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WO1996001262A1 - Nouveau compose de quinoleine et son procede de preparation - Google Patents

Nouveau compose de quinoleine et son procede de preparation Download PDF

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Publication number
WO1996001262A1
WO1996001262A1 PCT/KR1995/000084 KR9500084W WO9601262A1 WO 1996001262 A1 WO1996001262 A1 WO 1996001262A1 KR 9500084 W KR9500084 W KR 9500084W WO 9601262 A1 WO9601262 A1 WO 9601262A1
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WIPO (PCT)
Prior art keywords
fluoro
compound
diazabicyclo
cyclopropyl
oxo
Prior art date
Application number
PCT/KR1995/000084
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English (en)
Inventor
Soon Ku Moon
Gwan Sun Lee
Eui Sang Ryoo
Yound Ho Moon
Nam Du Kim
Original Assignee
Hanmi Pharmaceutical Co., Ltd.
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Filing date
Publication date
Application filed by Hanmi Pharmaceutical Co., Ltd. filed Critical Hanmi Pharmaceutical Co., Ltd.
Publication of WO1996001262A1 publication Critical patent/WO1996001262A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • 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

Definitions

  • the present invention relates to a novel quinoline compound represented by the following general formula (I) which has an excellent antibacterial activity against gram-positive and gram-negative bacteria, particularly methicillin or ofloxacin resistant bacteria and also has a broad antibacterial spectrum and a highly improved pharmacokinetic property :
  • R 1 represents hydrogen or ester forming group
  • R 2 represents hydrogen, amino, lower alkylamino, hydroxy, lower alkoxy, mercapto, lower alkylthio or halogen;
  • Z represents an amine compound having the following
  • R 3 represents hydrogen or lower alkyl
  • R 4 and R 5 are identical to or different from each other, and independently represent hydrogen or C 1 -C 2 alkyl
  • x represents N or C-R 6 (wherein, R 6 represents hydrogen, halogen, hydroxy, methyl, cyano, nitro or methoxy).
  • the present invention also relates to a process for preparing the compound of formula (I), as defined above, and to an antibacterial composition comprising the compound of formula (I) as an active ingredient.
  • European Patent Application No. 215,650-A 2 discloses a compound of the following general formula [A] : in which,
  • A represents CH, CF, CCl or N
  • Y represents C 1 -C 3 alky C 1 -C 3 haloalkyl , cyclopropyl, vinyl, methoxy, N-methylamino, P-fluorophenyl, Phydroxyphenyl, P-aminophenyl or, when A is carbon, the
  • a and the nitrogen to which Y is attached can form 5 or 6 membered ring comprising oxygen and substituted by methyl or methylene group;
  • R 1 represents hydrogen, pharmaceutically acceptable
  • R 2 represents a diazabicycloalkyl group selected from the compounds of the following general formulas :
  • n is an integer of 1 to 3
  • m is 1 or 2
  • p is 0 or 1
  • Q represents hydrogen or C 1 -C 3 alkyl
  • European Patent Application No. 266,576-A 2 discloses a compound of the following general formula [B] :
  • R 1 represents substituted or unsubstituted t-alkyl
  • Z represents N-heterocyclic compound selected from the following general formulas :
  • R 2 represents hydrogen or alkyl
  • n is an integer of 0 to 3
  • diazabicycloamine derivatives mentioned above also do not show an improved, antimicrobial activity compared with the early-stage antibacterial agents.
  • European Patent Application No. 191,185- A 1 discloses a compound of the following general formula [C] :
  • X 1 and X 2 independently represent hydrogen or halogen
  • X 3 represents a halogen
  • R 1 , R 2 and R represent hydrogen or lower alkyl.
  • European Patent Application No. 341,493- A 2 discloses a compound of the following general formula [D] :
  • X 2 represents a halogen
  • R 2 can be selected from the compounds of the following general formulas :
  • the above compound shows more improved characteristics in view of pharmacokinetic property and toxicity.
  • a quinolone compound having a fluorocyclopropyl group on N-1 position and a 3,6-diazabicyclo[3.1.0]hexane derivative on C-7 position of the quinoline nucleus can exhibit a potent antibacterial activity against gram-positive and gram-negative strains, particularly Staphylococcus aureus strain as well as highly reduced toxicity in comparison to the prior quinoline based derivatives, and then completed the present invention.
  • R 1 represents hydrogen or ester forming group
  • R 2 represents hydrogen, amino, lower alkylamino, hydroxy, lower alkoxy, mercapto, lower alkylthio or halogen;
  • Z represents an amine compound having the following
  • R 3 represents hydrogen or lower alkyl
  • R 4 and R 5 are identical to or different from each other, and independently represent hydrogen or C 1 -C 2 alkyl
  • X represents N or C-R 6 (wherein, R 6 represents hydrogen, halogen, hydroxy, methyl, cyano, nitro or methoxy). It is another object of the present invention to provide a process for preparing the compound of formula (I) :
  • R 1 , R 2 , Z and X are defined as previously described, characterized in that a 3-quinoline carboxylic acid derivative having the following general formula (II) :
  • It is a further object of the present invention to provide an antibacterial composition comprising a novel quinoline compound of the formula (I) according to the present invention as an active component together with a pharmaceutically acceptable carrier.
  • the present invention relates to a novel quinoline compound having the following formula (I)
  • R 1 represents hydrogen or ester forming group
  • R 2 represents hydrogen, amino, lower alkylamino, hydroxy, lower alkoxy, mercapto, lower alkylthio or halogen;
  • Z represents an amine compound having the following general formula,
  • R 3 represents hydrogen or lower alkyl
  • R 4 and R 5 are identical to or different from each other, and independently represent hydrogen or C ⁇ C ⁇ alkyl
  • X represents N or C-R 6 (wherein, R 6 represents hydrogen, halogen, hydroxy, methyl, cyano, nitro or methoxy) .
  • lower alkyl means a straight or branched, saturated hydrocarbon radical having 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, etc.;
  • lower alkoxy means a form inwhich the lower alkyl group as mentioned above is connected with oxy, amino or thio group respectively;
  • alkenyl means a straight or branched, unsaturated hydrocarbon radical, for example, ethenyl, propenyl, isopropenyl, etc.;
  • halpalkyl means an alkyl group substituted with one or more halogen atoms which are identical to or different from each other; and the term “halogen” means fluorine, chlorine, bromine, iodine,
  • ester forming group defines all the known ester forming group comprising lower alkyl, cycloalkyl having 3 to 7 carbon atoms and benzyl; and the term “amino protecting group” defines a known amino protecting group such as acyl, alkoxycarbonyl, substituted sulfonyl, substituted or unsubstituted benzyloxycarbonyl, substituted or unsubstituted benzyl, etc.
  • One preferred group of the novel compound of formula (I) according to the present invention includes the compound, wherein
  • R 1 represents a hydrogen
  • R 2 represents hydrogen or amino
  • Z represents an amine compound having the following
  • R 3 represents hydrogen or lower alkyl
  • R 4 and R 5 are identical to or different from each other, and independently represent hydrogen or C 1 -C 2 alkyl
  • X represents N or C-R 6 (wherein, R 6 represents hydrogen, halogen or methoxy).
  • Typical examples of the compound of formula (I) provided by the present invention are as follows. (1) 6,8-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-7-(6- methyl-3,6-diazabicyclo[3.1.0]hexan-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and the salt thereof;
  • the compounds of formula (I) defined above there exist some compounds in their optically active states, especially in the form of pure D isomer, pure L isomer or a mixture thereof, racemate, meso-isomer, dl- isoraer, diastereomer mixture, etc. And, an additional asymmetric carbon atom can exist in a substituent such as an alkyl group or in a linking part.
  • the present invention includes all of those optical isomers of the compound of formula (I) and their mixtures.
  • the compound of formula (I) according to the present invention can form a pharmaceutically acceptable salt.
  • the "pharmaceutically acceptable salt” herein means a nontoxic acid-addition salt or a base addition salt which is formed with an alkali metal, an alkaline earth metal or an organic amine.
  • T h e aforementioned salt can be prepared in the same reaction system during the final separation or purification step. And it can also be obtained by reacting the compound of formula (I) with an appropriate organic acid, an inorganic acid or a base, respectively, after final separation step.
  • Typical examples of the acid-addition salt as mentioned hereinabove comprise hydrochloride, hydrobromide, sulfate, hydrogen sulfate, formate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, p-toluenesulfonate, methane- sulfonate, citrate, maleate, fumarate, succinate, tarta- rate and ascorbate, more preferably, hydrochloride, lactate and methanesulfonate.
  • Typical examples of the alkali metal and alkaline earth metal salt include sodium, potassium, calcium and magnesium salt.
  • organic amines there may be mentioned N,N- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, procaine.
  • the compound of formula (I) can be prepared by reacting a 3- quinoline carboxylic acid derivative of the following general formula (II) with a 3,6-diazabicyclo[3.1.0]hexane derivative of the following general formula (III). Therefore, it is another object of the present invention to provide a process for preparing the novel compound of formula (I)
  • R 1 , R 2 , Z and X are defined as previously described; and represents a halogen.
  • the compound of formula (I) can be prepared according to the above reaction scheme 1, however if appropriately, it can also be conveniently prepared by reacting a complex compound of the compound of formula (II), preferably a boron complex compound represented by following general formula (II-1), with the compound of formula (III) :
  • R 2 , X and Y are defined as previously described.
  • reaction can be carried out in the absence of any solvent, and of course it can also be practiced in the presence of an appropriate solvent such as tetrahydrofuran, dimethylsulfoxide, N,N-dimethylforma- mide, N,N-dimethylacetamide, N-methylpyrrolidone, acetoni- trile, water, alcohol (for example, methanol, ethanol, n- propanol or isopropanol), glycolmonomethylether, pyridine, or a mixture thereof.
  • an appropriate solvent such as tetrahydrofuran, dimethylsulfoxide, N,N-dimethylforma- mide, N,N-dimethylacetamide, N-methylpyrrolidone, acetoni- trile, water, alcohol (for example, methanol, ethanol, n- propanol or isopropanol), glycolmonomethylether, pyridine, or a mixture thereof.
  • a base can facilitate the completion of the reaction 1 by scavenging the halogenated hydrogen produced during the reaction, it is preferable to add a base to the reaction mixture unless the used solvent is basic (for example, pyridine).
  • the used solvent for example, pyridine.
  • Conventional inorganic or organic bases such as alkali metal hydroxide, alkali metal carbonate, organic amine and amidine can be used in this reaction.
  • one or more bases selected from a group consisting of sodium hydroxide, potassium hydroxide, triethylamine, pyridine, picoline, ruthidine, 1,4-diazabicyclo[2.2.2]- octane(DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU), 1,5-diazabicyclo[4.3.0]non-5-ene(DBN) or excessive amount of the amine compound of formula (III).
  • bases selected from a group consisting of sodium hydroxide, potassium hydroxide, triethylamine, pyridine, picoline, ruthidine, 1,4-diazabicyclo[2.2.2]- octane(DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU), 1,5-diazabicyclo[4.3.0]non-5-ene(DBN) or excessive amount of the amine compound of formula (III).
  • the above reaction 1 can be conducted preferably at the temperature of 15 to 200°C, more preferably at 60 to 120°C or reflux temperature of the solvent used.
  • reaction can be carried out for several days, it is advantageous to carry out for 1 to 24 hours, and conventionally, higher reaction temperature may have an effect of shortening the reaction time.
  • the amine compound of formula (III) can be used in the form of an inorganic or an organic acid salt such as hydrochloride, hydrobromide, sulfate, formate, acetate and oxalate.
  • the reactant (III) is preferably used in an amount of 1 to 6 times equivalence with respect to the quinoline carboxylic acid derivative (II).
  • the compound of formula (II) used as the starting material in the above reaction scheme 1 is a known compound and can be readily prepared according to a method known in the prior publication, for example European Patent Application Nos. 191,185-A 1 and 341,493-A 2 , as depicted in the following reaction scheme 2.
  • the 2-fluorocyclopropylamine compound of formula (V) used for preparing the compound of formula ( II ) in the above reaction scheme 2 can be existed as the following four stereochemical isomeric forms ;
  • each isomers in above may be used in the present invention as a pure isomer or a mixture thereof. However, it is most preferable to use the (1R,2S) isomer of the formula (V-1) among them.
  • said compound of formula (V-1) can be prepared according to a modified method of the known one(see: Tetrahedron Lett., 33(24), 3483-3486) as depicted in the following reaction scheme 3.
  • reaction schjeme 3 which represents the synthesis of the compound of formula (V-1)
  • a R- (+)-methylbenzylamine of the formula (V-la) can be reacted with an acetaldehyde to obtain an imine compound, which -is then reacted with bistrichloromethylcarbonate to prepare a N-vinylcarbamoylchloride of the formula (V-1b).
  • prepared compound (V-1b) is treated with 1-(-)-menthol to obtain a carbamate compound of formula (V-lc) and the N- vinyl group in the compound (V-1c) is reacted with carbene to prepare a compound of formula (V-1d).
  • one side amino protecting group of the compound of formula (V-1d) is removed by means of Pd-C/HCOOH to synthesize a compound of formula (V-1e), which is then recrysttllized 3 to 5 times in a mixture of ethylacetate/hexane solvents to obtain an optically active compound of formula (V-1f).
  • the desired amine compound of formula (V-1) can be prepared with the isomeric purity over 97% by deprotecting the carbamate of formula (V-1f) using a trifluoroacetic acid.
  • R represents an amino protecting group which can be
  • R 3 , R 4 and R 5 are defined as previously described.
  • an maleic anhydride compound (III-1) as a starting material is reacted with benzylamine or substituted derivative thereof to obtain a maleaminic acid compound (III-2a + IIl-2b), which is then cyclized to a maleimide compound of formula (III- 3) in the presence of acetic anhydride and sodium acetate.
  • the resulting maleimide compound (III-3) is treated with an azide compound (R 3 -N 3 ) under 1,3-dipolar cycload- dition reaction to synthesize a triazoline compound (III- 4a + III-4b), which is then subjected to photolytic or pyrolytic reaction to obtain a compound of formula (III-5) in a combined form of aziridine and pyrrolidine ring.
  • the imide group among the compound (III-5) thus obtained is reduced with a reductant such as lithium aluminium hydride to prepare a compound (III-6), which is then deprotected by hydrolysis or hydrogenolysis to obtain the desired amine compound of formula (III).
  • X' represents a halogen such as chlorine or bromine; and R, R 3 , R 4 and R 5 are defined as previously described.
  • a compound of formula (III-8) (it can be commer- cially purchased when R 4 and R 5 respectively represent hydrogen, or it can be prepared by reducing first a maleic anhydride derivative of formula (III-1) to a compound of formula (III-7) and then halogenating the hydroxy groups of the compound (III-7) when R 4 and R 5 respectively repre- sent an alkyl) is cyclized with an amine compound (R-NH 2 ) to prepare a 3-pyrroline derivative of formula (III-9).
  • 3-pyrroline derivative (III-9) is treated with chlorine gas to obtain a chlorohydrin derivative, which is then reacted with a base to synthesize an epoxide compound of formula (111-10).
  • a mixture of aminoalcohol compounds (III-lla) and (Ill-lib) can be prepared by means of an addition reaction using amine compound (R 3 -NH 2 ) as a reactant.
  • the resulting mixture is treated with diethylazodicarboxylate(DEAD) and triphenylphosphine(Ph 3 P) to obtain the aziridine compound of formula (III-6), which is then deprotected to obtain the desired amine compound (III).
  • R 6 represents an amino protecting group which can be
  • X represents a leaving group such as halogen, methane- sulfonyloxy, paratoluenesulfonyloxy, diethylphosphory- loxy, diethylthiophosphoryloxy," acetoxy or alkoxy;
  • R, R 3 , R 4 and R 5 are defined as previously described.
  • a compound of formula (111-10) is reacted with sodium azide(NaN 3 ) to obtain an azidoalcohol mixture of compounds (III-12a) and (III-12b). And subsequently, these com- pounds can be converted to a mixture of compounds (III- 13a) and (III-13b) due to a derivazation of the alcohol groups with a suitable leaving group.
  • the mixture thus prepared is reduced to an azide compound of formula (III- 6a) and finally the desired compound of formula (III) can be produced by deprotecting directly the compound (III-6a) or by introducing a protecting group to the aziridine ring and then removing the protecting group from the pyrroli- dine ring and aqiridine ring successiveively.
  • the synthetic methods as mentioned above will be more specifically- explained in the following preparations and examples.
  • the present invention also provides an antibacterial composition
  • an antibacterial composition comprising at least one quinoline compound of formula (I) defined above or a pharmaceutically acceptable salt thereof as an active component, together with a pharmaceutically acceptable carrier.
  • the compound of formula (I) which is desired by the present invention shows a broad antibacterial spectrum and a potent antibacterial activity against gram-positive and gram-negative strains.
  • the present compound (I) exhibits a highly excellent activity against resistant strains which cause serious problems recently.
  • the compound (I) according to the present invention also shows a similar or very high bioavailability in comparison to the prior agents in view of the pharmacokinetic property. And after the compound is absorbed into a living body, since it is distributed broadly and in high concentration over each organs it can be applied to both topical and generalized bacterial infections.
  • the compound according to the present invention is less toxic, it can be effectively used for antibiotic treatment of diseases caused by sensitive bacterial infections in warm-blooded animals including human being. And it can also be used as a washing solution for surface suppression of the growth of bacteria on a contact surface.
  • Sensitive strains generally include the gram-positive or gram-negative and aerobic or anaerobic strains such as Staphylococcus, Lactobacillus, Streptococcus, Sarcina, Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinetobacter, Proteus, Citrobacter, Nisseria, Baccullus, Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia, Haemophilus, Brucella, etc.
  • the compound according to the present invention when used as an antibacterial agent, it may be formulated into pharmaceutical compositions for parenteral injection, oral administration in solid or liquid phase or rectal administration, or into a patchs by combining the compound of formula (I) with a pharmaceutically acceptable inert carrier.
  • the injectable preparation for parenteral administration may be prepared in the form of sterile aqueous or nonaqueous solution, suspension, or emulsion.
  • a nonaqueous carrier, diluents, solvents or excipients which can be appropriately used include propyleneglycol, polyethyleneglycol, vegitable oils (for example, olive oil, sesame oil), organic ester for injection (for example, ethyloleate).
  • compositions can be sterilized by filtering or incorporating a sterilizing agent into a solid composition which can be solubilized in sterilized water or other sterilized injectable carrier.
  • the solid preparation for oral administration includes capsules, tablets, pills, powders and granules.
  • the active ingredient is mixed with one or more inert solid carriers selected from the group consisting of sucrose, lactose, dicalciumphosphate, cellulose, pectin, dextrin, gelatine and starch.
  • the solid preparation can comprise an additional component (for example, lubricants such as magnesium stearate) besides the inert solid carrier and it can also comprise a buffering agent in the case of capsules, tablets or pills.
  • the liquid preparation for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions and syrups which are formulated by comprising adjuvants such as humectant, emulsifying agents, suspending agents, sweeteners, aromatics or flavoring agents including inert diluents.
  • adjuvants such as humectant, emulsifying agents, suspending agents, sweeteners, aromatics or flavoring agents including inert diluents.
  • composition for rectal administration includes suppository which can comprise excipients such as a cocoa oil or a wax for suppository besides the active ingredient.
  • the aforementioned patchs comprise a pharmaceutically acceptable carrier and a metal salt of the compound of formula (I).
  • the carrier can be a hydrophilic carrier or an oil-water one which are dispersive in water, especially a water-dispersive carrier or an aqueous oil-water emulsions in a form of semi-soft or cream type. Said carriers can be used with minimum indisposition on the burned or infected surface.
  • This composition can also be prepared by mixing simply or homogeneously the micronized active component with a hydrophilic carrier or a basic plaster.
  • the amount of active compound in the composition according to the present invention can be varied depending on the pathway of administration to produce the desired antibacterial activity effectively. Therefore, the dosage level can be determined according to various factors such as efficacy of the active compound to be used, administration pathway, expected treatment period, etc.
  • the effective daily amount is about 0.5 to 500 mg of the active ingredient per kg of body weight. If required, the daily amount can be administered over several times, for example 2 to 4 times at appropriate intervals throughout a day. Those skilled in the art could easily determine the effective daily amount depending on the specific conditions.
  • N-benzylmaleimide 5g(24 mmole) of N-benzylmaleaminic acid and 1.2g of sodium acetate were mixed in 12ml of acetic anhydride and the mixture was stirred for 1.5 hours at 95 to 105°C. After stirring, the reaction solution was poured into 50g of micronized ice and stirred for 2 hours by a mechanical stirrer. Water phase was removed from the solution and to the semi-solid dark brown product thus obtained was added 500 ml of ether. Then, after stirring for 20 minutes and removing the ether-insoluble dark brown solid by filtration, the ether filtrate was washed with aqueous sodium bicarbonate solution.
  • a conduit was connected in order to transfer the methane azide produced in the reaction vessel to the N- benzylmaleimide solution and a sodium hydroxide trap was installed in the middle of the conduit. While maintaining the temperature of the aqueous solution in the reaction vessel at 75 to 85°C, 37.2ml (0.4 mole) of dimethylsulfate was added dropwise over 40 minutes and then the flask containing N-benzylmaleimide solution was removed from the dryice-acetone bath. The flask was allowed to stand after the internal temperature being elevated to normal temperture.
  • reaction solution was stirred for 3 hours under refluxing and cooled under ice bath. Then, 0.85ml of water, 0.85ml of 15%-KOH and 2.5ml of water were successiveively added thereto while maintaining the temperature around 10°C. The tetrahydrofuran was removed under reduced pressure, and to the residue was added 100ml of chloroform to extract a product. Then, the product was washed with water and saturated sodium chlo- ride solution, dried and filtered.
  • Step (2) Synthesis of ethyl 8-chloro-6,7-difluoro-1- [(1R,2S)-2-fluoro-1-cyclopropyl]-4-oxo-1,4- dihydroquinoline-3-carboxylate; 4.9g of ethyl 3-(3-chloro-2,4,5-trifluorophenyl)-2- [(1R,2S)-2-fluoro-1-cyclopropyl)amino]methylene-3-oxopropionate was dissolved in 50ml of N,N-dimethylformamide and 0.9g of sodium fluoride (NaF) was added thereto.
  • NaF sodium fluoride
  • the following examples 17 to 22 relate to the preparation of antibacterial composition which contain the quino line based compound according to the present invention as an active ingredient.
  • the above components were mixed with ethanol and granulated according to the conventional method and then filled into 100 capsules.
  • Example 20 The above components were mixed with ethanol and granulated according to the conventional method and then compressed into 100 tablets.
  • Example 20 The above components were mixed with ethanol and granulated according to the conventional method and then compressed into 100 tablets.
  • the above components were mixed with ethanol and granulated according to the conventional method and then compressed into 100 tablets.
  • Example 21 The compound prepared in Example 2 0.5g
  • Example 22 The compound prepared in Example 6 0.5g
  • the antibacterial activity of the compounds according to the present invention was evaluated by measuring their minimum inhibitory concentration (MIC; ⁇ g/ml) against strains according to the agar plate dilution method (see: Chemotheraphy, 29(1), p76-79, 1981).
  • the overnight culture of the pathogenic strain (10 6 cells/ml) was inoculated to Mueller-Hinton agar so that each spot contained about 10 4 colony forming particles. After the agar was cultured for 18 hours at 37 °C, the minimum concentration at which the test compounds could inhibit the apparent growth of the strains was determined as the minimum inhibitory concentration(MIC, ⁇ g/ml).
  • the compounds according to the present invention show an excellent antibacterial activity against resistant strains which cause great problems recently as well as against broad range of gram-positive and gram- negative strains.
  • Escherichia coli DC 2 10. Escherichia coli TEM
  • the bioavailability of the compound according to the present invention was determined using ICR mouse weighing about 30g. Specifically, the test compounds of the present invention were orally administered in an amount of
  • test mouse ICR mouse, 5 weeks old, 25-29g
  • results are represented as PD 50 .
  • the compounds according to the present invention have more excellent antiinflammatory effect than the ciprofloxacin used as a control drug.
  • test results as to the distribution of the compounds in living tissues were determined against male ICR mouse. Specifically, the compound according to the present invention (the compound prepared in Example 2) and ciprofloxacin and ofloxacin were tested. They were orally administered in an amount of 40mg/kg of body weight to test animals and then the distributions at each tissue were determined. The results are described in the following Table 6.
  • the compounds according to the present invention are existed in almost every living tissue with a still higher concentration in contrast to the control compounds.

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Abstract

L'invention concerne un nouveau composé de quinoléine représenté par la formule générale (I), ainsi que son sel acceptable pharmaceutiquement, qui présente une efficacité antibactérienne supérieure à celle des agents antibactériens connus à base de quinoléine: formule dans laquelle: R1 représente hydrogène ou un groupe de formation d'ester; R2 représente hydrogène, amino, alkylamino inférieur, hydroxy, alcoxy inférieur, mercapto, alkylthio inférieur ou halogène; Z représente un composé d'amine possédant la formule générale (α): (dans laquelle R3 représente hydrogène ou alkyle inférieur; R4 et R5 sont identiques ou différents et représentent indépendamment hydrogène ou alkyle C¿1?-C2); et X représente N ou C-R?6¿ (dans laquelle R6 représente hydrogène, halogène, hydroxy, méthyle, cyano, nitro ou méthoxy).
PCT/KR1995/000084 1994-07-02 1995-06-30 Nouveau compose de quinoleine et son procede de preparation WO1996001262A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004033451A1 (fr) * 2002-10-09 2004-04-22 Pharmacia & Upjohn Company Llc Derives d'oxazolidinone bicyclique [3.1.0] antimicrobien
US7867992B2 (en) 2004-07-21 2011-01-11 Aicuris Gmbh & Co. Kg Substituted quinolones
US7977349B2 (en) 2006-02-09 2011-07-12 Aicuris Gmbh & Co. Kg Substituted quinolones III
US9937172B2 (en) 2014-09-30 2018-04-10 Derek Alton Lightner Mixtures of heteropolycycles

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WO1992012155A1 (fr) * 1991-01-14 1992-07-23 Hanmi Pharmaceutical Co., Ltd. Nouveaux composes de quinoleine et leurs procedes de preparation
EP0603887A2 (fr) * 1992-12-25 1994-06-29 Daiichi Pharmaceutical Co., Ltd. Dérivés bicycliques d'amines

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Publication number Priority date Publication date Assignee Title
WO1992012155A1 (fr) * 1991-01-14 1992-07-23 Hanmi Pharmaceutical Co., Ltd. Nouveaux composes de quinoleine et leurs procedes de preparation
EP0603887A2 (fr) * 1992-12-25 1994-06-29 Daiichi Pharmaceutical Co., Ltd. Dérivés bicycliques d'amines

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004033451A1 (fr) * 2002-10-09 2004-04-22 Pharmacia & Upjohn Company Llc Derives d'oxazolidinone bicyclique [3.1.0] antimicrobien
US6875784B2 (en) 2002-10-09 2005-04-05 Pharmacia & Upjohn Company Antimibicrobial [3.1.0.] bicyclic oxazolidinone derivatives
US7867992B2 (en) 2004-07-21 2011-01-11 Aicuris Gmbh & Co. Kg Substituted quinolones
US7977349B2 (en) 2006-02-09 2011-07-12 Aicuris Gmbh & Co. Kg Substituted quinolones III
US9937172B2 (en) 2014-09-30 2018-04-10 Derek Alton Lightner Mixtures of heteropolycycles
US10231970B2 (en) 2014-09-30 2019-03-19 NV Heterocycles Methods of producing heteropolycycles via bis-epoxidation

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