product was obtained by filtration. The crude solid was isolated with EtOAc EtOAc EtOAc (EtOAc:
  • Example 5 was synthesized by Route 2, and the specific experimental details are as follows:
  • the minimum inhibitory concentration (MIC) test of the examples was performed using a standard broth double dilution method.
  • the antibacterial drug has a concentration range of 256-0.002 mg/L.
  • the final concentration of the test solution was about 5 x 10 5 CFU/ml.
  • the high dose (10 mg) of Example 3 was administered for 5 consecutive days to substantially eliminate the C. difficile in the intestine of the mice, and showed good protection against the mice infected with Clostridium difficile during the treatment period. The rate is 100%, and the efficacy in vivo is better than oxazolamide.
  • MRSA Methicillin-resistant Staphylococcus aureus

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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention se rapporte à un nouveau dérivé d'oxazolidinone-fluoroquinolone et à ses utilisations et concerne le domaine des médicaments chimiques. La présente invention se rapporte également à un composé représenté par la formule (I), un racémique optique, un stéréoisomère, un sel, un solvate, un hydrate ou un promédicament pharmaceutiquement acceptables de ce dernier et à des applications d'une composition pharmaceutique le contenant en prévention ou traitement d'infections (telles qu'une infection bactérienne). Ce sont des agents antimicrobiens efficaces et ils peuvent résister efficacement à de multiples pathogènes sur des corps humains et des animaux et les pathogènes comprennent, sans limitation, les bactéries à Gram positif, les bactéries à Gram négatif, les micro-organismes anaérobies et les micro-organismes acido-tolérants.
PCT/CN2017/078798 2016-04-12 2017-03-30 Nouveau dérivé d'oxazolidinone-fluoroquinolone et ses utilisations Ceased WO2017177828A1 (fr)

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CN201610220830.4A CN107286182A (zh) 2016-04-12 2016-04-12 新型噁唑烷酮‑氟喹诺酮衍生物及用途

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040132764A1 (en) * 2002-10-23 2004-07-08 Morphochem Aktiengesellschaft Fuer Kombinatorische Chemie Antibiotics for the treatment of infections in acidic environments
CN1832746A (zh) * 2003-04-30 2006-09-13 莫弗凯姆联合化学股份公司 噁唑烷酮－喹啉杂化物抗生素用于治疗炭疽和其它感染的用途
CN1898238A (zh) * 2003-12-18 2007-01-17 莫弗凯姆联合化学股份公司 噁唑烷酮－喹诺酮杂化物抗生素

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6689769B2 (en) * 2000-12-21 2004-02-10 Pharmacia & Upjohn Company Antimicrobial quinolone derivatives and use of the same to treat bacterial infections
ES2186550B2 (es) * 2001-06-27 2003-11-16 Vita Lab Nuevos derivados de oxazolidinonas como antibacterianos.
WO2003031443A1 (fr) * 2001-10-04 2003-04-17 Morphochem Aktiengesellschaft für kombinatorische Chemie Antibiotiques a action duale renfermant une oxazolidinone et une quinolone ou une fraction de naphthyridinone

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040132764A1 (en) * 2002-10-23 2004-07-08 Morphochem Aktiengesellschaft Fuer Kombinatorische Chemie Antibiotics for the treatment of infections in acidic environments
CN1832746A (zh) * 2003-04-30 2006-09-13 莫弗凯姆联合化学股份公司 噁唑烷酮－喹啉杂化物抗生素用于治疗炭疽和其它感染的用途
CN1898238A (zh) * 2003-12-18 2007-01-17 莫弗凯姆联合化学股份公司 噁唑烷酮－喹诺酮杂化物抗生素

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