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WO1990012799A1 - Agents de pyrido(1,2,3-de)-1,4-benzoxazinone a action antibacterienne - Google Patents

Agents de pyrido(1,2,3-de)-1,4-benzoxazinone a action antibacterienne Download PDF

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Publication number
WO1990012799A1
WO1990012799A1 PCT/US1990/000286 US9000286W WO9012799A1 WO 1990012799 A1 WO1990012799 A1 WO 1990012799A1 US 9000286 W US9000286 W US 9000286W WO 9012799 A1 WO9012799 A1 WO 9012799A1
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Prior art keywords
compound
hydrogen
methyl
pyrido
oxo
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PCT/US1990/000286
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English (en)
Inventor
Sharon N. Bisaha
Ronald B. Gammill
Thomas M. Judge
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Pharmacia and Upjohn Co
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Upjohn Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/06—Peri-condensed systems
    • 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

Definitions

  • the present invention relates to new 2-[4-[6-carboxy-9-fluoro- 2,3-dihydro-7-oxo-7H-pyrido(1,2,3-de)-1,4-benzoxazin-10-yl]diaminyl]- 2-butendioic acid, 1,4 disubstituted esters useful as antibacterial agents.
  • Ofloxacin and various analogs are known for their antibacterial properties, however new antibacterials are continually sought especially those which exhibit both gram positive and gram negative activity.
  • U.S. Patent 4,777,253 discloses various methods of producing the racemate and enantiomers of 9-fluoro-3-methyl-10-substituted amino-7- oxo-2,3-dihydro-7H-pyrido[l,2,3-de]-1,4-benzoxazine-6-carboxylic acid compounds.
  • the present invention is directed toward new compounds useful as antibacterials or in the preparation of antibacterial compositions.
  • the compound of the present invention is as shown in Formula I or therapeutically acceptable salts wherein:
  • R 1 is hydrogen or hydroxyl
  • R 2 is hydrogen or methyl
  • R 3 is hydrogen, halogen, amine or hydroxyl
  • R 4 , R 5 , R 6 , R 7 are independently hydrogen, hydroxyl, halogen, C 1 -C 4 alkyl, ethenyl, ethynyl, C 3 -C 6 cycloalkyl, fluoromethyl, difluoromethyl, difluoroethyl, trifluoromethyl, hydroxymethyl, C 1 - C 18 alkoxy methyl, phenoxymethyl, C 1 -C 3 alkyl aminomethyl, C 1 -C 3 dialkyl aminomethyl, C 6 -C 12 aryl, substituted aryl, heteroaryl or substituted heteroaryl containing at least one O, N or S;
  • R 8 Is hydrogen, hydroxyl, amine, C 1 -C 4 alkoxy or aryloxy, -SH, C 1 -C 6 thioalkyl or thioaryl;
  • R 9 is C 1 -C 4 alkyl, C 6 -C 12 aryl, alkylaryl, heteroaryl, -(CH 2 ) n - CO 2 -(CH 2 ) m -R 11 , wherein R 11 is hydrogen, hydroxyl, methyl, alkyloxy, aryloxy or an amine, n is 0-4 and m is 0-4;
  • R 10 is hydrogen, -(CH 3 ) o, C 2 -C 4 alkyl, C 6 -C 12 aryl, alkylaryl, heteroaryl, or acetyl, where o is 0 or 1;
  • R 12 is hydrogen CN, halogen, or R 9 ;
  • Z is (CH 2 ) q where q is 0-2, CH-CH 3 or C(CH 3 ) 2 .
  • R 10 is -(CH 3 ) o where o is 0 and preferably, Z is (CH 2 ) q where q is 0.
  • Preferred compounds of the present invention include (E)-2-[4- [6-carboxy-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido(1,2,3-de)- 1,4-benzoxazin-10-yl]-1-piperazinyl]-2-butendioic acid, 1,4-dimethyl ester (Compounds 1) and (E)-2-[4-[6-carboxyethyl-9-fluoro-2,3- dihydro-7-oxo-7H-pyrido(1,2,3-de)-1,4-benzoxazin-10-yl]-1- piperazinyl]-2-butendioic acid, 1,4-dimethyl ester (Compound 2).
  • the present invention is a pharmaceutical composition containing an antibacterially effective amount of a compound or therapeutically acceptable salts thereof according to Formula I in admixture with a pharmaceutical carrier.
  • the composition can contain from about 0.5 to about 90% by weight of such compound.
  • the composition can be present in unit dose form of tablets, pills, dragees, capsules, ampules or suppositories.
  • the present invention is method for treating bacterial infection in animals including humans which comprises administering an antibacterially effective amount of a compound or therapeutically acceptable salts thereof according to Formula I.
  • the compound can be administered orally or parenterally.
  • the presenf. invention relates to pyrido(1,2,3-de)-1,4- benzoxazinone carboxylic acids incorporating a novel 1,2-dicar- boxyethylene substitutent and antibacterial agents containing these compounds.
  • the benzoxazinone compounds are structurally represented by Formula I, shown on the Formula Sheet, and includes therapeutically acceptable salts thereof wherein R 1 is hydrogen or hydroxyl; R 2 is hydrogen or methyl; R 3 is hydrogen, halogen, amine or hydroxyl; R 4 , R 5 , R 6 , R 7 are independently hydrogen, hydroxyl, halogen, C 1 -C 4 alkyl, ethenyl, ethynyl, C 3 -C 6 cycloalkyl, fluoromethyl, difluoro- methyl, difluoroethyl, trifluoromethyl, hydroxymethyl, C 1 -C 18 alkoxy methyl, phenoxy-methyl, C 1 -C 3 alkyl aminomethyl, C
  • R 10 is -(CH 3 ) o where o is
  • Z is (CH 2 ) q where q is 0.
  • Preferred compounds of Formula la are where R 1 is hydroxy, R 2 is hydrogen or methyl, R 3 is hydrogen or fluorine, R 4 , R 5 , R 6 and R 7 are hydrogen, R 8 is methoxyl, R 9 is a carbomethoxyl ester so as to form either the dimethylester of maleic or fumaric acid and R 10 is- (CH 3 ) o where o is 0.
  • Preferred compounds of Formula lb are when R 1 is hydroxyl and R 2 is hydrogen or methyl and R 11 are hydrogen, R 8 is O-CH 3 , R 9 is C(O)OCH 3 , X and Y are C(F) and Z is (CH 2 ) q where q is zero.
  • C 1 -C 10 alkyl are one to ten carbon atoms such as methyl, ethyl, propyl, butyl, etc. and isomeric forms thereof.
  • the "C 2 -C 4 alkylenes” are ethylene, propylene and 1 or 2-butylene and isomeric forms thereof.
  • Examples of "C 3 -C 10 cycloalkyl” are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. and "heterocycloalkyl”are cycloalkyl ring which contain at least one heteroatom such as oxygen, sulfur or nitrogen.
  • C 6- C 12 aryl are compounds such as phenyl, ⁇ -naphfchyl, ⁇ -naphthyl, m-methylphenyl, p-trifluoromethyIphenyl and the like.
  • the aryl groups can also be substituted with one to 3 hydroxy, C 1 -C 3 alkoxy, C 1 -C 3 alkyl, trifluoromethyl, fluoro, chloro or bromo groups.
  • alkylaryl are alkyl chains of one to eight carbon atoms and isomeric forms thereof which are substituted with aryl groups of 6 to 12 carbon atoms, for example, benzyl.
  • heteroaryls are 6 to 12 carbon atom aryls which contain at least one heteroatom such as nitrogen, sulfur and oxygen.
  • amine is meant to Include primary, secondary and tertiary amines , preferably primary amine (NH 2 ).
  • Halogen is meant to include F, Cl, Br and I.
  • “Therapeutically acceptable salts” are those compounds of Formula I wherein a carboxyl group is substituted with a counter ion such as Li, Na, K, Ca or other acceptable counter ions for carboxylic acids .
  • the compounds according to the invention have good actions against Gram-positive and Gram-negative bacteria, particularly against enterobacteriaceae.
  • the effectiveness of the subject compounds on bacteria were obtained by performing a dip disk assay.
  • the antibacterial activity of the compounds was determined by the disk-diffusion method. Paper disks (12.7 mm) were loaded with 0.05 ml of drug solution prepared at a concentration of 0.1 mcg/ml; the disks were allowed to air dry.
  • microorganism-seeded agar assay trays which contained the bacterial strain Pseudomonas aeruginosa UC 95 (PA), Escherichia coli UC 51 (EC), Klebsiella pneumoniae UC 57 (KP), Staphylococcus aureus UC 80 (SA), Penicillium oxalicum UC 1268 (PO), Streptococcus pyogenes UC 6055 (ST), Bacteroides fragilis UC 6513 (BF), Candida albicans UC 1392 (CA),
  • PA bacterial strain Pseudomonas aeruginosa UC 95
  • EC Escherichia coli UC 51
  • KP Klebsiella pneumoniae UC 57
  • SA Staphylococcus aureus UC 80
  • PO Penicillium oxalicum UC 1268
  • ST Bacteroides fragilis UC 6513
  • Staphylococcus aureus UC 6685 SR
  • Staphylococcus epidermidis UC 719 SE
  • Streptococcus pneumoniae UC 9207 SO
  • UC 241 (SF), Serratica marcescens UC 6888 (SM), Bordetella bronchiseptica UC 6481 (BR) or Clostridium perfringens UC 6509 (CP).
  • SF Serratica marcescens UC 6888
  • BR Bordetella bronchiseptica UC 6481
  • CP Clostridium perfringens UC 6509
  • MIC minimum inhibitory concentration
  • McFarland standard Is obtained.
  • the bacteria are diluted one to 20 in TSB and inoculated on the plates (1 ⁇ l using a Steers replicator).
  • the plates are incubated at 35°C for 20 hours and the MIC is read to be the lowest concentration of drug that completely inhibits visible growth of the bacteria.
  • the MIC test results of selected compounds of this invention are found in Tables I.
  • the compounds according to the invention have a potent and broad antimicrobial efficacy. These properties make it possible to use them as chemotherapeutic active compounds in medicine and as substances fpr preserving inorganic and organic materials, in particular organic materials of all types, for example polymers, lubricants, dyes, fibers, leather, paper and wood, foodstuffs and water.
  • the compounds according to the invention are active against Gram-negative and Gram-positive bacteria and bacterioid microorganisms. Thus, diseases caused by these pathogens can be treated.
  • the compounds according to the invention are particularly active against bacteria and bacterioid microorganisms. Thus, they are particularly well suited for the chemotherapy of local and systemic infections caused by these pathogens in medicine.
  • Micrococcaceae such as staphylococci, for example Staphylococcus aureua, Staph. Epidermidis, (Staph.
  • Lactobacteriaceae such as streptococci, for example Streptococcus pyogenes, ⁇ - and ⁇ -haemolytic streptococci, non ( ⁇ -) haemolytic streptococci, enterococci and Dlplococcus pneumoniae (pneumococci) (Str - Streptococcus); Enterobacteriaceae, such as encherichiae bacteria of the coli group; encherichia bacteria, for example Escherichia coli, enterobacter bacteria, for example aerogenes, E. cloacae, Klebsiella bacteria, for example K.
  • streptococci for example Streptococcus pyogenes, ⁇ - and ⁇ -haemolytic streptococci, non ( ⁇ -) haemolytic streptococci, enterococci and Dlplococcus pneumoniae (pneumococci) (Str - Streptoc
  • pneumoniae serratin, for example Serratia marcescens (E. - Enterobacter) (K. - Klebsiella), proteae bacteria of the proteus groups; proteus, for example Proteus vulgaris, Pr. morganii, Pr. rettgeri and Pr. mirabilis (Pr. - Proteus); pseudomonadaceae, such as pseudomonas bacteria, for example Pseudomonas aeruginosa (PS. - Pseudomonas); bacteroidaceae, such as bacteroides bacteria, for example Bacteroides fragilis (B. - Bacteroides); mycoplasma, for example Mycoplasma pneumonia.
  • serratin for example Serratia marcescens (E. - Enterobacter) (K. - Klebsiella), proteae bacteria of the proteus groups; proteus, for example Proteus vulgaris, Pr. morganii, Pr. rettgeri
  • the present invention includes pharmaceutical preparations which in addition to non-toxic, inert pharmaceutically suitable excepients contain one or more compounds according to the invention or which consist of one or more active compounds according to the invention, and processes for the production of these preparations.
  • the present invention also Includes pharmaceutical preparations in dosage units.
  • the preparations are in the form of individual parts, for example tablets, dragees, capsules, pills, suppositories and ampoules, of which the content of active substance corresponds to a fraction or a multiple of an individual dose.
  • An individual dose preferably contains the amount of active compound which is given in one administration and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.
  • non-toxic, inert pharmaceutically suitable excipients there are solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds.
  • Preferred pharmaceutical preparations are tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays.
  • Tablets, dragees, capsules, pills and granules can contain the active compound or compounds alongside the customary excipients such as (a) fillers and extenders, for example starches, lactose, sucrose, glucose, mannitol and silica, (b) binders, for example carboxymethylcellulose, alginates, gelatine and polyvinylpyrrolidone, (c) humectants, for example glycerine, (d) disintegrating agents, for example agar-agar, calcium carbonate and sodium carbonate, (e) solution retarders, for example paraffin, and (f) absorption accelerators, for example quaternary ammonium compound (g) wetting agents, for example cetyl alcohol or glycerine monostearate, (h) adsorbents, for example kaolin and bentonite, and (i) lubricants, for example talc, calcium stearate and magnesium stearate and solid polyethylene glycols, or
  • the tablets, dragees, capsules, pills and granules can be provided with the customary coatings and shells, optionally containing opacifying agents, and can also be of such composition that they release the active compound or compounds only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner, examples of embedding compositions which can be used being polymeric substances and waxes.
  • the active compound or compounds can also be in a micro- encapsulated form.
  • Suppositories can contain, in addition to the active compound or compounds, the customary water-soluble or water-insoluble excipients, for example polyethylene glycols, fats, for example cacao fat, and higher esters (for example C 14 -alcohol with C 16 -fatty acid) or mixtures of these substances.
  • the customary water-soluble or water-insoluble excipients for example polyethylene glycols, fats, for example cacao fat, and higher esters (for example C 14 -alcohol with C 16 -fatty acid) or mixtures of these substances.
  • Ointments, pastes, creams and gels can contain the customary excipients in addition to the active compound or compounds, for example animal and vegetable fats, waxes, paraffins, starch, traga- canth, cellulose derivatives, polyethylene glycols, silicones, ben- tonites, silica, talc and zinc oxide or mixtures of these substances.
  • Powders and sprays can contain the customary excipients in addition to the active compound or compounds, for example lactose, talc, silica, aluminum hydroxide, calcium silicate and polyamide powders or mixtures of these substances.
  • Sprays can additionally contain the customary propellents, for example chlorofluorohydro- carbons.
  • Solutions and emulsions can contain the customary excipients in addition to the active compound or compounds, such as solvents, solubilising agents and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, groundnut oil, maize germ oil, olive oil, castor oil and sesame oil, glycerine, glycerineformal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances.
  • solvents such as solvents, solubilising agents and emulsifiers
  • solubilising agents and emulsifiers for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, e
  • the solutions and emulsions can be in a sterile form which is isotonic with blood.
  • Suspensions can contain the customary excipients in addition to the active compound or compounds, such as liquid diluents, for example water, ethyl alcohol or propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances.
  • liquid diluents for example water, ethyl alcohol or propylene glycol
  • suspending agents for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances.
  • the formulation forms mentioned can also contain dyestuffs, preservatives and additives which improve the odour and flavour, for example peppermint oil and eucalyptus oil, and sweeteners, for example saccharin.
  • the therapeutically active compounds should preferably be present in the above mentioned pharmaceutical preparations in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95, percent by weight of the total mixture.
  • compositions can also contain other pharmaceutical active compounds in addition to the active compounds according to the invention.
  • compositions are manufactured in the usual manner according to known methods, such as by mixing the active compound or compounds with the excipient or excipients.
  • the active compounds or the pharmaceutical preparations can be administered locally, orally, parenterally, intraperitoneally and/or rectally, preferably orally or parenterally, such as intravenously or intramuscularly.
  • the active compound or compounds in total amounts of about 0.5 to about 50, preferably 1 to 30, especially preferably 1-20 mg/kg of body weight, orally or parenterally, every 24 hours, optionally in the form of several individual administrations, in order to achieve the desired results.
  • An individual administration contains the active compound or the active compounds preferably in amounts of about 1 to about 250, especially of 3 to 60, mg/kg of body weight.
  • the compounds of Formula I according to this invention may be provided as pharmaceutically acceptable acid addition and base salts wherein the anion or cation, respectively, does not contribute significantly to the toxicity of the salt and which salts are compatible with the standard and conventional pharmaceutically acceptable carriers and other conventional adjuvants and excipients customarily employed in producing pharmaceutical compositions adapted for oral or parenteral administration.
  • the acid addition salts are formed by conventional techniques involving reaction of compounds of Formula I with mineral acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid, and with organic carboxylic and sulfonic acids such as, for example, aspartic acid, glutamic acid, galaeturonic acid, gluconic acid, acetic acid, citric acid, maleic acid, succinic acid, benzoic acid, tartaric acid, ascorbic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, and the like.
  • mineral acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid
  • organic carboxylic and sulfonic acids such as, for example, aspartic acid, glutamic acid, galaeturonic acid, gluconic acid, acetic acid, citric acid, maleic
  • this invention is a pharmaceutical composition comprising an antibacterially effective amount of a compound of Formula I above.
  • this invention is a method of combatting hacterial Infection in warm-blooded animals comprising administering to said animals an antibacterially effective amount of a compound of Formula I err of a pharmaceutical composition thereof.
  • Pharmaceutically acceptable base salts are formed by conventional techniques involving reaction of the compounds of Formula I with alkali (Na,K) and alkaline earth (Ca, Ba, Zn, Mn) metal bases, more preferably with alkali metal bases such as, for example, dilute solutions of sodium hydroxide and potassium carbonate.
  • pharmaceutically acceptable base salts are formed by conventional techniques involving reaction with amines such as, for example, triethyl- amine, dibenzylamine, triethanolamine, ethanolamine, N,N'-dibenzyl- ethylenediamine, procaine and equivalent amines.
  • the new compounds can be utilized as feedstuff.
  • Dimethyl acetylene dicarboxylate (55 ⁇ L, 0.45 mmol) is added to a stirring solution of 9-fluoro-3-methyl-10-(1-piperazinyl)-7-oxo- 2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (0.15 g, 0.45 mmol) in dimethyl formamide (5 ml, DMF).
  • the solution is stirred at room temperature for 8 hours, the solvent evaporated off under a stream of nitrogen.
  • the residue is flash chromatographed over silica gel (15 g, 0.5% acetone in 10% methanol/methylene chloride) to yield 0.13 g of Compound #1 (m.p. 235-238oC).
  • Hayakawa et al. and can be prepared in accordance with Procedure 2.
  • Dimethyl acetyl dicarboxylate (0.19 ml, 1.5 mol) is added to a stirring solution of 9-fluoro-3-methyl-10-(3-amino-1-pyrrolidinyl)-7- oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (0.52 g, 1.5 mmol) in dimethylformamide (13 ml).
  • the solution is stirred at room temperature for 3 days, the solvent evaporated off under a stream of nitrogen.
  • Triethylorthoformate (15.8 g, 106 mmol) is added to a solution of ⁇ , ⁇ -DIoxo-2,3,4,5.-tetrafluoro-benzenebutanoic acid, ethyl ester (50 g, 0.19 mmol) in acetic anhydride (80ml). After refluxing for 5 hours, the solvent is evaporated and azeotroped with toluene twice in vacuo at 60°C to yield 67 g of 2,3,4,5-tetrafluoro- ⁇ -[(ethoxy)- methylene]- ⁇ -oxo-benzenepropanoic acid, ethyl ester. The product is stored at -20°C and can be use in subsequent steps without further purificiation.
  • D,L-Alanol (2.34 g, 31.2 mmol) is added to a solution of 2,3,4,5-tetrafluoro- ⁇ -[(ethoxy)methylene]- ⁇ -oxo-benzenepro ⁇ anoic acid, ethyl ester (10.0 g, 31.2 mmol of Part A) in methylene chloride (50 ml).
  • Piperazine (0.9 g, 10.5 mmol) is added to a solution of the difluoro acid 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido(- 1,2,3-de)-1,4-benzoxazine-6-carboxylic acid (0.75 g, 2.67 mmol) in DMSO (15 ml). After stirring at 120°C for 3 h, the solvent is evaporated in vacuo at 60°C. The residue is washed with cold water to afford 0.42 g of crude product.
  • 3-Acetoaminopyrrolidine (3.84 g, 30 mmol) is added to a solution of the difluOro ester (4.65 g, 15 mmol, Procedure 1, Part C) in pyridijie (55 ml). After stirring at 60"C for 6 days, the solvent is evaporated in vacuo at 60"C.

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Abstract

L'invention concerne de nouveaux acides carboxyliques de benzoxazinone comportant un nouveau substituant de 1,2-dicarboxyéthylène diméthyle, ainsi que leur utilisation dans le traitement des infections bactériennes chez les animaux à sang chaud et chez l'homme. Les composés de la présente invention, qui sont représentés par la formule (I), sont facilement préparés au moyen de réactions chimiques traditionnelles.
PCT/US1990/000286 1989-04-26 1990-01-22 Agents de pyrido(1,2,3-de)-1,4-benzoxazinone a action antibacterienne Ceased WO1990012799A1 (fr)

Applications Claiming Priority (2)

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US34388089A 1989-04-26 1989-04-26
US343,880 1989-04-26

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WO1990012799A1 true WO1990012799A1 (fr) 1990-11-01

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JP (1) JPH04504852A (fr)
AU (1) AU5404790A (fr)
WO (1) WO1990012799A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000050428A1 (fr) * 1999-02-24 2000-08-31 Samsung Electronics Co., Ltd. Procede de preparation de derives de l'acide (-)pyridobenzoxazine carboxylique
RU2191179C2 (ru) * 1995-11-07 2002-10-20 Орто-Макнейл Фармасьютикал, Инк. Бензоксазиновые или пиридооксазиновые соединения, способы их получения, промежуточные соединения, фармацевтические композиции, обладающие антибактериальной активностью, способы лечения бактериальных инфекций
KR100542600B1 (ko) * 2004-05-17 2006-01-11 주식회사 카이로켐 광학활성 (s)-피리도벤즈옥사진 카르복실산 반수화물 유도체의 제조 방법

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4120646A1 (de) * 1991-06-22 1992-12-24 Bayer Ag 7-isoindolinyl-chinolon- und naphthyridoncarbonsaeure-derivate

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0225552A2 (fr) * 1985-12-10 1987-06-16 Bayer Ag Enantiomères pures des acides 4-quinolone-3-carboxyliques, 1,8 pontés, procédé pour leur préparation ainsi que médicaments les contenant et leur utilisation pour la préparation de médicaments
EP0284935A1 (fr) * 1987-04-02 1988-10-05 Bayer Ag Dérivés de l'acide quinolone carboxylique et naphtyridone carboxylique substitués sur la position 5

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0225552A2 (fr) * 1985-12-10 1987-06-16 Bayer Ag Enantiomères pures des acides 4-quinolone-3-carboxyliques, 1,8 pontés, procédé pour leur préparation ainsi que médicaments les contenant et leur utilisation pour la préparation de médicaments
EP0284935A1 (fr) * 1987-04-02 1988-10-05 Bayer Ag Dérivés de l'acide quinolone carboxylique et naphtyridone carboxylique substitués sur la position 5

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2191179C2 (ru) * 1995-11-07 2002-10-20 Орто-Макнейл Фармасьютикал, Инк. Бензоксазиновые или пиридооксазиновые соединения, способы их получения, промежуточные соединения, фармацевтические композиции, обладающие антибактериальной активностью, способы лечения бактериальных инфекций
US6316618B1 (en) 1998-02-24 2001-11-13 Samsung Electronics Co., Ltd. Process for preparing (-)pyridobenzoxazine carboxylic acid derivatives
WO2000050428A1 (fr) * 1999-02-24 2000-08-31 Samsung Electronics Co., Ltd. Procede de preparation de derives de l'acide (-)pyridobenzoxazine carboxylique
KR100542600B1 (ko) * 2004-05-17 2006-01-11 주식회사 카이로켐 광학활성 (s)-피리도벤즈옥사진 카르복실산 반수화물 유도체의 제조 방법

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JPH04504852A (ja) 1992-08-27
AU5404790A (en) 1990-11-16

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