WO2014161412A1 - Dérivé de quinolone tricyclique, et procédé de préparation et utilisation de ce dérivé - Google Patents

Dérivé de quinolone tricyclique, et procédé de préparation et utilisation de ce dérivé Download PDF

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WO2014161412A1
WO2014161412A1 PCT/CN2014/072773 CN2014072773W WO2014161412A1 WO 2014161412 A1 WO2014161412 A1 WO 2014161412A1 CN 2014072773 W CN2014072773 W CN 2014072773W WO 2014161412 A1 WO2014161412 A1 WO 2014161412A1
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salt
group
compound
formula
hydrate
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PCT/CN2014/072773
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Chinese (zh)
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黄小光
陈矛
朱少璇
鲍颖霞
张小娜
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广州白云山制药股份有限公司广州白云山制药总厂
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Publication of WO2014161412A1 publication Critical patent/WO2014161412A1/fr

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    • 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
    • C07D498/04—Ortho-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
    • A61K31/535—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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • 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

Definitions

  • the present invention is based on a Chinese patent application No. 201310112906.8 filed on Apr. 2, 2013, the content of which is hereby incorporated by reference.
  • the present invention relates to the field of medicinal chemistry and chemotherapeutics, and in particular to a method for preparing a tricyclic quinolone compound or a salt thereof and a hydrate thereof, and to use thereof for treating a medicament for bacterial infectious diseases.
  • Quinolones are an important class of fully synthetic antibiotics that are widely used in the clinic due to their excellent pharmacodynamics, pharmacokinetic properties, excellent antibacterial properties and few side effects.
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSE methicillin-resistant Staphylococcus epidermidis
  • PRSP penicillin-resistant Streptococcus pneumoniae
  • VRE vancomycin-resistant enterococci
  • Levofloxacin is one of the best quinolone antibiotics with good efficacy and safety, and is also the best-selling antibiotic drug. This drug is against Gram-positive bacteria (G (+) ), Gram. Negative bacteria (G (-)), anaerobic bacteria, mycoplasma, chlamydia and Mycobacterium tuberculosis have good curative effect, and are clinically effective, with low side effects, especially in cardiotoxicity (QT gap prolongation) and light In terms of toxicity, it is much lower than other quinolone drugs and has a good drug safety advantage (Mol. Pharmacol U, 59: 122).
  • An object of the present invention is to provide a novel quinolone compound having an antibacterial activity, a pharmaceutically acceptable salt thereof and a hydrate thereof.
  • Another object of the present invention is to provide a novel quinolone compound having antibacterial activity, a pharmaceutically acceptable salt thereof, and a process for producing the same.
  • Another object of the present invention is to provide a novel quinolone compound having antibacterial activity, a pharmaceutically acceptable salt thereof and a hydrate thereof, for use in the preparation of a medicament for treating and/or preventing a disease caused or caused by a bacterial infection. application.
  • R 2 is H or a C 1 C 10 -containing alkyl or aralkyl group which may be substituted;
  • n 1, 2 or 3;
  • q 1, 2 or 3.
  • the substituent group at the C10 position of the quinolone derivative of the formula (I) may have one or more asymmetric carbon atoms, and the possible optical isomers thereof may be in the form of an optically active or racemic form.
  • the corresponding optically active material is obtained by standard organic chemistry techniques well known in the art, such as synthesis from chiral starting materials or resolution by racemate.
  • the quinolone derivative of the formula (I) of the present invention is 11 or a C1-C10-containing acyl group which may be substituted; the acyl group is selected from a C1-C10 alkanoyl group, a mono- or di- or a halogenated C2-C10 chain.
  • lower refers to a group having from 1 to 6, preferably from 1 to 4 carbon atoms.
  • acyl include lower alkanoyl [eg formyl, acetyl, propionyl, hexanoyl, pivaloyl, etc.], one (or two or three) halo (lower) alkanoic acid groups [eg chloroacetyl) a group, a trifluoroacetyl group, etc., a lower alkoxycarbonyl group [e.g., a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butoxycarbonyl group, a t-pentyloxycarbonyl group, a hexyloxycarbonyl group, etc.], a carbamoyl group, an aromatic group
  • An acyl group e.g., benzoyl, toluyl or the like]
  • an aryl (lower) alkanoyl group e.g., phenylacetyl group, phenylpropionyl group,
  • the formula (I) may be selected from formyl, acetyl, propionyl, hexanoyl, pivaloyl, chloroacetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, uncle Butoxycarbonyl, tert-amyloxycarbonyl, hexyloxycarbonyl, carbamoyl, benzoyl, toluyl, phenylacetyl, phenylpropanoyl, phenylglyoxyl, benzyloxycarbonyl, benzene Ethyloxycarbonyl, p-nitrobenzyloxycarbonyl.
  • the quinolone derivative R 2 in the formula (I) of the present invention is H or a C1 C10-containing alkyl or aralkyl group which may be substituted, wherein the alkyl group represents a C1 C10 alkyl group which may be substituted;
  • the aralkyl group represents an arylmethyl group which may be substituted, and an arylethyl group which may be substituted.
  • a suitable R 2 is a C1 C10-containing alkyl group, and the C1 C10-containing alkyl group may have 1 to 5 selected from a halogen atom, a hydroxyl group, a cyano group, a lower alkoxy group, and a lower stage.
  • the preferred substituent group for R 2 in the general formula (I) is methyl, ethyl, propyl, 1-methylethyl, 1-methyl Propyl, 2-methylpropyl, 1-ethylpropyl, 2-ethylpropyl, butyl, or hexyl.
  • the term "pharmaceutically acceptable salt” includes a carboxylate formed with an alkali metal, a salt of an inorganic base such as sodium, potassium, calcium or magnesium; a carboxylate formed with an organic base such as a a salt of an amine, glucosamine, trimethylamine, triethylamine, dicyclohexylamine, N, N-dibenzyl-1,2-ethanediamine, arginine, lysine or the like; and hydrochloric acid, An addition salt of a mineral acid such as hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; and lactic acid, acetic acid, methanesulfonic acid, maleic acid, succinic acid, tartaric acid, citric acid, fumaric acid, oxalic acid, malonic acid, malic acid , an addition salt of an organic acid such as picric acid.
  • an addition salt of an organic acid such as picric acid.
  • the quinolone compound of the present invention and a pharmaceutically acceptable salt thereof and a hydrate thereof, may, for example, be a lactate, an acetate, a methanesulfonate, a maleate, a succinate or a tartrate. Citrate, fumarate, oxalate, malonate, malate, picrate, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, sodium, potassium, Calcium, magnesium, zinc, meglumine, glucosamine, trimethylamine, triethylamine, dicyclohexylamine, N, N-dibenzyl-1, 2-ethane Amine salts, arginine salts, lysine salts.
  • the compound of the formula (I) of the present invention is more specifically selected from the following compounds:
  • the present invention also provides a process for the preparation of a compound of formula (I), which comprises: coupling a compound of formula (III) and a compound of formula (IV) in the presence of an acid binding agent to give a compound of formula (V) And removing the carboxy protecting group ⁇ ) from the compound of formula (V), and then forming a salt of the compound of formula (I) by salt formation or ester formation:
  • R 2 is H or a C1 C10 -containing alkyl or aralkyl group which may be substituted; n is 1, 2 or 3; q is 1, 2 or 3; X is a boron-containing carboxyl protecting group.
  • the specific step of the method is to prepare a compound of the formula (V) by reacting a compound of the formula (III) with a compound of the formula (IV) in the presence of an acid-binding base at a temperature of from room temperature to 200 ° C, and then removing the compound of the formula (V).
  • a boron-containing group protecting group is to prepare a compound of the formula (V) by reacting a compound of the formula (III) with a compound of the formula (IV) in the presence of an acid-binding base at a temperature of from room temperature to 200 ° C, and then removing the compound of the formula (V).
  • the intermediate compound of the formula (V) is prepared by reacting a compound of the formula (III) with a compound of the formula (IV) in the presence of a solvent in the presence of a suitable base at a temperature of from room temperature to 200 °C.
  • any solvent which does not adversely influence the reaction can be used, and pyridine, acetonitrile, dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone or hexamethylphosphoramide is preferably used.
  • This reaction is generally carried out in the presence of an acid binding agent.
  • an excess of the reactant (IV) is used, for example, an equimolar amount to a 10-fold molar amount relative to the starting material (III), preferably an equimolar amount to a 5-fold molar amount.
  • the unreacted compound of the formula (IV) remaining after the reaction can be recovered and reused for another reaction.
  • Preferred acid binding agents for the reaction include inorganic bases such as sodium hydrogencarbonate and potassium carbonate, and the like, and the following organic bases: pyridine, triethylamine, diisopropylethylamine, hydrazine, hydrazine-dimethylaniline, hydrazine, ⁇ -Dimethylaminopyridine, 1, 8-diazabicyclo[[5.4.0]undec-7-ene or 1,4-diazabicyclo[2.2.2]octane.
  • organic bases such as sodium hydrogencarbonate and potassium carbonate, and the like, and the following organic bases: pyridine, triethylamine, diisopropylethylamine, hydrazine, hydrazine-dimethylaniline, hydrazine, ⁇ -Dimethylaminopyridine, 1, 8-diazabicyclo[[5.4.0]undec-7-ene or 1,4-diazabicyclo[2.2.2]oct
  • This reaction can be removed by hydrolysis depending on the relevant properties of the protecting group X.
  • it can be stored in a solvent in acid or alkali.
  • the treatment is carried out at a temperature of 0 to 130 ° C to remove the protecting group.
  • Acids usable for this purpose include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.; organic acids such as acetic acid, trifluoroacetic acid, formic acid, toluenesulfonic acid, etc.; or Lewis acids such as boron tribromide, aluminum chloride, etc. .
  • an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide or the like; an alkali metal carbonate such as sodium carbonate, potassium carbonate or the like; an alkali metal alkoxide may be used.
  • a solvent for example, water or an organic solvent such as ethanol, tetrahydrofuran, dioxane, ethylene glycol, acetic acid or the like, or a mixture of such an organic solvent and water, if necessary, the reaction can be carried out without any It is carried out in the presence of a solvent.
  • the preparation of the compound of the formula (III) of the present invention can be carried out by reacting a compound of the formula (?) with a boron-containing protecting reagent, as shown in the following reaction scheme:
  • X is a boron-containing carboxyl protecting group.
  • the preparation is carried out by reacting a compound of the formula (b) with boric acid and an organic acid such as acetic acid, propionic acid, trifluoroacetic acid or an organic acid anhydride such as acetic anhydride, propionic anhydride, trifluoroacetic anhydride or the like in the presence of zinc chloride.
  • the amount of boric acid used is 1.1 2 molar equivalents relative to the compound of the formula ( ⁇ ), and the obtained boronic acid ester derivative (III)
  • the novel quinolone compound having antibacterial activity of the present invention is a commercially available raw material (-9,10-difluoro-3-methyl-7-carbonyl-3,7-dihydro-2H-[ 1,4]oxazine [2,3,4]quinoline-6-carboxylic acid ethyl ester ( ⁇ )
  • ⁇ Starting from zinc chloride catalyzed reaction with boric acid and acetic anhydride to give bis(acetyl-O)[(3 - 9,10-difluoro-2,3-dihydro-3-methyl-7-dihydro-7H-pyridine [1,2,3-[1,4]benzoxazine-6-carboxylate- O 6 ,O 7 ]boron
  • step a step a
  • intermediate ( ⁇ ) reacts with the free amine side chain (IV) at the C10 position (or its hydrochloride) in the presence of an organic base to give the corresponding coupling product (V') (step b); (4)
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the novel quinolone compound having antibacterial activity or a plurality of pharmaceutically acceptable carriers and/or diluents according to the present invention.
  • the carrier means a conventional pharmaceutical carrier in the field of pharmaceutical technology, a binder such as a cellulose derivative, gelatin or polyvinylpyrrolidone, etc.; a filler such as starch or the like; a cracking agent such as calcium carbonate or sodium hydrogencarbonate; a diluent such as water Alternatively, other adjuvants such as flavoring agents and/or sweeteners may also be added to the composition.
  • a conventional solid preparation such as a tablet, a powder or a capsule, etc.; when it is used for injection, it can be prepared as an injection.
  • compositions of the present invention can be prepared by methods conventional in the medical arts.
  • the composition of the present invention and the above carrier can be administered to a patient in need of such treatment by intravenous injection, subcutaneous injection or oral administration.
  • the pharmaceutical compositions are in the form of a pharmaceutically acceptable preparation.
  • the medicinal preparation is selected from the group consisting of a tablet, a sugar-coated tablet, a film-coated tablet, an enteric coated tablet, a sustained-release tablet, a capsule, a hard capsule, a soft capsule, a sustained-release capsule, an oral solution, a mixture, Oral, granules, granules, pills, powders, ointments, dandruffs, suspensions, solutions, injections, powders, lyophilized powders, suppositories, ointments, plasters, creams, sprays, granules Aerosols, drops, patches.
  • dosage forms of the above pharmaceutical compositions preferred are injections or oral preparations.
  • the pharmaceutical composition of the present invention can be used in the preparation of solid or semisolid pharmaceutical preparations in the form of powders, tablets, dispersible powders, capsules, cachets, suppositories and ointments.
  • the solid carrier which can be used is preferably one or more selected from the group consisting of a diluent, a flavoring agent, a solubilizing agent, a lubricant, a suspending agent, a binder, a swelling agent and the like, or may be an encapsulating substance.
  • 5% or 10-70% of the micronized active ingredient is contained in the carrier.
  • Suitable solid carriers are selected from the group consisting of magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, yellow gum, methylcellulose, sodium sulphonate, low boiling wax, One or more of cocoa butter and the like. Because of their ease of administration, tablets, powders, cachets, and capsules represent the most advantageous oral solid formulations.
  • Liquid preparations of the invention include solutions, suspensions and emulsions.
  • an injectable preparation for parenteral administration may be in the form of water or water-propylene glycol solution, adjusting its isotonicity, pH and the like to make physiological conditions suitable for living organisms.
  • the liquid preparation can also be prepared in the form of a solution in polyethylene glycol or an aqueous solution.
  • An oral aqueous solution can be prepared by dissolving the active ingredient in water, followed by the addition of suitable coloring agents, flavoring agents, stabilizing agents and thickening agents.
  • the aqueous suspension suitable for oral administration can be prepared by dispersing the micronized active ingredient in a viscous material such as natural or synthetic gum, methylcellulose, sodium methacrylate, and other known suspending agents.
  • Dosage unit form of the formulation refers to a physically discrete unit suitable as a single dose, each unit containing a calculated predetermined amount of active ingredient which produces the desired therapeutic effect.
  • dosage unit forms can be in the form of a package such as a tablet, a capsule or a powder in a vial or vial, or an ointment, gel or cream in a tube or vial.
  • the quinolonecarboxylic acid derivatives provided by the present invention are used in the preparation of a medicament for preventing and/or treating bacterial infectious diseases.
  • the bacterial infectious disease is selected from the group consisting of sepsis, pustule, pneumonia, bronchitis, pharyngitis, endocarditis, urinary tract infection, gastrointestinal infection, skin infection, bacteremia , pyelonephritis, cystitis, wound infection, multiple folliculitis.
  • the compounds of the present invention have stronger antibacterial activity and broad antibacterial spectrum against various pathogenic organisms including Gram-negative bacteria and Gram-positive strains.
  • the antibacterial activity of the compounds of the present invention against Gram-negative strains is higher than that of known antibacterial agents such as levofloxacin and ciprofloxacin.
  • the antibacterial activity of the compounds of the present invention against S. aureus is much higher than that of known antibacterial agents. Activity.
  • quinolone compound of the present invention or a salt or hydrate thereof can also be produced by a method known for the preparation of a related compound, and in the examples, some representative methods are also listed, wherein, unless otherwise stated, n, q, Ri, R 2 has any of the meanings defined above for the quinacridone derivative of formula (I), and in the examples also describes the preparation of the starting material, or A similar method of the prior art obtains the necessary raw materials.
  • [1,4]oxazine [2,3,4]quinolin-6-carboxylic acid (6.63 g), water (34 ml) and acetone (40 ml), and then added L-arginine (3.19 g) with stirring.
  • the water content was determined by the Karl Fischer method: 11.80%.
  • the water content was determined by the Karl Fischer method: 3.71%.
  • Gram-positive bacteria Staphylococcus aureus CMCC26112, clinical isolation of methicillin-sensitive Staphylococcus aureus (MSSA); clinical isolation of methicillin-resistant Staphylococcus aureus (MRSA); methicillin-resistant Staphylococcus epidermidis (MRSE).
  • Gram-negative bacteria Escherichia coli CMCC44113; Pseudomonas aeruginosa CMCC10211.
  • MH Movable e r-Hinton susceptibility agar medium (in which PBS medium containing 5% defibrinated sheep blood of Streptococcus pneumoniae and Enterococcus faecalis) and MH broth dry powder medium (French bioMerieux) the company).
  • Positive control drugs ciprofloxacin hydrochloride, levofloxacin hydrochloride, vancomycin hydrochloride (China National Institute for the Control of Pharmaceutical and Biological Products).
  • Test equipment ES02 multi-point inoculation instrument (Japan); QMI300SVBA type carbon dioxide incubator (USA); DESICHEKIDK214408 turbidimeter.
  • test compounds Q1 and Q2 showed strong activity, especially for the resistant strains, showing stronger activity than the positive control drug.
  • compound Q1 showed a relatively balanced antibacterial activity against Gram-positive bacteria (G(+)) and Gram-negative bacteria (0(-)), and its antibacterial activity against Staphylococcus aureus CMCC26112 was levofloxacin hydrochloride 8 More than double, it is more than 32 times the activity of ciprofloxacin; in particular, the activity of MRSA is 2000 times or more of levofloxacin hydrochloride and ciprofloxacin.
  • Reagents and drugs 1) Compound Ql, self-made according to Example 1, white powder, purity 98%, good water solubility, saturated aqueous solution at room temperature 10 mg/ml ; 2) levofloxacin hydrochloride bulk drug, purchased from China The Institute for the Control of Pharmaceutical and Biological Products, a white powder, is easily soluble in water and is relatively stable after dissolution.
  • Preparation of drug solution Accurately weigh levofloxacin hydrochloride, dissolved in physiological saline, the appearance is light yellow transparent liquid, pH is 5.0, diluted step by step according to the required concentration, the highest concentration is 30 mg/ml, 0.22 ⁇ M small filter filter sterilization The dose ratio between groups was 0.8.
  • Test method Take 60 rats of Kunming mice fasted for 15 hours at room temperature at 20 °C, male and female, divided into 6 groups, 10 in each group. Each group of animals was administered intravenously at a dose of 0.02 ml/g. Referring to the pre-experimental results, the minimum 100% lethal dose was 600 mg/kg, which was set as the highest dose group, and the dose ratio of the other groups was 0.8.
  • the dissolved liquid has stable properties, a transparent yellowish appearance, a pH of 8.5, diluted with physiological saline, and diluted stepwise at the desired concentration.
  • the highest concentration is 100 mg/ml, and the dose ratio between groups is 0.8.
  • Test method Take 70 mice of Kunming mice fasted for 15 hours at room temperature of 20 °C, male and female, randomly divided into 7 groups, 10 in each group. All groups of animals were administered intravenously. The highest dose group and 3% NaHC0 3 solvent control dose was 0.025 ml/g, and the other groups were 0.02 ml/g. Refer to the pre-test results, the lowest The 100% lethal dose was 2.5 g/kg, which was set to the highest dose group, and the dose ratio of the other groups was 0.8.
  • the rats were changed to intermittent observation and observed until the 7th day after administration.
  • the observation included: animal appearance signs, behavioral activities, gland secretion, respiration, feces, local administration, and number of animal deaths. , time of death, reaction before death, etc. Animals that died due to sudden death during the test, animals that died, and animals that survived at the end of the experiment were grossly dissected, and major organ changes were visually observed. If abnormalities were recorded, histopathological examination should be performed.
  • the LD 5Q and 95% confidence limits were calculated using the Bliss method.
  • the present invention provides a tricyclic quinolone derivative or a salt thereof and a hydrate thereof, which are tested for activity by various strains, and have antibacterial activity against various sensitive strains and resistant strains, and can be used for Gram-negative, positive bacteria cause infections, especially for methicillin-resistant Staphylococcus aureus (MRSA) and P. aeruginosa infections.
  • MRSA methicillin-resistant Staphylococcus aureus
  • P. aeruginosa infections The compound is stable in nature, is not easy to absorb moisture, is easy to store and is made into a corresponding pharmaceutical preparation, and is advantageous for industrial batch production, and has industrial applicability. It can be a safe and effective drug, and it is of great significance for the treatment of bacterial infectious diseases.

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  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

L'invention porte sur un dérivé de quinolone tricyclique ayant une nouvelle structure, avec un groupe périphérique en position C10 substitué par des substituants non alcalins ou des sels et hydrates de ce dérivé. Ces composés se sont révélés avoir une activité antimicrobienne contre toute une gamme de souches sensibles et de souches résistantes aux médicaments, grâce à des essais d'activité réalisés sur différentes souches, peuvent être utilisés pour traiter des maladies infectieuses provoquées par des bactéries gram-négatives et gram-positives, et conviennent en particulier au traitement de maladies provoquées par des infections à Staphylococcus aureus résistant à la méthicilline (MRSA) et à Pseudomonas aeruginosa.
PCT/CN2014/072773 2013-04-02 2014-03-04 Dérivé de quinolone tricyclique, et procédé de préparation et utilisation de ce dérivé WO2014161412A1 (fr)

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