WO2010012138A1 - Dérivés de l'acide carboxylique de quinoline 7-[4-(aminométhyl)-4-fluoro-3-(alkoxyimino)pyrrolidin-1-yle] et leurs procédés de préparation - Google Patents

Dérivés de l'acide carboxylique de quinoline 7-[4-(aminométhyl)-4-fluoro-3-(alkoxyimino)pyrrolidin-1-yle] et leurs procédés de préparation Download PDF

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WO2010012138A1
WO2010012138A1 PCT/CN2008/071843 CN2008071843W WO2010012138A1 WO 2010012138 A1 WO2010012138 A1 WO 2010012138A1 CN 2008071843 W CN2008071843 W CN 2008071843W WO 2010012138 A1 WO2010012138 A1 WO 2010012138A1
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fluoro
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alkyl
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陈萍
季子为
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南京明生医药技术有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • 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
    • 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
    • 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
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to a novel quinolinecarboxylic acid derivative having excellent antibacterial activity and a preparation method thereof.
  • Quinolones began with the discovery of nalidixic acid (J. Med. Chem. 1962, 5, 1063) in 1962 and have since evolved into a broad-spectrum, high-efficiency, low-toxic synthetic chemotherapy drug.
  • Early quinolones have strong antibacterial activity against Gram-negative bacteria, but have lower activity against Gram-positive bacteria, although newly marketed quinolones such as gatifloxacin (Drug, 1999, 58 ( 4 ) : 683 ) and moxifloxacin (EP 550903) have improved antibacterial activity, but overall, the activity against Gram-positive bacteria needs to be further enhanced, and it is necessary to enhance certain specific bacteria such as Streptococcus pneumoniae and Enterococcus. Antibacterial activity.
  • Gemifloxacin is a new broad-spectrum high-efficiency quinolone antibiotic developed by LG in South Korea. It is especially active against Staphylococcus and Streptococcus pneumoniae than other new quinolones already on the market (eg Moxifloxacin).
  • the activity against G-bacteria is similar to that of ciprofloxacin.
  • the ED50 against Pseudomonas aeruginosa is 2.1 mg/kg, which is also lower than 3.11 mg/kg of ciprofloxacin, which is the best of all respiratory quinolones. .
  • quinolone resistance and cross-resistance are still a major obstacle that has not been overcome.
  • Still another object of the present invention is to provide an application of the above compound in the preparation of an antibacterial agent.
  • a final object of the invention is to provide intermediate compounds of the above compounds.
  • the object of the invention can be achieved by the following measures:
  • ⁇ 11, substituted or unsubstituted dC 6 alkyl, 5-methyl-2-oxo-1,3-dioxol-4-enylmethyl or alkylacyloxymethyl preferably H Or a substituted or unsubstituted dC 6 alkyl group wherein the substituent is a hydroxyl group, a halogen or an amino group.
  • Y is most preferably H, but the carboxylic acid is readily reacted with an alcohol to form an ester such that Y becomes a substituted or unsubstituted dC 6 alkyl group.
  • A is CH, CF, C-C1, C-OCH 3 , C-CH 3 or N;
  • « is a 3- alkyl, dC 3 fluoroalkyl, cyclopropyl, fluorocyclopropyl, phenyl or halophenyl group, or A and 1 ⁇ are linked to form C-0-CH 2 -CH(CH 3 )- Bridge bond; preferably dC 3 alkyl, F-CH 2 CH 2 -, cyclopropyl, fluorocyclopropyl or halophenyl, or and! ⁇ is linked to form a bridge from A to R ⁇ C-0-CH 2 -CH(CH 3 )- such that the compound of formula (I) contains a structure of pyridobenzoxazine.
  • Z is H, halogen, NH 2 or CH 3 ;
  • R 2 or R 3 are each independently H, dC 6 alkyl or amino protecting group, wherein said amino protecting group is formyl, acetyl, trifluoroacetyl, substituted or unsubstituted benzoyl, p-toluenesulfonyl , methoxy or ethoxy or t-butoxy or isobutoxy or trichloroethoxycarbonyl, p-methoxybenzyloxycarbonyl and benzyloxycarbonyl, alkyl acyloxymethyl, p-methoxybenzyl and benzyl, Trityl, tetrahydrofuranyl, 5-methyl-2-oxo-1,3-oxacyclo-4-enemethyl or ⁇ -aminoalkyl acyl; R 2 or R 3 are each independently preferably H , dC 6 alkyl, formyl, acetyl or trifluoroacetyl.
  • alkyl group as used in the present invention generally means an alkyl group having 1 to 6 carbon atoms, unless otherwise specified.
  • the present invention relates to a compound of the formula (I), in the pyrrolidine moiety of the compound of the formula (I), wherein the carbon atom of the substituted fluorine and the amine methyl group is an asymmetric carbon atom, and thus may be in the form of a mixture of R or S or R and S.
  • the present invention includes all such isomers and mixtures.
  • the compounds of formula (I) of the invention may form pharmaceutically acceptable non-toxic salts.
  • These salts include inorganic acids such as hydrochloric acid and hydrogen. a salt of bromic acid, phosphoric acid, sulfuric acid, etc., with an organic acid such as acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid or malate, And an amino acid salt such as alanine, aspartic acid or lysine or a salt with a sulfonic acid such as methanesulfonic acid or p-toluenesulfonic acid.
  • Their alkali metal salts, alkaline earth metal salts, silver salts, phosphonium salts and the like can also be produced by a conventional conversion method.
  • esters of the compounds of the formula (I) of the present invention include not only substituted or unsubstituted fatty esters, especially 1 to 6 carbon atoms, such as lower alkyl esters such as methyl esters, but also chemical hydrolysis or enzymatic hydrolysis by in vivo,
  • the compounds of the formula (I) of the present invention may also exist in the form of solvates (e.g., hydrates), and therefore, these solvates are also included in the compounds of the present invention.
  • the compound of the present invention exhibits strong antibacterial activity against a broad spectrum of pathogenic bacteria including Gram-positive bacteria and Gram-negative strains, and thus the compound of the present invention can be made into an antibacterial agent as an active ingredient and a pharmaceutically acceptable excipient. combination.
  • Y, Ri R 2 , R 3 , , Z and A are as defined above, and X is a halogen.
  • the reaction is carried out by adding a base in a solvent at room temperature to 200 ° C with or without pressure for 0.5 to 10 hours.
  • reaction formula of another preparation method is as follows:
  • Y, Ri R 2 , R 3 , , Z and A are as defined above, and R is a C 2 -C 6 aliphatic carboxy group substituted with or without a hetero atom, wherein said hetero atom is ? ⁇ , S, 0 or halogen; X is halogen.
  • (II) is first reacted with a tribasic borate derivative (VIII) in a solvent to obtain (V), and then reacted with the formula (III) (specifically, one of the above methods) to form (VI) ), and finally remove the group in an acidic or alkaline solvent.
  • the compounds of the invention can be obtained in particular by the following route:
  • Y, Ri R 2 , R 3 , , Z and A are as defined above; and X represents a halogen atom, preferably fluorine, chlorine and bromine.
  • the reaction formula (II) can be stirred at room temperature to 200 ° C with or without pressure by using an excess of the compound of the formula (III) in the presence of a solvent with or without a solvent.
  • the compound of formula (I) is prepared by compound and compound of formula (III) for 0.5-10 hours.
  • a compound of the formula (III) or a salt thereof such as hydrochloric acid, hydrobromic acid or trifluoroacetic acid may be used in the form of a free mixture.
  • any solvent which does not adversely affect the reaction can be used. Preference is given to using acetonitrile, dimethylformamide, dimethyl sulfoxide, pyridine or hexamethylphosphoramide.
  • This reaction is generally carried out in the presence of an acid acceptor.
  • an excess of the reactant compound of the formula (III) is used, for example, equimolar to 10-fold molar amount to the relative starting material, superiority, etc.
  • the molar amount is 5 times the molar amount.
  • Acid acceptors which are preferably used in the reaction include inorganic bases such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium fluoride and the like, and organic bases such as triethylamine, diisopropylethylamine, pyridine, hydrazine, hydrazine. - dimethylaminopyridine, hydrazine, hydrazine-dimethylaminoaniline, 1,8-diazabicyclo[5,4,0] ⁇ -carbon-7-ene (DBU), 1,4-diazabicyclo[ 2, 2, 2] octane (DABCO) and the like.
  • the compound of the formula (I) of the present invention can also be produced by the method shown in the following Reaction Scheme 2.
  • Y, Ri R 2 , R 3 , , Z and A are as defined above; and X represents a halogen atom, and preferably fluorine, chlorine and bromine.
  • X represents a halogen atom, and preferably fluorine, chlorine and bromine.
  • one of R 2 and R 3 is 11.
  • the compound of the formula ( ⁇ ) is the same as in the reaction scheme 1, and in the scheme 2, a compound of the formula ( ⁇ ) in the form of a free compound, or a salt thereof with hydrochloric acid, hydrobromic acid or trifluoroacetic acid can be used.
  • Any protecting group conventionally used in the field of organic chemistry and which is easily removed after the reaction without decomposing the structure of the target compound can be used as a suitable amino protecting group in the compound of the formula (III).
  • Specific examples of the protecting group which can be used for this object include formyl group, acetyl group, trifluoroacetyl group, substituted or unsubstituted benzoyl group, p-toluenesulfonyl group, methoxycarbonyl group, ethoxycarbonyl group, isobutoxycarbonyl group, Tert-Butoxycarbonyl, substituted or unsubstituted benzyloxycarbonyl, substituted or unsubstituted benzyl, trityl, tetrahydropyranyl, 5-methyl-2-oxo-1,3-oxeane- 4-enylmethyl, alkanoyloxymethyl, ⁇ -aminoalkylacyl and the like.
  • the amino protecting group present in the formed compound of the formula ( ⁇ ) can be removed by hydrolysis, solvolysis or reduction depending on the relevant nature of the protecting group.
  • a compound of the formula ( ⁇ ) is treated in a solvent in the presence of an inorganic acid or a base at a temperature of from 0 to 150 ° C to remove the protecting group.
  • the acid which can be used for this purpose may be a mineral acid such as hydrochloric acid, hydrobromic acid, phosphoric acid or the like, and an organic acid such as acetic acid, trifluoroacetic acid, formic acid, toluenesulfonic acid or the like.
  • Lewis acid such as: boron tribromide, alumina, etc.
  • an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, cesium hydroxide or the like, an alkali metal carbonate such as sodium carbonate, calcium carbonate or the like, an alkali metal alkoxide such as: Sodium methoxide, sodium ethoxide, etc., or sodium acetate.
  • the reaction can be carried out in a solvent such as 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 solvent In progress.
  • the protecting group is p-toluenesulfonyl, benzyl, trityl, p-methoxybenzyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, trichloroethoxycarbonyl, ⁇ -iodoethoxy
  • the carbonyl group is equal, these groups can be effectively removed by reduction.
  • the reduction reaction conditions for removing the protecting group vary depending on the nature of the relevant protecting group, but the reduction is generally carried out in a hydrogen stream in an inert solvent at a temperature of from 10 to 150 ° C in the presence of a catalyst such as platinum, palladium or Raney nickel.
  • the next step is carried out with sodium metal or lithium metal in aqueous ammonia at a temperature of -50 ° C to -10 ° C.
  • R represents an aliphatic carboxyl group of 2 to 6 carbon atoms substituted with or without a hetero atom, or an aromatic carboxyl group of 7 to 11 carbon atoms
  • Y, R 2 , R 3 , Z, and A are as defined above
  • X represents a halogen atom, and is preferably fluorine, chlorine or bromine.
  • a compound of the formula (V) can be produced by reacting a compound of the formula (II) with a tribasic borate derivative of the formula (VIII) in the presence of a solvent.
  • the triacid borate derivative of the formula (VIII) can be used in an amount equivalent to 50 equivalents of the compound of the formula (II).
  • reaction solvent an organic acid such as acetic acid, propionic acid or trifluoroacetic acid can be used.
  • the reaction temperature is in the range of 20 to 200 ° C, preferably 20 ° C to the boiling point of the solvent used.
  • the triacid borate derivative of the formula (VIII) can be prepared by reacting boric acid with an organic acid such as acetic acid, propionic acid, trifluoroacetic acid or an organic acid anhydride in the presence or absence of zinc chloride (e.g. Reaction with acetic anhydride, propionic anhydride, trifluoroacetic anhydride).
  • the amount of boric acid used is 1.1 to 5 equivalents based on the compound of the formula. It is preferably 1.5 equivalents.
  • the obtained triacid borate derivative can be directly used for the reaction with the compound of the formula ( ⁇ ) without isolation.
  • the compound represented by the formula (V) is condensed with a compound represented by the formula (III) or the formula (?).
  • the compound of the formula (III) and the formula ( ⁇ ) is the same as in the reaction schemes 1, 2, and in the reaction scheme 3, the reaction can be used in this step.
  • the reaction formula (II) can be stirred at room temperature to 200 ° C with or without pressure by using an excess of the compound of the formula (III) in the presence of a solvent with or without a solvent.
  • the compound of formula (I) is prepared by compound and compound of formula (III) for 0.5-10 hours.
  • a compound of the formula (III) or a salt thereof such as hydrochloric acid, hydrobromic acid or trifluoroacetic acid may be used in the form of a free mixture.
  • any solvent which does not adversely affect the reaction can be used. Preference is given to using acetonitrile, dimethylformamide, dimethyl sulfoxide, pyridine or hexamethylphosphoramide.
  • This reaction is generally carried out in the presence of an acid acceptor.
  • an excess of the reactant compound of the formula (III) is used, for example, equimolar to 10-fold molar amount for the relative starting material, superiority, etc.
  • the molar amount is 5 times the molar amount.
  • Acid acceptors which are preferably used in the reaction include inorganic bases such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium fluoride and the like, and organic bases such as triethylamine, diisopropylethylamine, pyridine, hydrazine, hydrazine. - dimethylaminopyridine, hydrazine, hydrazine-dimethylaminoaniline, 1,8-diazabicyclo[5,4,0] ⁇ -carbon-7-ene (DBU), 1,4-diazabicyclo[ 2, 2, 2] octane (DABCO) and the like.
  • inorganic bases such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium fluoride and the like
  • organic bases such as triethylamine, diisopropylethylamine, pyridine, hydrazine, hydrazine. - dimethylaminopyridine, hydr
  • Any protecting group conventionally used in the field of organic chemistry and which is easily removed after the reaction without decomposing the structure of the target compound can be used as a suitable amino protecting group in the compound of the formula (III).
  • Specific examples of the protecting group which can be used for this object include formyl group, acetyl group, trifluoroacetyl group, substituted or unsubstituted benzoyl group, p-toluenesulfonyl group, methoxycarbonyl group, ethoxycarbonyl group, isobutoxycarbonyl group, Tert-Butoxycarbonyl, substituted or unsubstituted benzyloxycarbonyl, substituted or unsubstituted benzyl, trityl, tetrahydropyranyl, 5-methyl-2-oxo-1,3-oxeane- 4-enylmethyl, alkanoyloxymethyl, ⁇ -aminoalkylacyl and the like.
  • an amino-protecting group is present in the formed compound of the formula (I), it may be removed by hydrolysis, solvolysis or reduction depending on the relevant properties of the protecting group.
  • a compound of formula (V) is treated in a solvent in the presence of an organic or inorganic acid or base at a temperature of from 0 to 15 CTC to remove the protecting group.
  • the acid which can be used for this purpose may be a mineral acid such as hydrochloric acid, hydrobromic acid, phosphoric acid or the like, and an organic acid such as acetic acid, trifluoroacetic acid, formic acid, toluenesulfonic acid or the like.
  • Lewis acid such as: boron tribromide, aluminum oxide, and the like.
  • an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, cesium hydroxide or the like, an alkali metal carbonate such as sodium carbonate, calcium carbonate or the like, an alkali metal alkoxide such as: Sodium methoxide, sodium ethoxide, etc., or sodium acetate.
  • a solvent such as water or an organic solvent such as: ethanol, tetrahydrofuran, dioxane, ethylene glycol, acetic acid, etc., or a mixture of such an organic solvent and water, if necessary, the reaction may be in the absence of any solvent. In progress.
  • the protecting group is p-toluenesulfonyl, benzyl, trityl, p-methoxybenzyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, trichloroethoxycarbonyl, ⁇ -iodine
  • these groups can be effectively removed by reduction.
  • the reduction reaction conditions for removing the protecting group vary depending on the nature of the relevant protecting group, the reduction is generally carried out in a hydrogen stream in an inert solvent at a temperature of from 10 to 150 ° C in the presence of a catalyst such as platinum palladium Raney nickel. Or using sodium metal or lithium metal in ammonia water at a temperature of -50 ° C to -10 ° C.
  • the compound of the formula ( ⁇ ) used as a starting material in the present invention is a known compound and can be easily produced by a method known in the prior art (for example: L A. Mitscher et al., J. Med. Chem 30, 2283 (1987); JM Domagala et al, J. Med. Chem. 31, 503 (1988); DTWChu et al, J. Med. Chem. 29, 2633 (1986); JM Domagala et al, J. Med. Chem. 34, 1142 (1991); D. Bouzard et al, J. Med. Chem. 35, 518 (1992); JM Domagala et al, J. Med. Chem. 31, 991 (1988)).
  • the invention also includes an intermediate (III) and ( ⁇ ) compound of the compound of formula (I),
  • the methoxyimino group at the 3-position may be replaced with another alkoxyimino group (e.g., C 2 -C 6 alkoxyimino) in the same manner.
  • the present invention also provides a compound of formula (I) as defined above, or a pharmaceutically acceptable ester, amide, hydrate, isomer thereof or a pharmaceutically acceptable non-toxic salt thereof, and their pharmaceutically acceptable
  • An antibacterial composition in which a carrier is combined with a compound as an active ingredient. When such an antibacterial composition is used for clinical purposes, it can be formulated into a solid, semi-solid or liquid pharmaceutical preparation for oral, parenteral or topical use by combining the compound of formula (I) with a pharmaceutically acceptable inert carrier. .
  • Pharmaceutically acceptable inert carriers which can be used for this purpose can be either solid or liquid.
  • Solid or semisolid pharmaceutical preparations in the form of powders, tablets, dispersible powders, capsules, suppositories, and gums can be prepared, in which case solid carriers are usually employed.
  • the solid carrier which can be used is preferably one or more of a diluent, a flavoring agent, a solubilizer, a lubricant, a suspending agent, a binder, a swelling agent and the like, or may be an encapsulating substance.
  • 5% to 70% of the micronized active ingredient is contained in the carrier.
  • suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, yellow gum, methylcellulose, sodium carboxymethylcellulose, low Boiling point waxes, cocoa butter, etc., because of their ease of administration, tablets, powders, capsules represent the most advantageous oral solid preparation for absorption.
  • Liquid preparations include solutions, suspensions and emulsions.
  • an injectable preparation for parenteral administration may be in the form of water or a solution of water and propylene glycol, adjusting its isotonicity, pH, etc., suitable for physiological conditions of a living body.
  • the liquid preparation can also be in the form of a polyethylene glycol aqueous solution.
  • An oral aqueous solution can be prepared by dissolving the active ingredient in water, followed by the addition of suitable coloring, flavoring, stabilizing and thickening agents.
  • the aqueous suspension for oral administration can be prepared by dispersing the micronized active ingredient in a viscous material such as natural or synthetic gum, methylcellulose, sodium acid methylcellulose and other known suspending agents.
  • Dosage unit form of the formulation refers to a physically discrete unit suitable as a single dose, and each unit contains 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 amount of active ingredient contained in the dosage unit form can vary, it is generally adjusted in the range of from 1 to 500 mg, depending on the potency of the active ingredient selected.
  • the active compound of the formula (I) of the present invention is used as a medicament for treating a bacterial infection, it is preferably administered in an amount of 6 to 14 mg/kg of body weight in the first stage.
  • the dosage administered can vary depending on the needs of the patient, the severity of the infection to be treated, the selected compound, and the like.
  • the preferred dosage for a particular situation can be determined in a conventional manner.
  • the amount of treatment initiated is lower than the optimal dose of the active ingredient, and then the dosage is gradually increased until the optimal therapeutic effect is achieved.
  • the total daily dose can be divided into several parts, administered in divided doses.
  • the compounds of the present invention have stronger antibacterial activity and broad antibacterial spectrum against various pathogenic microorganisms including Gram-negative bacteria and Gram-positive bacteria.
  • the antibacterial activity of the compounds of the present invention against Gram-positive strains, particularly Staphylococcus including MRSA and MRSE, is much higher than that of the recently marketed quinolone antibacterial agent gemifloxacin (gemifl 0xaCin ).
  • the drug sensitivity test was carried out by using the plate double dilution method and the Denlay multi-point inoculator.
  • the experimental bacteria were enriched with nutrient broth and annoying infusion; after the drug was dissolved, the MH broth was diluted twice to various desired concentrations, respectively. Appropriate amount into the plate, dissolve the MH agar medium and quantitatively inject into the plate containing the drug solution.
  • the final concentration of the drug is 0.03, 0.06, 0.125... 128 ⁇ ⁇ / ⁇ 1, and the medium in the plate is solidified.
  • the multi-point inoculator was inoculated with the experimental bacteria (105 cfh/point), and the results were observed after incubation at 35 ° C for 18 hours.
  • the minimum concentration of the drug contained in the aseptically grown plate was the minimum inhibitory concentration.
  • the activity was measured by two-fold dilution of the plate, and the medium was MH (DIFCO) medium.
  • the strains used in the experiment were clinical isolates collected from Sichuan and Beijing, and the strains used were collected and separated (Huaxi Medical University Branch, Department of Infectious Diseases of Chongqing Medical University and Bacterial Room of Beijing Hospital) were all identified by automatic bacteria detector.
  • the compound of the present invention has a suitable water solubility as compared with known quinolone compounds, and thus can be well absorbed in the body, exhibits a very high bioavailability, and is suitably used as an antibacterial agent.
  • the compound of the present invention has low toxicity, it can be effectively used for the prevention and treatment of warm-blooded animals including humans.
  • the compounds prepared by the methods of Examples 6, 8, and 10 were subjected to toxicity tests, and solutions containing the three compounds at different concentrations were orally administered to male mice at a dose of O. lmL/lOg body weight, the number of dead rats was counted after 7 days, and the half lethal dose (LD50) of each compound was calculated by Bliss program. The results are shown in Table 3.
  • Test compound LD50 (mg/Kg)
  • Example 1 Synthesis of 4-(N-tert-butoxycarbonyl)aminemethyl-4-fluoro-1-(N-tert-butoxycarbonyl)-pyrrolidin-3-ol (4) Lithium tetrahydrogenate Aluminium (3.6 g, 94.7 mmol) was dissolved in anhydrous THF (150 ml), and a solution of 2 (1 lg, 47.6 mmol) dissolved in anhydrous THF (100 ml) in an ice salt bath (-5 ° C) was used.
  • Acetyl chloride (10 ml) was added dropwise to ice-cooled methanol (20 ml), and the mixture was added dropwise, stirring was continued for 0.5 h at the same temperature, then a solution of 9 (1.Og, 2.77 mmol) in methanol (10 ml) was added.
  • the above solution of hydrogen chloride pentahydrate was stirred at room temperature for 0.5 h. After completion of the reaction, the solvent was evaporated, and then ethyl acetate was evaporated and evaporated.
  • Example 5 1-(2,4-Difluorophenyl)-6-fluoro-7-[4-(aminomethyl)-4-fluoro-3-(alkoxyimino)pyrrolidin-1-yl -1,4-Dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid
  • Method 1 Compound 7-Chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid (0.5 g, 1.40 mmol), DBU (0.43 ml, 5 mmol), m.
  • Example 9 1-Cyclopropyl-6-fluoro-7-[4-(aminomethyl)-4-fluoro-3-(alkoxyimino)pyrrolidin-1-yl]-8-methoxy -1,4-dihydrogen -4-oxoquinoline-3-carboxylic acid
  • the ethyl 1-ethyl-6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate is first converted into a chelating ester of a boron ester.
  • the compound was reacted with the compound of Example 4 to give a pale yellow solid product (yield: 87.5%, mp: 186 to 187.5 ° C).
  • the preparation method of the compound of the same example 9 is carried out from 1-cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid
  • the ester is first converted into a chelate of a boron ester, and the compound 4-N-acetylmethylamine methyl-4-fluoro-3-(; alkoxyimino;)pyrrolidine prepared in Scheme 4 is reacted to obtain Product, yield 63.66%, mp: 186-188 °C.
  • the in vitro antibacterial activity of the compounds of the present invention was achieved by measuring their minimum inhibitory concentration (MlC ⁇ g/ml) against the strain.
  • the known antibacterial compound gemifloxacin was used as a control drug.
  • the minimum inhibitory concentration was determined by the following method: The test compound was diluted by the two-fold dilution method, and then dispersed in a DIFCO medium adjusted to a pH of 8.0 and autoclaved, and then inoculated with the bacterial solution, and cultured at 37 ° C. Hour. The results of the measurements are listed in Table 1.
  • Example 13 Coated tablets:
  • the above ingredients are uniformly mixed, granulated, sieved, granulated, dried, and tableted to make 100 core pieces.

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Abstract

L'invention concerne un composé de formule (I) et ses sels et hydrates de qualité pharmaceutique, leurs procédés de préparation et leur application dans la préparation d'antibiotiques. Y représente H, en C1-C6 alkyle substitué ou non, 5-méthyl-2-oxo-1, 3- dioxycyclopenten-4-ylméthyle ou alkylocyclométhyle, le substituant étant hydroxyle, halogène ou amino. A représente C-H, C-F, C-Cl, C-OCH3, C-CH3 ou N; R1 est alkyle en C1-C3, fluoroalkyle en C1-C3, cyclopropyle, fluorocyclopropyle, phényle ou halogénobenzényle, ou alors A et R1 forment un groupe de pontage C-O-CH2-CH(CH3)-. Z représente H, halogène, NH2 ou CH3. R2 ou R3 sont respectivement H, un alkyle en C1-C6 ou un groupe de protection de la fonction amine. R4 représente un alkyle en C1-C6.
PCT/CN2008/071843 2008-07-28 2008-08-01 Dérivés de l'acide carboxylique de quinoline 7-[4-(aminométhyl)-4-fluoro-3-(alkoxyimino)pyrrolidin-1-yle] et leurs procédés de préparation WO2010012138A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0688772A1 (fr) * 1994-06-16 1995-12-27 LG Chemical Limited Dérivés de l'acide quinolinecarboxylique ayant des substituants 7-(4-amino-méthyl-3-oxime)-pyrrolidine et procédé pour leur préparation
WO2000071541A1 (fr) * 1999-05-20 2000-11-30 Dong Wha Pharm. Ind. Co., Ltd. Derives d'acide quinoleine-carboxylique actifs optiquement presentant des substituts 7-pyrrolidines amenant une activite optique et leur procede de preparation
WO2006134608A1 (fr) * 2005-06-15 2006-12-21 Hetero Drugs Limited Procede de preparation de la gemifloxacine et polymorphes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0688772A1 (fr) * 1994-06-16 1995-12-27 LG Chemical Limited Dérivés de l'acide quinolinecarboxylique ayant des substituants 7-(4-amino-méthyl-3-oxime)-pyrrolidine et procédé pour leur préparation
US5698570A (en) * 1994-06-16 1997-12-16 Lg Chemical Ltd. Quinoline carboxylic acid derivatives having 7-(4-amino-methyl-3-oxime)pyrrolidine substituent and processes for preparing thereof
WO2000071541A1 (fr) * 1999-05-20 2000-11-30 Dong Wha Pharm. Ind. Co., Ltd. Derives d'acide quinoleine-carboxylique actifs optiquement presentant des substituts 7-pyrrolidines amenant une activite optique et leur procede de preparation
WO2006134608A1 (fr) * 2005-06-15 2006-12-21 Hetero Drugs Limited Procede de preparation de la gemifloxacine et polymorphes

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