WO1992012155A1 - Nouveaux composes de quinoleine et leurs procedes de preparation - Google Patents

Nouveaux composes de quinoleine et leurs procedes de preparation Download PDF

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Publication number
WO1992012155A1
WO1992012155A1 PCT/KR1992/000003 KR9200003W WO9212155A1 WO 1992012155 A1 WO1992012155 A1 WO 1992012155A1 KR 9200003 W KR9200003 W KR 9200003W WO 9212155 A1 WO9212155 A1 WO 9212155A1
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WIPO (PCT)
Prior art keywords
diazabicyclo
carbon atoms
dihydro
oxo
cyclopropyl
Prior art date
Application number
PCT/KR1992/000003
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English (en)
Inventor
Soon Ku Moon
Gwan Sun Lee
Eui Sang Ryoo
Young Kil Chang
Young Ho Moon
Sang Tae Kim
Jong Pil Chun
Joon Hyung Koh
Young Hwan Gil
Original Assignee
Hanmi Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR1019910017787A external-priority patent/KR940008419B1/ko
Priority claimed from KR1019910025396A external-priority patent/KR940008420B1/ko
Application filed by Hanmi Pharmaceutical Co., Ltd. filed Critical Hanmi Pharmaceutical Co., Ltd.
Priority to JP4502607A priority Critical patent/JPH06509792A/ja
Publication of WO1992012155A1 publication Critical patent/WO1992012155A1/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
    • 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

  • This invention relates to novel quinolone compounds having more improved antimicrobial activity and their pharmaceutically acceptable salts, and processes for preparation thereof.
  • quinolone antimicrobial agents such as norfloxacin, pefloxacin, ofloxacin, ciprofloxacin, and sparfloxacin show excellent antimicrobial activities against gram negative bacteria, but show comparatively low activities against gram positive bacteria.
  • diazabicyclic compounds are reported as a substituent at 7-position of quinolone antimicrobial agents, and some examples are described in the following.
  • R 2 is a diazabicycloalkyl group selected from the following structural formula.
  • n 1, 2, or 3, m is 1 or 2, P is 0 or 1, Q is hydrogen or (C 1 ⁇ C 3 ) alkyl
  • R 1 is substituted or unsubstituted tert-alkyl group
  • Z is a N-heterocyclic group selected from the following structural formula.
  • n is an integer from 0 to 3).
  • the object of present invention is to provide more potent and improved quinolone antimicrobial agents than previously developed ones both against gram positive and negative bacteria by introducing novel amine substituents at C 7 -position of quinolone nucleus.
  • This invention relates to novel quinolone compounds of Formula(I) and thier pharmaceutically acceptable salts.
  • R 1 is hydrogen or protective group
  • R 2 is hydrogen, amino, alkylamino from one to four carbon atoms, hydroxy, alkoxy from one to four carbon atoms, mercapto, alkylthio from one to four carbon atome, or halogen,
  • R 3 is alkyl from one to four carbon atoms, alkenyl from two to four carbon atoms, cycloalkyl from three to six carbon atoms, haloalkyl, hydroxyalkyl from two to four carbon atoms, methoxy, amino, alkylamino from one to two carbon atoms, dimethylamino, or optionally substituted phenyl with more than one of halogen atoms or alkyl from one to three carbon atoms,
  • R 4 is hydrogen or alkyl from one to four carbon atoms
  • R 5 and R 7 are, same or different, hydrogen or alkyl from one to two carbon atoms
  • X is N or C-R 6 (wherein, R 6 is hydrogen, hydroxy, methyl, cyano, nitro, methoxy, halogen, or can form a bridge of the following Formula with R 3 ;
  • This invention includes a process for preparing a compound of the above Formula(I) by reacting a compound of Formula(II) with a compound of Formula (III) in the presence of a solvent and a base.
  • R 1 , R 2 , R 3 , X and Z are as defined above, and Y is halogen.
  • novel quinolone compound of the above Formula(I) in accordance with this invention has excellent antimicrobial activity both against gram positive and negative bacteria.
  • the compound of Formula(I) in this invention is characterized by introducing Z group, a novel 3,6-diazabicyclo[3.1.0] hexane derivative of the following Formula.
  • R 4 , R 5 and R 7 are as defined above, at C 7 -position of quinolone nucleus.
  • This invention also relates to the process for preparing a compound of Formula( ⁇ ) by reacting 3-quinolinecarboxylic acid derivative of Formula(II) with
  • the compound of Formula(I) is easily prepared by reacting a compound of Formula(II) with an amine of Formula(III) according to the following scheme,
  • R 1 , R 2 , R 3 , Z, X, and Y are as defined above.
  • a compound of Formula(II) can be prepared according to the reported methods or applying them, for example, Chem. Pharm. Bull., 34(10), 4098- 4102(1986), J. Med. Chem., 30(3), 504-509(1987), U.S .Patent No. 4,885,386, E.P.
  • a novel amine compound of Formula(III) is prepared in three ways according to the following reaction schemes.
  • R 5 and R 7 are as defined above,
  • R is amino protective group which can be removed by acid or base hydrolysis, or catalytic hydrogenation, and
  • R' is alkyl from one to four carbon atoms or amino protective group.
  • the maleimide compound of Formula(III-3) is obtained by reacting maleic anhydride compound of Formula(III- 1) with benzylamine derivatives (R-NH 2 ) and cyclizing the mixture of maleamic acid(III-2a + III-2b) with acetic anhydride-sodium acetate system, or by in situ reaction of maleic anhydride compound of Formula(III-1) with benzylamine devivatives(R-NH 2 ) and bisbenzylammonium sulfate. 1,3-Dipolar cycloaddition of (III-3) with alkyl azide(R'-N 3 ) affords a mixture of triazoline compounds(III-4a + III-4b). Subsequent thermolysis or photolysis reaction of the above mixture affords a compound of Formula(III-5) which the pyrrolidine ring and aziridine ring are fused together.
  • X' is halogen such as chloro or bromo
  • R, R 4 , and R 5 are as defined above.
  • 3-Pyrroline derivative (III-9) is reacted with chlorine gas, and the resulting chlorohydrine intermmediate is cyclized with base to obtain an epoxide compound of Formula(III-10).
  • Reaction of (III- 10) with an amine (R 4 -NH 2 ) affords a mixture of amino alcohols (III-11a+III-11b), which is subsequently cyclized to aziridine compound of Formula(III-6) with diethylazodicarboxylate(DEAD) and triphenylphosphine(Ph 3 P).
  • R' is an amino protective group
  • X" is a leaving group such as halogen, methanesulfonyl oxy, p-toluene-sulfonyloxy, diethylphosphoryl oxy, diethylthiophosphoryloxy, acetoxy, or alkoxy, R, R 4 , and R 5 are as defined above.
  • a compound of Formula(III-10) is reacted with sodium azide(NaN 3 ) to obtain a mixture of azido alcohols (III-12a+III- 12b), which is subsequently derivatized to a mixture of compounds (III-13a+III- 13b) having good leaving group. Reduction of the above mixture affords an aziridine compound of Formula(III-6a).
  • a compound of Formula(III-6a) is directly deprotected or another protective group is introduced at aziridine ring followed by selective deprotection to afford a novel amine compound of Formula(III).
  • a compound of Formula(I) is prepared by reacting a compound of Formula(II) with an amine of Formula(III).
  • proper reaction solvents include tetrahydrofuran, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpymolidone, acetonitrile, water, alcohol(for example, methanol, ethanol, n-propanol, or iso-propanol), glycol monomethyl ether, pyridine, or a mixture of them.
  • This reaction can be carried out in the absence of solvent, but it is desirable to add some base in the reaction mixture if the solvent is not a basic solvent(ex. pyridine).
  • the base promotes the completion of reaction by reacting with hydrohalide formed from the reaction mixture.
  • Typical inorganic or organic base such as alkali metal hydroxide, alkali metal carbonate, organic amine and amidine, especially, triethylamine, 1,4-diazabicyclo[2.2.2] octane(DABCO), 1,8-diazabicyclo[5.4.0]unde-7-cene(DBU), 1,5-diazabicyclo[4.3.0] non-5-ene(DBN), or excess amount of amine(III) can be desirably used.
  • alkali metal hydroxide alkali metal carbonate
  • organic amine and amidine especially, triethylamine, 1,4-diazabicyclo[2.2.2] octane(DABCO), 1,8-diazabicyclo[5.4.0]unde-7-cene(DBU), 1,5-diazabicyclo[4.3.0] non-5-ene(DBN), or excess amount of amine(III) can be desirably used.
  • This reaction can be carried out at a temperature of 15 ⁇ 300oC , desirably at
  • This reaction can be carried out for several days, desirably for 1 ⁇ 24 hr. Typically, the higher reaction temperature reduces the reaction time.
  • the amine compound of Formula(III) can be used in the reaction in the form of an inorganic or organic salt.
  • inorganic or organic salt include hydrochloride, hydrobromide, sulfate, formate, acetate and oxalate.
  • one to six equivalent of amine compound of Formula(III) against quinoline carboxylic acid of Formula(II) is desirably used.
  • the compounds of the invention are therefore useful in the antibiotic treatment of susceptible bacterial infections in both humans and animals.
  • the compounds may be used in scrub solutions, for surface inhibition of bacterial growth, e.g., on counter surfaces, and the like.
  • Susceptible organisms generally include those gram positive and gram negative, aerobic and anaerobic organisms whose growth can be inhibited by the compounds of the invention, such as Staphylococcus, Lactobacillus, Streptococcus, Sarcina, Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinetobacter,
  • Salmonella Schigella, Serratia, Haemophilus, Brucella, and other organisms.
  • the in vitro activity spectrum of the compounds according to this invention was measured by two fold agar-dilution method using Mueller-Hinton agar. According to the standard procedure recommended by Japanese Society of
  • the MIC was defined as the lowest drug concentration which prevented visible bacterial growth.
  • the MIC of compounds according to the invention is listed in Table 1 compared with ciprofloxacin, and the test compounds are denoted as the number of
  • Test compound was administered orally and subcutaneously to ICR mouse weighed about 18g as 40mg/kg of dose, collected serum after 10, 20, 30, 45, 60, 90, 120, 150, 180, 240 min and urine for 24 hr after administration.
  • the pharmacokinetic parameters were determined by bioassay using E. coli 055 as a standard organism, and the results are denoted in Table 2.
  • the compounds of Formula(I) according to this invention are capable of forming pharmaceutically acceptable salts, herein the term
  • “pharmaceutically acceptable salts” means nontoxic acid addition and base salts formed by alkali metal, alkaline earth metal, or organic amines.
  • salts can be prepared in situ during the final isolation and purification of the compounds of Formula(I), or by separately reacting the base or acid functions with a suitable organic or inorganic acid or base, respectively.
  • Representative acid addition salts in this case include hydrochloride, hydrobromide, sulfate, bisulfate, formate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, p-toluenesulfonate, methanesulfonate, citrate, maleate, fumarate, succinate, tartarate, and ascorbate, and representative alkali metal and alkali earth metal salts include sodium, potassium, calcium, and magnesium salts.
  • Suitable organic amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.
  • carboxyl protective group is intended to include all the reported protective groups such as alkyl of from one to four carbon atoms, cycloalkyl of from three to seven carbon atoms and benzyl group, and amino protective group include acyl, alkoxycarbonyl,
  • alkyl is intended to include both straight and branched carbon chains such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, and so on, alkenyl also include both straight and branched carbon chains such as ethenyl, propenyl, iso-propenyl, and so on.
  • haloalkyl is intended to include alkyl group substituted with more than one halogen atom which is same or different, and the term, halogen, include fluorine, chlorine, bromine and iodine.
  • halogen include fluorine, chlorine, bromine and iodine.
  • Asymmetric caibon atoms may be present in a substituent such as an alkyl group or fused caibon atoms, but all such isomers as well as mixtures thereof are intended to be included in the invention.
  • the compounds of this invention may also be formulated into compositions together with pharmaceutically acceptable carriers for parental injection, for oral administration in solid or liquid form, for rectal administration, for ointment, and the like.
  • compositions according to the invention for parental injection may comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, suspensions or emulsions.
  • suitable nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils, such as olive oil or sesame oil, and injectable organic esters such as ethyl oleate.
  • compositions may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one inert carrier such as sucrose, lactose, dicalcium phosphate, cellulose, pectin, dextrin, gelatin or starch.
  • Such dosage forms can also comprise, as in normal practice, additional substances other than inert solid carriers, e.g., lubricating agents such as magnesium stearate.
  • the dosage form may also comprise buffering agents.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, and syrups containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
  • compositions for rectal administration are preferably suppositories which may contain, in addition to active substance, excipients such as cocoa butter or a suppositiony wax.
  • Ointment preparations contain metal salts of a compound of
  • the carrier is desirably a conventional water-dispersible hydrophilic or oil-in-water carrier, particularly a conventional semi-soft or cream-like water-dispersible or water-soluble, oil-in-water emulsion which may be applied to an affected burn surface or infected surface with a minimum of discomfort.
  • Suitable compositions may be prepared by merely incorporating or homogeneously admixing finely divided compounds with the hydrophilic carrier or base or ointment.
  • compositions of the invention may be varied so as to obtain an amount of active ingredient effective to achieve antibacterial activity in accordance with the desired method of administration.
  • the selected dosage level therfore depends upon the nature of the active compound administered, the route of administration, the desired duration of treatment and other factors. Generally, daily dosage levels of the compounds of Formula(I) of about 0.5 to about 500mg of active ingredient per kg of body weight are effective when administered orally to a mammalian patient suffering from an infection caused by a susceptable organism. If desired, the daily dose may be divided into multiple doses for administration, e.g., two or four times per day.
  • reaction mixture was heated to reflux for 3hr, cooled in an ice bath, and added 0.85ml of water, 0.85 ml of 15%-KOH solution, and 2.5ml of water, successively. Tetrahydrofuran was evaporated in vacuo, and the residue was extracted with 100ml of chloroform. The chloroform extract was washed with saturated sodium chloride solution, dried, filtered, and evaporated in vacuo to afford
  • the two vessels were connected by glass tube in order for the methyl azide gas evolved to be transferred into the maleimide solution, and NaOH trap was connected between them.
  • reaction solution was irradiated with 254nm UV lamp for 6hr.
  • reaction mixture was heated to reflux for 3hr, cooled in an ice bath, and added 0.85ml of water, 0.85ml of 15%-KOH solution, and 2.5ml of water, successively, at about 10oC .
  • Tetrahydrofuran was evaporated in vacuo, and the residue was extracted with 100 ml of chloroform.
  • the chloroform extract was washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated in vacuo.
  • the pH of the solution was adjusted to 9 ⁇ 10 by adding 20%-NaOH solution, extracted with 50ml of methylene chloride, and evaporated in vacuo. To the residue was added 5ml of 20%-NaOH solution and stirred overnight at room temperature.
  • reaction mixture was stirred for 8hr at room temperature, added 0.5 ml of water as dropwise, transferred the solution to separatoiy funnel, and washed with water. Benzene layer was separated, dried over magnesium sulfate and evaporated in vacuo.
  • reaction mixture was evaporated in vacuo, and the residue was used in the next step without further purification.
  • Example 12 9-Fluoro-2,3-dihydro-3-methyl- 10-( 1,6-dimethyl-3,6- diazabicyclo[3.1.0]hexan-3-yl)-7-oxo-7H-pyrido[l,2,3,-de]- 1,4-benzoxazine-6-carboxylic acid
  • reaction mixture was cooled to room temperature, filtered the crystals formed, and washed successively with small amount of acetonitrile, water, and acetonitrile. It was recrystallized from N,N-dimethylformamide, and afforded 44mg(yield : 36%) of titled compound as a white solid.
  • reaction mixture was cooled to room temperature, solid was filtered and washed successively with small amount of acetonitrile, water, and acetonitrile, and dried to afford 55mg(yield : 39%) of titled compound as a yellow solid.
  • Example 21 7-(3,6-Diazabicyclo[3.1.0]hexan-3-yl)-6,8-difluoro-1- ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
  • the reaction mixture was cooled, and obtained the crystal by filtration.
  • the crystal was dispersed in 10ml of methanol, filtered, and dried to afford
  • Example 36 1-Ethyl-7-(1,5-dimethyl-3,6-diazabicyclo[3.1.0]hexan-3-yl)- 6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid
  • the precipitate was obtained by filtration, the filtrate evaporated in vacuo, and added 3ml of methanol to the residue for crystallization.
  • the two crops of precipitate were combined, dispersed in 5ml of methanol, filtered, and dried to afford 79mg(yield : 59%) of titled compound as a pale green solid.
  • Example 45 to 47 illustrate pharmaceutical compositions containing the compounds of the invention as active ingredients.
  • Talc 1.5g The above components were blended with ethanol, granulated and filled into 100 capsules in accordance with conventional methods.
  • the above components were blended with ethanol, granulated and made into 100 tablets in a known manner.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Nouveau composé de quinoléine répondant à la formule (I) et présentant une excellente activité antimicrobienne à la fois contre les bactéries Gram positif et contre les bactéries Gram négatif; son sel pharmaceutiquement acceptable; et son procédé de préparation. Dans ladite formule (I), R1 représente hydrogène ou un groupe protecteur; R2 représente hydrogène, amino, alkylamino C¿1-4?, hydroxy, alcoxy C1-4, mercapto, alkylthio C1-4 ou halogène; R?3¿ représente alkyle C¿1-4?, alcényle C2-4, cycloalkyle C3-6, haloalkyle, hydroxyalkyle C2-4, méthoxy, amino, alkylamino C1-2, diméthylamino, ou phényle éventuellement substitué par au moins un atome d'halogène ou par alkyle C1-3; Z représente une amine répondant à la formule (II), dans laquelle R?4¿ représente hydrogène ou alkyle C¿1-4? et R?5 et R7¿ sont identiques ou différents et représentent hydrogène ou alkyle C¿1-2?; et X représente N ou C-R?6 où R6¿ représente hydrogène, hydroxy, méthyle, cyano, nitro, méthoxy ou halogène, ou forme, conjointement avec R3, un pont répondant à l'une des formules (a), (b), (c) ou (d).
PCT/KR1992/000003 1991-01-14 1992-01-14 Nouveaux composes de quinoleine et leurs procedes de preparation WO1992012155A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP4502607A JPH06509792A (ja) 1991-01-14 1992-01-14 新規なキノロン化合物及びその製造方法

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
KR91-446 1991-01-14
KR910000446 1991-01-14
KR91-17787 1991-10-10
KR1019910017787A KR940008419B1 (ko) 1991-01-14 1991-10-10 신규한 퀴놀린계 화합물과 그 제조방법
KR1019910025396A KR940008420B1 (ko) 1991-12-30 1991-12-30 신규한 퀴놀론계 화합물과 그 제조 방법
KR91-25396 1991-12-30

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EP (1) EP0571400A1 (fr)
AU (1) AU1161492A (fr)
CA (1) CA2100242A1 (fr)
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996001262A1 (fr) * 1994-07-02 1996-01-18 Hanmi Pharmaceutical Co., Ltd. Nouveau compose de quinoleine et son procede de preparation
EP0924213A1 (fr) * 1996-09-27 1999-06-23 Daiichi Pharmaceutical Co., Ltd. Derives de pyridobenzoxazine
US9937172B2 (en) 2014-09-30 2018-04-10 Derek Alton Lightner Mixtures of heteropolycycles

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3514076A1 (de) * 1984-04-26 1985-10-31 Toyama Chemical Co. Ltd., Tokio/Tokyo 1,4-dihydro-4-oxonaphthyridin-derivate und salze derselben, verfahren zu ihrer herstellung und antibakterielle mittel mit einem gehalt derselben
GB2170804A (en) * 1985-01-23 1986-08-13 Toyama Chemical Co Ltd Preparation of 1-aryl-1, 4-dehydro-4-oxo-1, 8-naphthyridine and intermediates therefor
EP0200307A1 (fr) * 1985-03-25 1986-11-05 Warner-Lambert Company Procédé pour la préparation d'agents antibactériens à base d'acide quinoléinecarboxylique-3
DE3632222A1 (de) * 1986-09-23 1988-04-07 Bayer Ag Topisch anwendbare zubereitungen von gyrase-inhibitoren
EP0266576A2 (fr) * 1986-10-08 1988-05-11 Bristol-Myers Squibb Company Acides carboxyliques de naphtyridines et quinoléines 1-tert-alkyl substituées comme agents antibactériens
EP0276700A1 (fr) * 1987-01-28 1988-08-03 Bayer Ag Acides 8-cyano-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinoleinecarboxyliques, procédé pour leur préparation et agents bactéricides les contenant

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3514076A1 (de) * 1984-04-26 1985-10-31 Toyama Chemical Co. Ltd., Tokio/Tokyo 1,4-dihydro-4-oxonaphthyridin-derivate und salze derselben, verfahren zu ihrer herstellung und antibakterielle mittel mit einem gehalt derselben
GB2170804A (en) * 1985-01-23 1986-08-13 Toyama Chemical Co Ltd Preparation of 1-aryl-1, 4-dehydro-4-oxo-1, 8-naphthyridine and intermediates therefor
EP0200307A1 (fr) * 1985-03-25 1986-11-05 Warner-Lambert Company Procédé pour la préparation d'agents antibactériens à base d'acide quinoléinecarboxylique-3
DE3632222A1 (de) * 1986-09-23 1988-04-07 Bayer Ag Topisch anwendbare zubereitungen von gyrase-inhibitoren
EP0266576A2 (fr) * 1986-10-08 1988-05-11 Bristol-Myers Squibb Company Acides carboxyliques de naphtyridines et quinoléines 1-tert-alkyl substituées comme agents antibactériens
EP0276700A1 (fr) * 1987-01-28 1988-08-03 Bayer Ag Acides 8-cyano-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinoleinecarboxyliques, procédé pour leur préparation et agents bactéricides les contenant

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996001262A1 (fr) * 1994-07-02 1996-01-18 Hanmi Pharmaceutical Co., Ltd. Nouveau compose de quinoleine et son procede de preparation
EP0924213A1 (fr) * 1996-09-27 1999-06-23 Daiichi Pharmaceutical Co., Ltd. Derives de pyridobenzoxazine
EP0924213A4 (fr) * 1996-09-27 2002-10-23 Daiichi Seiyaku Co Derives de pyridobenzoxazine
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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EP0571400A1 (fr) 1993-12-01
CA2100242A1 (fr) 1992-07-15
AU1161492A (en) 1992-08-17

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