EP0489733A1 - Antibacterial pyrido(1,2,3-de)-1,4-benzoxazinone agents - Google Patents

Antibacterial pyrido(1,2,3-de)-1,4-benzoxazinone agents

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Publication number
EP0489733A1
EP0489733A1 EP90906002A EP90906002A EP0489733A1 EP 0489733 A1 EP0489733 A1 EP 0489733A1 EP 90906002 A EP90906002 A EP 90906002A EP 90906002 A EP90906002 A EP 90906002A EP 0489733 A1 EP0489733 A1 EP 0489733A1
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EP
European Patent Office
Prior art keywords
compound
hydrogen
methyl
pyrido
oxo
Prior art date
Legal status (The legal status 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 status listed.)
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Application number
EP90906002A
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German (de)
French (fr)
Inventor
Sharon N. Bisaha
Ronald B. Gammill
Thomas M. Judge
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacia and Upjohn Co
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Upjohn Co
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Filing date
Publication date
Application filed by Upjohn Co filed Critical Upjohn Co
Publication of EP0489733A1 publication Critical patent/EP0489733A1/en
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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D498/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02Heterocyclic 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
    • C07D498/06Peri-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial 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.The invention relates to novel benzoxazinone carboxylic acids comprising a new substituent of 1,2-dicarboxyethylene dimethyl, as well as their use in the treatment of bacterial infections in warm-blooded animals and in humans. The compounds of the present invention, which are represented by formula (I), are easily prepared by means of conventional chemical reactions.

Description

ANTIBACTERIAL PYRIDO(1,2, 3-DE) -1,4-BENZOXAZINONE AGENTS
BACKGROUND OF THE INVENTION
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 preparation of various piperazinyl and 3-amino-l-pyr- rolidinyl naphthyridine derivatives, including 2-(4-(1-cyclopropyl-3- carboxy-6-fluoro-1,4-dihydro-4-oxo-7-quinolinyl)-1-piperazinyl)-2- butanedioic acid, 2-(4-(1-cyclopropyl-3-carboxyethyl-6-fluoro-1,4- dihydro-4-oxo-7-quinolinyl)-1-piperazinyl)-2-butanedioic acid, dimethyl ester, 2-(4-(1-ethyl-3-carboxy-6-fluoro-1,4-dihydro-4-oxo-7- quinolinyl)-1-piperazinyl)-2-butanedioic acid, and 2-(4-(1-ethyl-3- carboxyethyl-6-fluoro-1,4-dihydro-4-oxo-7-quinolinyl)-1-piperazinyl)- 2-butanedioic acid, dimethyl ester are disclosed in Japanese publication 62-207258 (Chem. Abst. 108(5):37868p) and Great Britain Patent Application 87-GB-002508.
BRIEF DESCRIPTION OF THE INVENTION
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:
R1 is hydrogen or hydroxyl;
R2 is hydrogen or methyl;
R3 is hydrogen, halogen, amine or hydroxyl;
R4, R5, R6, R7 are independently hydrogen, hydroxyl, halogen, C1-C4 alkyl, ethenyl, ethynyl, C3-C6 cycloalkyl, fluoromethyl, difluoromethyl, difluoroethyl, trifluoromethyl, hydroxymethyl, C1- C18 alkoxy methyl, phenoxymethyl, C1-C3 alkyl aminomethyl, C1-C3 dialkyl aminomethyl, C6-C12 aryl, substituted aryl, heteroaryl or substituted heteroaryl containing at least one O, N or S; R8 Is hydrogen, hydroxyl, amine, C1-C4 alkoxy or aryloxy, -SH, C1-C6 thioalkyl or thioaryl;
R9 is C1-C4 alkyl, C6-C12 aryl, alkylaryl, heteroaryl, -(CH2)n- CO2-(CH2)m-R11, wherein R11 is hydrogen, hydroxyl, methyl, alkyloxy, aryloxy or an amine, n is 0-4 and m is 0-4;
R10 is hydrogen, -(CH3)o, C2-C4 alkyl, C6-C12 aryl, alkylaryl, heteroaryl, or acetyl, where o is 0 or 1;
R12 is hydrogen CN, halogen, or R9; and
Z is (CH2)q where q is 0-2, CH-CH3 or C(CH3)2.
The dotted bonds indicate that the carbon atom having the R5 group can be bonded to either the nitrogen to form Formula la or the carbcp atom having the R6 group to form Formula lb. When the structure Is as depicted in Formula la then R10 is -(CH3)o where o is 0 and preferably, Z is (CH2)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).
In another aspect, 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.
In yet another aspect, 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. In the method the compound can be administered orally or parenterally.
DETAILED DESCRIPTION OF INVENTION
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 R1 is hydrogen or hydroxyl; R2 is hydrogen or methyl; R3 is hydrogen, halogen, amine or hydroxyl; R4, R5, R6, R7 are independently hydrogen, hydroxyl, halogen, C1-C4 alkyl, ethenyl, ethynyl, C3-C6 cycloalkyl, fluoromethyl, difluoro- methyl, difluoroethyl, trifluoromethyl, hydroxymethyl, C1-C18 alkoxy methyl, phenoxy-methyl, C1-C3 alkyl aminomethyl, C1-C3 dialkyl aminomethyl, C6-C12 aryl, substituted aryl, heteroaryl or substituted heteroaryl; R8 is hydrogen, hydroxyl, amine, C1-C4 alkoxy or aryloxy, -SH, C1-C6 thioalkyl or thioaryl; R9 is C1-C4 alkyl, C6-C12 aryl, alkylaryl, heteroaryl, -(CH2)n-CO2-(CH2)m-R11, wherein R11 is hydrogen, hydroxyl, methyl alkyloxy, aryloxy or an amine, n is 0-4 and m is 0-4; R10 is hydrogen, -(CH3)o C2-C4 alkyl, C6-C12 aryl, alkylaryl, heteroaryl, or acetyl, where o is 0 or 1; R12 is hydrogen CN, halogen, or R9; X is nitrogen or carbon substituted by fluorine; Y is nitrogen, a carbon substituted with hydrogen, hydroxyl, cyano, nitro, halogen, C1-C4 alkyl, or an amine; and Z is (CH2)q where q is 0-2, CH-CH3 or C(CH3)2.
The dotted bonds indicate that the carbon atom having the R5 group can be bonded to either the nitrogen to form Formula la or the carbon atom having the R6 group to form Formula lb. When the structure is as depicted in Formula la then R10 is -(CH3)o where o is
0 and preferably, Z is (CH2)q where q is 0.
Preferred compounds of Formula la are where R1 is hydroxy, R2 is hydrogen or methyl, R3 is hydrogen or fluorine, R4, R5, R6 and R7 are hydrogen, R8 is methoxyl, R9 is a carbomethoxyl ester so as to form either the dimethylester of maleic or fumaric acid and R10 is- (CH3)o where o is 0. Preferred compounds of Formula lb are when R1 is hydroxyl and R2 is hydrogen or methyl and R11 are hydrogen, R8 is O-CH3, R9 is C(O)OCH3, X and Y are C(F) and Z is (CH2)q where q is zero.
Examples of "C1-C10 alkyl" are one to ten carbon atoms such as methyl, ethyl, propyl, butyl, etc. and isomeric forms thereof. The "C2-C4 alkylenes" are ethylene, propylene and 1 or 2-butylene and isomeric forms thereof. Examples of "C3-C10 cycloalkyl" are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. and "heterocycloalkyl"are cycloalkyl ring which contain at least one heteroatom such as oxygen, sulfur or nitrogen. Examples of "C6-C12 aryl" are compounds such as phenyl, α-naphfchyl, β-naphthyl, m-methylphenyl, p-trifluoromethyIphenyl and the like. The aryl groups can also be substituted with one to 3 hydroxy, C1-C3 alkoxy, C1-C3 alkyl, trifluoromethyl, fluoro, chloro or bromo groups. Examples of "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. Examples of "heteroaryls" are 6 to 12 carbon atom aryls which contain at least one heteroatom such as nitrogen, sulfur and oxygen.
An "amine" is meant to Include primary, secondary and tertiary amines , preferably primary amine (NH2).
"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 .
A generic scheme for the preparation of the Formula la compounds is illustrated in Chart 1.
A generic scheme for the preparation of the Formula lb compounds is illustrated in Chart 2.
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.
They were then applied to the surface of 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),
Staphylococcus aureus UC 6685 (SR), Staphylococcus epidermidis UC 719 (SE), Streptococcus pneumoniae UC 9207 (SO), Streptococcus faecalis
UC 241 (SF), Serratica marcescens UC 6888 (SM), Bordetella bronchiseptica UC 6481 (BR) or Clostridium perfringens UC 6509 (CP). The assay trays were incubated overnight under aerobic condition to allow for the growth of the organisms. Zones of growth inhibition due to the action of the antibiotic were then measured to the nearest millimeter.
The results show that compounds 1 and 2, all of Formula la, corresponding to Examples 1 and 2, below, have potent gram negative and positive activity.
Compounds of this invention can also be tested for in vitro antimicrobial activity using standard testing procedures such as the determination of minimum inhibitory concentration (MIC) by agar dilu- tion as described in "Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically" (MFT) published January 1983 by the National Committee for Clinical Laboratory Standards, 771 East Lancaster Avenue, Villanova, PA 19084, USA. Briefly, MIC values are determined in unsupplemented Mueller Hinton Agar (MHA). The compounds tested are diluted serially into molten MHA at 47°C. The agar is poured into petri dishes and allowed to harden. The various bacteria used for testing are grown overnight on MHA at 35°C and transferred to Tryptloase soy broth (TSB) until a turbidity of 0.5
McFarland standard Is obtained. The bacteria are diluted one to 20 in TSB and inoculated on the plates (1 μl 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.
For example, local and/or systemic diseases caused by the following pathogens or by mixtures of the following pathogens can be treated and/or prevented: Micrococcaceae, such as staphylococci, for example Staphylococcus aureua, Staph. Epidermidis, (Staph. - Staphylococcus); Lactobacteriaceae, such as streptococci, for example Streptococcus pyogenes, α- and β-haemolytic streptococci, non (ν-) 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. 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.
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. This means that 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.
By 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 mixtures of the substances listed under (a) to (i).
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, optionally together with one or more of the above mentioned excipients, 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 C14-alcohol with C16-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.
For parenteral administration, 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.
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.
The above mentioned pharmaceutical preparations can also contain other pharmaceutical active compounds in addition to the active compounds according to the invention.
The above mentioned pharmaceutical preparations 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.
In general, it has proved advantageous in medicine to administer 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. However, it can be necessary to deviate from the dosages mentioned and in particular to do so as a function of the nature and body weight of the subject to be treated, the nature and the severity of the illness, the nature of the preparation and of the administration of the medicine, and the time or interval over which the administration takes place. Thus it can suffice in some cases to manage with less than the above mentioned amount of active comp und whilst in other cases the above mentioned amount of active compound must be exceeded. The particular required optimum dosage and the type of administration of the active compounds can easily be decided by anyone skilled in the art, on the basis of his expert knowledge.
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.
It is to be understood that the formulas herein representing the various compounds according to the invention are intended to embrace all optical isomers, as well as racemic mixtures thereof, within the scope of the given formulas unless otherwise indicated.
In another aspect, as is mentioned above, this invention is a pharmaceutical composition comprising an antibacterially effective amount of a compound of Formula I above.
In still another aspect, 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. Also, 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.
Example 1 Preparation of (E)-2-[4-[6-carboxy-9-fluoro-2,3- dihydro-3-methyl-7-oxo-7H-pyrido(l,2,3-de)-1,4- benzoxazin-10-yl]-1-piperazinyl]-2-butendioic acid,
1,4-dimethyl ester (Compound #1)
The starting material 9-fluoro-3-methyl-10-(l-piperazinyl)-7- oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid is disclosed in Chem. Pharm. Bull., 32:4907 (1984) by I. Hayakawa et al. and can be prepared in accordance with Procedure 1.
Dimethyl acetylene dicarboxylate (55 μL, 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).
Example 2 Preparation of (E)-2-[4-[6-carboxyethyl-9-fluoro-2,3- dihydro-7-oxo-7H-pyrido(l,2,3-de)-1,4-benzoxazin-10- yl]-1-piperazinyl]-2-butendioic acid, 1,4-dimethyl ester (Compound #2)
The starting material 9-fluoro-10-(1-piperazinyl)-7-oxo-2,3- dihydro-7H-pyrido[1 ,2,3-de]-1,4-benzoxazine-6-carboxylic acid ethyl ester is disclosed in Chem. Pharm. Bull. 32:4907 (1984) by I.
Hayakawa et al. and can be prepared in accordance with Procedure 2.
9-fluoro-10-(1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3- de]-1,4-benzoxazine-6-carboxylic acid ethyl ester (335 mg, 0.93 mmol) is dissolved in chloroform (25 ml) and dimethyl acetylene dicarboxylate (150 μl , 1.2 mmol) is added. The mixture is stirred at 23°C for 30 min, then concentrated and recrystallized from ethyl acetate/- Skellysolve B to give the malonate ester as a white solid (421 mg, 90%). Of this product, (200 mg, 0.40 mmol) is dissolved in tetrahydrofuran (10 ml) and 1.6 equivalents of potassium triethyl silanolate (85 mg, 0.66 mmol) is added at 23°C. The mixture is stirred for 1 h. Turning from a deep red color to pale, the solvent is then evaporated to give an orange oil which is chromatographed over SiO2 slurry with methylene chloride/ethanol/acetic acid (89:10:1) to give 140 mg of white solid (74%). The Lilly compound is recrystallized from methanol as a white solid (104 mg) m.p. 271-3°C dec.
Example 3 Preparation of (E)-2-[4-[6-carboxy-9-fluoro-2,3- dihydro-3-methyl-7-oxo-7H-pyrido(l,2,3-de)-1,4- benzoxazine-10-yl]-3-aminopyrrolIdinyl]-2-butendioic acid, 1,4-dimethyl ester (Compound #3) [13 of Chart 3 where R2 - CH3 and R3 - H]
The starting material 9-fluoro-3-methyl-10(3-amino-l-pyr- rolidinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6- carboxylic acid is disclosed in Chem. Pharm. Bull. 32:4907 (1984) by
I. Hayakawa et al. and can be prepared in accordance with Procedure
1, making non-critical modifications, and utilizing the appropriate starting material.
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. The residue is chromatographed over silanized silica gel (80 g, chloroform) to yield 0.31 g of compound #3 which is recrystallized from methylene chloride/hexane (m.p. 145- 152°C).
Procedure 1 Preparation 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, ethyl ester
Part A:
Triethylorthoformate (15.8 g, 106 mmol) is added to a solution of α,α-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-α-[(ethoxy)- methylene]-β-oxo-benzenepropanoic acid, ethyl ester. The product is stored at -20°C and can be use in subsequent steps without further purificiation.
Part B:
D,L-Alanol (2.34 g, 31.2 mmol) is added to a solution of 2,3,4,5-tetrafluoro-α-[(ethoxy)methylene]-β-oxo-benzeneproρanoic acid, ethyl ester (10.0 g, 31.2 mmol of Part A) in methylene chloride (50 ml). After stirring for 22 h, the solvent is evaporated in vacuo and the residue flash chromatographed over silica gel (400 g, 5 x 40 ml fractions of 50% ethyl acetate/methylene chloride) to yield 8.54 g of 2,3,4,5-tetrafluoro-α-[[(2-hydroxy-1-methylethyl)amino]methylene]- β-oxo-benzenepropanoic acid, ethyl ester.
Part C:
Sodium hydride (60% oil dispersion, 2.08 g, 53 mmol) is added to a solution of 2,3,4,5-tetrafluoro-α-[[(2-hydroxy-1-methylethyl)- amino]methylene]-β-oxo-benzenepropanoic acid, ethyl ester (8.5 g, 24.3 mol, Part B) in tetrahydrofuran (165 ml) stirring at 0°C. The ice bath is removed and the solution is stirred at ambient temperature. After stirring for 6 h and evaporation of the solvent in vacuo, the residue is transferred to a separatory funnel with chloroform/water. Extraction with chloroform (3x) and drying the combined organic layers with magnesium sulfate affords 5.30 g of crude 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7-pyrido(1,2,3-de)- 1,4-benzoxazine-6-carboxylic acid, ethyl ester.
Flash chromatography over silica gel (500 g, 3% methanol/methyl- ene chloride, 40 ml fractions) to afford 3.30 g of 9,10-difluoro-2,3- dihydro-3-methyl-7-oxo-7-pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid, ethyl ester (44%, fractions 31-50).
Part D:
9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7-pyrido(1,2,3-de)- 1,4-benzoxazine-6-carboxylic acid, ethyl ester (2.0 g, 6.5 mmol) is refluxed in 6N hydrochloric acid (HC1) (50 ml). After 8 h, the solvent is evaporated off under a stream of nitrogen. Trituration with hot ethanol affords 1.7 g (93%) of crystalline 9,10-difluoro- 2,3-dihydro-3-methyl-7-oxo-7H-pyrido(1,2,3-de)-1,4-benzoxazine-6- carboxylic acid. Mp 320°C.
Part E:
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. Recrystallization from DMF affords 0.18 g 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, ethyl ester (20%) . Mp 255-260°C.
Procedure 2 Preparation 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.
Part A:
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. The residue is chromatographed over silica gel (550 g, 5% methanol/methylene chloride) to afford 2.92 g of 9-fluoro-3-methyl-10-(3-acetoamino-1-pyrrolidinyl)-7-oxo-2,3- dIhydro-7H-pyrido[1,2,3-de]-1,4-benoxazine-6-carboxylic acid, ethyl ester (47%). M.p. 217-220"C.
Part B:
9-Fluoro-3-methyl-10-(3-acetoamino-1-pyrrolidinyl)-7-oxo-2,3- dihydro-7H-pyrido[1,2,3-de]-1,4-benoxazine-6-carboxylic acid, ethyl ester (0.63 g, 1.5 mmol, Part A) is refluxed in 6N hydrochloric acid
(HC1) (32 ml). Aftex 45 min, the solvent is evaporated off under a stream of nitrogen. Water is added and the pH adjusted to 7.0 with IN sodium hydroxide. Evaporation of the solvent affords crude 9- fluoro-3-methyl-10-(3-amino-1-pyrrolidinyl)-7-oxo-2,3-dihydro-7H- pyrido[1,2,3-de]-1,4-benoxazine-6-carboxylic acid, which is not further purified and used in Example 3.

Claims

1. A compound structurally represented by the formula (I):
and therapeutically acceptable salts thereof wherein
R1 is hydrogen or hydroxyl;
R2 is hydrogen or methyl;
R4, R5, R6, R7 are independently hydrogen, hydroxyl, halogen, C1-C4 alkyl, ethenyl, ethynyl, C3-C6 cycloalkyl, fluoromethyl, difluoromethyl, difluoroethyl, trifluoromethyl, hydroxymethyl, C1-C18 alkoxy methyl, phenoxymethyl, C1-C3 alkyl aminomethyl, C1-C3) dialkyl aminomethyl, C6-C12 aryl, substituted aryl, heteroaryl or substituted heteroaryl containing at least one 0, N or S;
R8 is hydrogen, hydroxyl, amine, C1-C4 alkoxy or aryloxy, -SH, G1-C6 thioalkyl or thioaryl;
R9 is C1-C4 alkyl, C6-C12 aryl, alkylaryl, heteroaryl, -(CH2)n- CO2-(GH2)m-R11, wherein R11 is hydrogen, hydroxyl, methyl alkyloxy, aryloxy or an amine, n is 0-4 and m is 0-4;
R10 is hydrogen, -(CH3)o, C2-C4 alkyl, C6-C12 aryl, alkylaryl, heteroaryl, or acetyl, where o is 0 or 1;
R12 is hydrogen CN, halogen, or R9; and
Z is (CH2)q where q is 0-2, CH-CH3 or C(CH3)2.
2. The compound of Claim 1 wherein R1 is hydroxy.
3. The compound of Claim 2 wherein R2 is methyl.
4. The compound of Claim 2 wherein R2 is hydrogen.
5. The compound of Claim 6 wherein R3 is fluorine.
6. The compound of Claim 6 wherein R3 is hydrogen.
7. The compound of Claim 6 wherein R3 is primary amine (NH2).
8. The compound of Claim 6 wherein R3 is hydroxy.
9. The compound of Claim 1 wherein R8 is methoxy and R9 is a carbomethoxy group.
10. The compound of Claim 1 wherein the carbon atom having the R5 group is bond to the nitrogen atom having the R10 group, R10 is -(CH3)o where o is 0, and Z is (CH2)q where q is 0.
11. The compound of Claim 10 which is (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 or (E)-2-[4-[6- carboxy-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.
12. The compound of Claim 1 wherein the carbon atom having the R5 group is bond to the carbon atom having the R6 group.
13. The compound of Claim 12 which is (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-(3-amino-pyrrolidinyl)]-2-butendioic acid, 1,4-dimethyl ester or (E)-2-[4-[6-carboxy-9-fluoro-2,3-dihydro-7-oxo-7H-pyrido(1,2,3-de)- 1,4-benzoxazin-10-yl]-1-(3-amino-pyrrolidinyl)]-2-butendioic acid, 1,4-dimethyl ester.
14. A pharmaceutical composition containing an antibacterially effective amount of a compound according to Claim 1 in admixture with a pharmaceutical carrier.
15. The composition of Claim 14 containing from about 0.5 to about 90% by weight of said compound.
16. The composition of Claim 14 which is in unit dose form of tablets, pills, dragees, capsules, ampules or suppositories.
17. A method for treating bacterial Infection in animals including humans which comprises: administering to said animal an antibacterially effective amount of a compound according to Claim 1.
18. The method of Claim 17 wherein said compound is administered orally ox parenterally.
EP90906002A 1989-04-26 1990-01-22 Antibacterial pyrido(1,2,3-de)-1,4-benzoxazinone agents Withdrawn EP0489733A1 (en)

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US343880 1989-04-26

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DE4120646A1 (en) * 1991-06-22 1992-12-24 Bayer Ag 7-ISOINDOLINYL-CHINOLONE AND NAPHTHYRIDONE CARBONIC ACID DERIVATIVES
KR100309871B1 (en) * 1999-02-24 2001-10-29 윤종용 Process for Preparing (-)Pyridobenzoxazine Carboxylic Acid Derivatives
KR100542600B1 (en) * 2004-05-17 2006-01-11 주식회사 카이로켐 Process for the preparation of optically active S-pyridobenzoxazine carboxylic acid hemihydrate derivatives

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DE3543513A1 (en) * 1985-12-10 1987-06-11 Bayer Ag ENANTIOMER-PURE 1,8-BRIDGED 4-CHINOLON-3-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE MEDICINAL PRODUCTS CONTAINING THEM AND THEIR USE FOR THE PRODUCTION OF MEDICINAL PRODUCTS
DE3711193A1 (en) * 1987-04-02 1988-10-13 Bayer Ag 5-SUBSTITUTED CHINOLON AND NAPHTHYRIDONE CARBONIC ACID DERIVATIVES

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JPH04504852A (en) 1992-08-27
WO1990012799A1 (en) 1990-11-01

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