NO169125B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 10-SUBSTITUTED 9-FLUOR-7-OXO-2,3-DIHYDRO-7H-PYRIDO (3.2.1-IJ) -1,3,4-BENZOXADIAZINE-6-CARBOXYLSYL - Google Patents

ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 10-SUBSTITUTED 9-FLUOR-7-OXO-2,3-DIHYDRO-7H-PYRIDO (3.2.1-IJ) -1,3,4-BENZOXADIAZINE-6-CARBOXYLSYL Download PDF

Info

Publication number
NO169125B
NO169125B NO873816A NO873816A NO169125B NO 169125 B NO169125 B NO 169125B NO 873816 A NO873816 A NO 873816A NO 873816 A NO873816 A NO 873816A NO 169125 B NO169125 B NO 169125B
Authority
NO
Norway
Prior art keywords
compound
methyl
dihydro
oxo
benzoxadiazine
Prior art date
Application number
NO873816A
Other languages
Norwegian (no)
Other versions
NO873816D0 (en
NO873816L (en
NO169125C (en
Inventor
Masahiro Aoki
Miyako Kamata
Tatsuo Ohtsuka
Nobuo Shimma
Kazuteru Yokose
Original Assignee
Hoffmann La Roche
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
Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche
Publication of NO873816D0 publication Critical patent/NO873816D0/en
Publication of NO873816L publication Critical patent/NO873816L/en
Priority to NO894109A priority Critical patent/NO174926C/en
Priority to NO894108A priority patent/NO171162C/en
Publication of NO169125B publication Critical patent/NO169125B/en
Publication of NO169125C publication Critical patent/NO169125C/en

Links

Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Quinoline Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

Foreliggende oppfinnelse vedrører analogifremgangsmåte ved fremstilling av terapeutisk aktive 10-substituerte 9-fluor-7-okso-2,3-dihydro-7H-pyrido-[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyrederivater med den generelle formel The present invention relates to an analogous method for the production of therapeutically active 10-substituted 9-fluoro-7-oxo-2,3-dihydro-7H-pyrido-[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid derivatives with the general formula

hvor R<1> er et hydrogenatom eller et karboksy-beskyttende radikal valgt fra lavere alkyl, benzyl og lavere alkanoylok-syalkyl; R<2> er et lavere alkyl-radikal som kan være substituert med et fluoratom; R<3> er et hydrogenatom eller et lavere alkyl-radikal som kan være substituert med et hydroksy-radikal eller med et dilavere alkylamino-radikal; R<5> er et lavere alkylradikal, og R<6> er et di-lavere alkyl-aminolavere alkylradikal, eller R<5> og R<6> tatt sammen med det hosliggende nitrogenatom kan danne - en piperazinring som kan være substituert i 3-stilling med metyl eller fenyl og/eller N-substituert med lavere metyl, etyl, acetyl aminobenzyl; - en morfolinring; - en 1,1-dioksydtiomorfolinring; - en pyrrolidinring som er substituert i 3-stilling med amino, metylamino, etylamino, aminometyl, metylaminometyl, etylaminometyl, metoksy eller klor eller i 4-stilling med metyl eller metoksy; - en imidazolring som kan være substituert med metyl i 4-stilling; eller - en piperidinring som kan være substituert med aminometyl, hydroksy, amino, metylamino eller metoksy; where R<1> is a hydrogen atom or a carboxy-protecting radical selected from lower alkyl, benzyl and lower alkanoyloxyalkyl; R<2> is a lower alkyl radical which may be substituted with a fluorine atom; R<3> is a hydrogen atom or a lower alkyl radical which may be substituted with a hydroxy radical or with a dilower alkylamino radical; R<5> is a lower alkyl radical, and R<6> is a di-lower alkyl-amino lower alkyl radical, or R<5> and R<6> taken together with the adjacent nitrogen atom can form - a piperazine ring which can be substituted in 3-position with methyl or phenyl and/or N-substituted with lower methyl, ethyl, acetyl aminobenzyl; - a morpholine ring; - a 1,1-dioxidethiomorpholine ring; - a pyrrolidine ring which is substituted in the 3-position with amino, methylamino, ethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, methoxy or chlorine or in the 4-position with methyl or methoxy; - an imidazole ring which may be substituted with methyl in the 4-position; or - a piperidine ring which may be substituted with aminomethyl, hydroxy, amino, methylamino or methoxy;

så vel som farmasøytisk akseptable salter derav og hydrater eller solvater av forbindelsene med formel I eller deres salter, som er anvendelige som effektive bestanddeler i antibakterielle midler. as well as pharmaceutically acceptable salts thereof and hydrates or solvates of the compounds of formula I or their salts, which are useful as effective ingredients in antibacterial agents.

De respektive radikaler i formel I som er definert ovenfor blir forklart i større detalj som følger: Referanse til uttrykket "lavere" har til hensikt å bety en karbonkjede, fortrinnsvis inneholdende opptil 7 karbonatomer med mindre noe annet er angitt. The respective radicals of formula I defined above are explained in greater detail as follows: Reference to the term "lower" is intended to mean a carbon chain, preferably containing up to 7 carbon atoms unless otherwise indicated.

Forklaring til R<1>: Explanation for R<1>:

R<1> er et hydrogenatom eller et karboksy-beskyttende radikal. R<1> is a hydrogen atom or a carboxy-protecting radical.

I det ovenforstående betyr karboksy-beskyttende radikal In the above, carboxy-protecting radical means

lavere alkyl, såsom metyl, etyl, n-propyl, t-butyl; laverealkanoyl-oksy-alkyl, (f.eks. acetoksymetyl, pivaloyloksymetyl, 1-acetoksy-etyl og 1-pivaloyloksyetyl);benzyl kan også brukes. lower alkyl, such as methyl, ethyl, n-propyl, t-butyl; lower alkanoyloxyalkyl, (eg acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl); benzyl can also be used.

Forklaring for R<2>: Explanation for R<2>:

R<2> er et lavere alkyl-radikal som kan være substituert med et fluoratom. R<2> is a lower alkyl radical which may be substituted with a fluorine atom.

I det ovenfornevnte inneholder lavere alkyl-radikal fortrinnsvis 1 til 4 karbonatomer, spesielt metyl, etyl, n-propyl, iso-propyl, n-butyl og lignende. In the above, lower alkyl radical preferably contains 1 to 4 carbon atoms, especially methyl, ethyl, n-propyl, iso-propyl, n-butyl and the like.

Forklaring for R<3>: Explanation for R<3>:

R<3> et hydrogenatom eller et lavere alkyl-radikal som kan være substituert med et hydroksyradikal eller et dilavere alkylamino-radikal. R<3> a hydrogen atom or a lower alkyl radical which may be substituted with a hydroxy radical or a dilower alkylamino radical.

De ovenfor nevnte lavere alkyl-radikaler inneholder fortrinnsvis 1 til 4 karbonatomer, spesielt metyl, etyl, n- The above-mentioned lower alkyl radicals preferably contain 1 to 4 carbon atoms, especially methyl, ethyl, n-

propyl, iso-propyl, n-butyl . Den di-lavere alkylaminoradikal kan være dimetylamino eller dietylamino og lignende. propyl, iso-propyl, n-butyl . The lower alkylamino radical can be dimethylamino or diethylamino and the like.

Forklaring for R<5> og R6:Explanation for R<5> and R6:

R<5> er et lavere alkyl-radikal, og R<6> er et dilavere alkyl-aminolavere alkylradikal; eller R<5> og R<6> tatt sammen med det R<5> is a lower alkyl radical, and R<6> is a dilower alkyl-amino lower alkyl radical; or R<5> and R<6> taken together with it

hosliggende nitrogenatom kan danne adjacent nitrogen atom can form

- en piperazinring som kan være substituert i 3-stilling med metyl eller fenyl og/eller N-substituert med metyl, etyl, acetyl aminobenzyl; - en morfolinring; - en 1,1-dioksydtiomorfolinring; - en pyrrolidinring som er substituert i 3-stilling med amino, metylamino, etylamino, aminometyl, metylaminometyl, etylaminometyl, metoksy eller klor eller i 4-stilling med metyl eller metoksy; - en imidazolring som kan være substituert med metyl i 4-stilling; eller - en piperidinring som kan være substituert med aminometyl, hydroksy, amino, metylamino eller metoksy; - a piperazine ring which can be substituted in the 3-position with methyl or phenyl and/or N-substituted with methyl, ethyl, acetyl aminobenzyl; - a morpholine ring; - a 1,1-dioxidethiomorpholine ring; - a pyrrolidine ring which is substituted in the 3-position with amino, methylamino, ethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, methoxy or chlorine or in the 4-position with methyl or methoxy; - an imidazole ring which may be substituted with methyl in the 4-position; or - a piperidine ring which may be substituted with aminomethyl, hydroxy, amino, methylamino or methoxy;

Spesielt foretrukkede radikaler representert av R<5>R<6>N- i formel I er 1-piperazinyl, 4-metyl-l-piperazinyl, 3-metyl-l-piperazinyl, 3-fenyl-l-piperazinyl, 4-etyl-l-pipefarzinyl, 4-(4-aminobenzyl)-1-piperazinyl, 4-acetyl-l-piperazinyl, morfolin, 1,l-dioksid-4-tiomorfolinyl, 4-(aminometyl)-1-piperidyl, 4-hydroksy-l-piperidyl, 4-amino-l-piperidyl, 4-(metylamino)-1-piperidyl, 3-amino-l-pyrrolidinyl, 3-(metylamino) -1-pyrrolidinyl , 3-(etylamino)-1-pyrrolidinyl, 3-(aminometyl)-l-pyrrolidinyl, 3-[(metylamino)metyl]-l-pyrrolidinyl, 3-[(etylamino)metyl]-1-pyrrolidinyl, 3-metoksy-1-pyrrolidinyl, 3-klor-l-pyrrolidinyl, 1-imidazolyl eller 4-metyl-l-imidazolyl og lignende. Particularly preferred radicals represented by R<5>R<6>N- in formula I are 1-piperazinyl, 4-methyl-l-piperazinyl, 3-methyl-l-piperazinyl, 3-phenyl-l-piperazinyl, 4-ethyl -l-pipefarzinyl, 4-(4-aminobenzyl)-1-piperazinyl, 4-acetyl-l-piperazinyl, morpholine, 1,1-dioxide-4-thiomorpholinyl, 4-(aminomethyl)-1-piperidyl, 4-hydroxy -l-piperidyl, 4-amino-l-piperidyl, 4-(methylamino)-1-piperidyl, 3-amino-l-pyrrolidinyl, 3-(methylamino)-1-pyrrolidinyl, 3-(ethylamino)-1-pyrrolidinyl , 3-(aminomethyl)-l-pyrrolidinyl, 3-[(methylamino)methyl]-l-pyrrolidinyl, 3-[(ethylamino)methyl]-1-pyrrolidinyl, 3-methoxy-1-pyrrolidinyl, 3-chloro-l -pyrrolidinyl, 1-imidazolyl or 4-methyl-1-imidazolyl and the like.

De nye 10-substituerte 9-fluor-7-okso-2,3-dihydro-7H-pyrido-[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyrederivater med formel I og deres farmasøytiske akseptable salter og hydrater eller solvater derav og av disse salter fremstilles i henhold til foreliggende oppfinnelse ved en fremgangsmåte som omfatter The new 10-substituted 9-fluoro-7-oxo-2,3-dihydro-7H-pyrido-[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid derivatives of formula I and their pharmaceutically acceptable salts and hydrates or solvates thereof and of these salts are prepared according to the present invention by a method which comprises

(a) å omsette en forbindelse representert av den generelle formel (a) to react a compound represented by the general formula

hvor R<1>, R<2> og R<3> er som definert ovenfor, og X<1> er et halogenatom; og amino-, hydroksy- og/eller karboksygrupper som er tilstede, kan være beskyttet, where R<1>, R<2> and R<3> are as defined above, and X<1> is a halogen atom; and amino, hydroxy and/or carboxy groups present may be protected,

med et amin representert av den generelle formel with an amine represented by the general formula

hvor R<5> og R<6> er som definert ovenfor, etterfulgt av, om nødvendig, fjerning av et beskyttende radikal, eller (b) å omsette en forbindelse representert av den generelle wherein R<5> and R<6> are as defined above, followed by, if necessary, removal of a protecting radical, or (b) reacting a compound represented by the general

hvor R<1>, R<2>, R<5> og R<5> er som definert ovenfor, og amino, hydroksy og/eller karboksygrupper som er tilstede kan være beskyttet, where R<1>, R<2>, R<5> and R<5> are as defined above, and amino, hydroxy and/or carboxy groups present may be protected,

med et aldehyd representert av den generelle formel with an aldehyde represented by the general formula

hvor R<3> er som definert ovenfor, eller dets polymer, acetal eller enol-eter, etterfulgt om nødvendig av fjerning av et beskyttelsesradikal, eller (c) for fremstilling av en forbindelse med formel I hvor R<5>R<6>N- er en N-substituert piperazinring som definert ovenfor, å omsette en forbindelse med formel I hvor R<5>R<6>n-er N-usubstituert piperazinyl, med er et middel som gir en slik N-substituent; eller (d) for fremstilling av en forbindelse med formel I hvor R<5>R<6>N- er 1,1-dioksyd-tiomorfolino ved å la en tilsvarende forbindelse hvor R<5>R<6>N- er tiomorfolino, undergå oksydasjon; eller (e) for fremstilling av en forbindelse av formel I hvor R<5>R<6>N- er en pyrrolidinring substituert med amino eller en piperidinring substituert med amino eller hydroksy, å avspalte den beskyttende gruppe fra en tilsvarende forbindelse som har en tilsvarende bestyttet amino- eller hydroksygruppe; eller (f) for fremstilling av en forbindelse med formel I hvor R<5>R<6>N- er en klorpyrrolidinring, å klorere en tilsvarende hydroksypyrrolidinforbindelse med formel I hvor R<1> er et hydroksybeskyttende radikal som definert ovenfor og hvis ønsket å avspalte nevnte beskyttende radikal R<1>; eller (g) for fremstilling av en forbindelse med formel I hvor R<5>R<6>N- er en aminobenzyl-piperazinring, å redusere nitro-gruppen i en tilsvarende nitrobenzyl-piperazinforbindelse med formel I, eller (h) for fremstilling av en forbindelse med formel I hvor R<1 >er et karboksy-beskyttende radikal som definert ovenfor, å underkaste en karboksylsyre av formel I en tilsvarende esterifisering, og hvis ønsket (i) for fremstilling av farmasøytisk akseptable salter, hydrater eller solvater av en forbindelse av formel I eller hydrater eller solvater av nevnte salter, å omdanne en forbindelse av formel I til et salt, hydrat eller solvat eller til et hydrat eller solvat av nevnte salt. wherein R<3> is as defined above, or its polymer, acetal or enol ether, followed if necessary by removal of a protecting radical, or (c) for the preparation of a compound of formula I wherein R<5>R<6> N- is an N-substituted piperazine ring as defined above, reacting a compound of formula I wherein R<5>R<6>n-is N-unsubstituted piperazinyl, with is an agent which gives such an N-substituent; or (d) for the preparation of a compound of formula I wherein R<5>R<6>N- is 1,1-dioxide-thiomorpholino by adding a corresponding compound wherein R<5>R<6>N- is thiomorpholino , undergo oxidation; or (e) for the preparation of a compound of formula I wherein R<5>R<6>N- is a pyrrolidine ring substituted with amino or a piperidine ring substituted with amino or hydroxy, cleaving the protecting group from a corresponding compound having a correspondingly protected amino or hydroxy group; or (f) for the preparation of a compound of formula I wherein R<5>R<6>N- is a chloropyrrolidine ring, to chlorinate a corresponding hydroxypyrrolidine compound of formula I wherein R<1> is a hydroxy protecting radical as defined above and if desired cleaving said protecting radical R<1>; or (g) for the preparation of a compound of formula I where R<5>R<6>N- is an aminobenzyl-piperazine ring, to reduce the nitro group in a corresponding nitrobenzyl-piperazine compound of formula I, or (h) for the preparation of a compound of formula I wherein R<1 >is a carboxy-protecting radical as defined above, to subject a carboxylic acid of formula I to a corresponding esterification, and if desired (i) for the preparation of pharmaceutically acceptable salts, hydrates or solvates of a compound of formula I or hydrates or solvates of said salts, to convert a compound of formula I into a salt, hydrate or solvate or into a hydrate or solvate of said salt.

Fremgangsmåte A: Procedure A:

Som angitt ovenfor kan de ønskede forbindelser erholdes ved å omsette en forbindelse representert av den generelle formel hvor R<1>, R<2> og R<3> er som definert ovenfor, og X' er et halogenatom, og amino-, hydroksy- og/eller karboksygrupper som er tilstede kan være beskyttet, med et amin representert av den generelle formel As indicated above, the desired compounds can be obtained by reacting a compound represented by the general formula where R<1>, R<2> and R<3> are as defined above, and X' is a halogen atom, and amino-, hydroxy - and/or carboxy groups present may be protected, with an amine represented by the general formula

hvor R<5> og R<6> er som definert ovenfor fulgt om nødvendig av fj erning av et beskyttende radikal. where R<5> and R<6> are as defined above followed if necessary by removal of a protecting radical.

I fremgangsmåte A er forbindelsen representert av formel III som blir brukt som en utgangsforbindelse en ny forbindelse, og denne kan fremstilles f.eks. i henhold til følgende reaksjonsskjema a) eller b). hvor R<2>, R<3> og X' er som tidligere definert ovenfor; R<1> er et beskyttende radikal såsom benzyl, metoksybenzyl, metoksy-metyl, metoksyetoksymetyl, tetrahydropyranyl, allyl, t-butyl, t-butyldimetylsilyl, acetyl, benzoyl og ligende; R<1>' er et beskyttende radikal såsom formamyl, acetyl, trifluoracetyl, benzoyl, etoksykarbonyl, 2,2,2-trikloretoksykarbonyl, fenoksykarbonyl, benzyloksykarbonyl, t-butoksykarbonyl og R'<11> er et hydrogenatom eller et etyl-radikal. In process A, the compound represented by formula III which is used as a starting compound is a new compound, and this can be prepared e.g. according to the following reaction scheme a) or b). where R<2>, R<3> and X' are as previously defined above; R<1> is a protecting radical such as benzyl, methoxybenzyl, methoxymethyl, methoxyethoxymethyl, tetrahydropyranyl, allyl, t-butyl, t-butyldimethylsilyl, acetyl, benzoyl and the like; R<1>' is a protecting radical such as formamyl, acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl and R'<11> is a hydrogen atom or an ethyl radical.

Dersom forbindelsene med formel IV inneholder en amino eller monoalkylamino substituent kan nevnte substituent om ønsket være beskyttet av et aminobeskyttende radikal såsom formyl, acetyl, trifluoracetyl, benzoyl, etoksykarbonyl, 2,2,2-trikloretoksykarbonyl, fenoksykarbonyl, benzyloksykabonyl, t-butoksykarbonyl . If the compounds of formula IV contain an amino or monoalkylamino substituent, said substituent can, if desired, be protected by an amino-protecting radical such as formyl, acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl.

Reaksjonen mellom forbindelsen av formel III og aminet av formel IV eller det passende beskyttede amin kan om nødvendig utføres med eller uten et oppløsningsmiddel fortrinnsvis ved øket temperatur i en tilstrekkelig tid slik at reaksjonen i hovedsak kan føres til avslutning. Den passende reaksjonstem-peratur er i området ca. 30°C til ca. 200°C, fortrinnsvis fra 80<6>C til 150°C for å erholde en tilstrekkelig rask reaksjons-hastighet. The reaction between the compound of formula III and the amine of formula IV or the suitably protected amine can, if necessary, be carried out with or without a solvent, preferably at an elevated temperature for a sufficient time so that the reaction can essentially be brought to completion. The appropriate reaction temperature is in the range of approx. 30°C to approx. 200°C, preferably from 80<6>C to 150°C to obtain a sufficiently fast reaction rate.

Reaksjonen utføres fortrinnsvis i nærvær av en syre-akseptor såsom trietylamin, pyridin, picolin, N,N-dimetylanilin, 1,8-diazabicyklo[5,4,0]undec-7-ene, 1, 4-diazabicyklo[2,2,2]-octan, alkali-metall, hydroksider, alkali-metallkarbonater . Alternativt kan et overskudd av aminene av formel (IV) anvendes som syre-akseptor. The reaction is preferably carried out in the presence of an acid acceptor such as triethylamine, pyridine, picoline, N,N-dimethylaniline, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,4-diazabicyclo[2,2 ,2]-octane, alkali metal, hydroxides, alkali metal carbonates . Alternatively, an excess of the amines of formula (IV) can be used as acid acceptor.

De passende oppløsningsmidler for denne reaksjon er ikke-reaktive oppløsningsmidler såsom acetonitril, alkoholer, dimetylsulfoksyd, dimetylformamid, dimetylacetamid, pyridin, picolin, lutidin, N, N'-dimetylpropylurea . Blandinger av to eller flere oppløsningsmidler kan også benyttes. The suitable solvents for this reaction are non-reactive solvents such as acetonitrile, alcohols, dimethylsulfoxide, dimethylformamide, dimethylacetamide, pyridine, picoline, lutidine, N,N'-dimethylpropylurea. Mixtures of two or more solvents can also be used.

Det beskyttende radikalet kan, om ønsket, fjernes etter reaksjonen ved fremgangsmåter kjent for fagmannen. For eksempel kan formyl-radikal fjernes ved sur eller basiskt hydrolyse fortrinnsvis basiskt hydrolyse og benzyloksykarbonyl-radikalet kan fjernes ved hydrogenolyse. The protective radical can, if desired, be removed after the reaction by methods known to those skilled in the art. For example, the formyl radical can be removed by acid or basic hydrolysis, preferably basic hydrolysis, and the benzyloxycarbonyl radical can be removed by hydrogenolysis.

Utgangsmaterialene representert av formel (III) kan eksempl-ifiseres som følger: 9,10-Difluor-3-metyl-7-okso-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre, etyl-9,10-difluor-3-metyl-7-okso-2,3-dihydro-7H-pyrido-[3,2,1-ij]-1,3,4-benzoksadiazin-6-karboksylat, benzyl-9,10-difluor-3-metyl-7-okso-2,3-dihydro-7H-pyrido-[3,2,1-ij]-1,3,4-benzoksadiazin-6-karboksylat, The starting materials represented by formula (III) can be exemplified as follows: 9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3 ,4-Benzoxadiazine-6-carboxylic acid, ethyl-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido-[3,2,1-ij]-1,3,4 -benzoxadiazine-6-carboxylate, benzyl-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido-[3,2,1-ij]-1,3,4-benzoxadiazine -6-carboxylate,

9,10-difluor-3-(2-fluoretyl)-7-okso-2,3-dihydro-7H-pyrido-[3,2,1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre, 9,10-difluoro-3-(2-fluoroethyl)-7-oxo-2,3-dihydro-7H-pyrido-[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid,

9,10-difluor-2,3-dimetyl-7-okso-2,3-dihydro-7H-pyrido-[3,2,1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre, 9,10-difluoro-2,3-dimethyl-7-oxo-2,3-dihydro-7H-pyrido-[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid,

9,10-difluor-2-(hydroksymetyl)-3-metyl-7-okso-2,3-dihydro-7H-pyrido[3,2-1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre, 9,10-difluoro-2-(hydroxymethyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2-1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid ,

9,10-difluor-2-[(dimetylamino)metyl]-3-metyl-7-okso-2,3-dihydro-7H-pyrido[3,2-1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre. 9,10-difluoro-2-[(dimethylamino)methyl]-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3,2-1-ij]-1,3,4-benzoxadiazine- 6-carboxylic acid.

Aminet av formel (IV) brukt i ovenfor angitte reaksjon er f.eks. piperazin, 4-metylpiperazin, 3-metylpiperazin, 3-fenylpiperazin, morfolin, tiomorfolin, 4-(aminometyl)-piperidin, 4-aminopiperidin, 4-(metylamino)piperidin, 4-(benzyloksykarbonylamino)piperidin, 4-(benzyloksykar-bonylmetylamino)piperidin, 4-hydroksy-piperidin, 4-met-oksypiperidin, 3-[(metylamino)metyl]pyrrolidin, 3-[(etylamino) -metyl ]pyrrolidin, 3-metoksypyrrolidin, 3-aminopyrroli-din, 3-(benzyloksykarbonylamino)pyrrolidin, 3-(metylamino)-pyrrolidin, 3-(benzyloksykarbonylmetylamino)pyrrolidin, 3-(benzyloksykarbonyletylamino)pyrrolidin. The amine of formula (IV) used in the above reaction is e.g. piperazine, 4-methylpiperazine, 3-methylpiperazine, 3-phenylpiperazine, morpholine, thiomorpholine, 4-(aminomethyl)piperidine, 4-aminopiperidine, 4-(methylamino)piperidine, 4-(benzyloxycarbonylamino)piperidine, 4-(benzyloxycarbonylmethylamino) )piperidine, 4-hydroxy-piperidine, 4-methoxypiperidine, 3-[(methylamino)methyl]pyrrolidine, 3-[(ethylamino)-methyl]pyrrolidine, 3-methoxypyrrolidine, 3-aminopyrrolidine, 3-(benzyloxycarbonylamino )pyrrolidine, 3-(methylamino)pyrrolidine, 3-(benzyloxycarbonylmethylamino)pyrrolidine, 3-(benzyloxycarbonylethylamino)pyrrolidine.

Fremgangsmåte B: Method B:

Den ønskede forbindelse kan erholdes ved å omsette en forbindelse representert av formel hvor R<1>, R<2>, R<5> og R<6> er som definert ovenfor og amino, hydroksy og/eller karboksygrupper som er tilstede kan være beskyttet med et aldehyd representert med den generelle formel The desired compound can be obtained by reacting a compound represented by formula where R<1>, R<2>, R<5> and R<6> are as defined above and amino, hydroxy and/or carboxy groups present may be protected with an aldehyde represented by the general formula

hvor R<3> er som definert ovenfor, og aminogrupper som er tilstede kan være beskyttet, where R<3> is as defined above, and amino groups present may be protected,

eller dets polymer, acetal, ketal eller enol-eter fulgt, om nødvendig, av fjerning av et beskyttende radikal. or its polymer, acetal, ketal or enol ether followed, if necessary, by removal of a protecting radical.

I fremgangsmåte B er forbindelsen representert av formel V som utgangsforbindelse en ny forbindelse og denne forbindelse kan dannes i henhold til ovenfor nevnte reaksjons-skjema a) eller b) eller ved å omsette en forbindelse (H) eller (Va) med et amin av formel (IV). In method B, the compound represented by formula V as starting compound is a new compound and this compound can be formed according to the above-mentioned reaction scheme a) or b) or by reacting a compound (H) or (Va) with an amine of formula (IV).

Reaksjonen kan, om ønsket, utføres i et oppløsningsmiddel såsom dioksan, tetrahydrofuran, acetonitril, kloroform, dimetylformamid, dimetylsulfoksid, N,N'-dimetylpropylurea, eddiksyre eller lignende. Blandinger av to eller flere oppløsningsmidler kan også bli brukt. The reaction can, if desired, be carried out in a solvent such as dioxane, tetrahydrofuran, acetonitrile, chloroform, dimethylformamide, dimethylsulfoxide, N,N'-dimethylpropylurea, acetic acid or the like. Mixtures of two or more solvents may also be used.

Reaksjonen kan, om nødvendig, utføres i nærvær av en syre-katalysator, såsom eddiksyre, saltsyre, svovelsyre, metansu-lfonsyre, p-toluensulfonsyre, pyridin p-toluensulfonat, jernklorid, sink-klorid, klorotrimetylsilan, Nafion-H (perfluorinert harpiks-sulfonsyre; Aldrich Chemical Co., Inc.), Amberlyst-15 (sterkt surt, makroretikulært resin; Aldrich Chemical Co., Inc.), . The reaction can, if necessary, be carried out in the presence of an acid catalyst, such as acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, pyridine p-toluenesulfonate, ferric chloride, zinc chloride, chlorotrimethylsilane, Nafion-H (perfluorinated resin sulfonic acid; Aldrich Chemical Co., Inc.), Amberlyst-15 (strongly acidic, macroreticular resin; Aldrich Chemical Co., Inc.), .

Reaksjonstemperaturen kan varieres innenfor et relativt bredt område. Generelt utføres reaksjonen ved en temperatur mellom 20°C og 150°C. The reaction temperature can be varied within a relatively wide range. In general, the reaction is carried out at a temperature between 20°C and 150°C.

I en foretrukket utførelsesform av fremgangsmåten fremskaffet i henhold til foreliggende oppfinnelse anvendes ca. 1 mol eller overskytende mol av karbonylforbindelsen av formel (VI) eller dets polymer, acetal eller enol-eter pr. mol av forbindelsen med formel (V). In a preferred embodiment of the method provided according to the present invention, approx. 1 mole or excess mole of the carbonyl compound of formula (VI) or its polymer, acetal or enol ether per moles of the compound of formula (V).

Utgangsmaterialene representert av formel (Va) kan eksempli-fiseres som følger: 6,7-Difluor-8-hydroksy-l-(metylamino)-4-okso-l,4-dihydro-3-kinolinkarboksylsyre, etyl-6,7-difluor-8-hydroksy-l-(metylamino)-4-okso-l,4-dihydro-3-kinolinkarboksylat. benzyl-6,7-difluor-8-hydroksy-l-(metylamino)-4-okso-l,4-dihydro-3-kinolinkarboksylat, The starting materials represented by formula (Va) can be exemplified as follows: 6,7-Difluoro-8-hydroxy-1-(methylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, ethyl-6,7- difluoro-8-hydroxy-1-(methylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylate. benzyl 6,7-difluoro-8-hydroxy-1-(methylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylate,

6,7-difluor-1-[(2-fluoretyl)amino]-8-hydroksy-4-okso-l,4-dihydro-3-kinolinkarboksylsyre, 6,7-difluoro-1-[(2-fluoroethyl)amino]-8-hydroxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid,

Utgangsmaterialene representert ved formel (V) kan eksem-plifiseres som følger: 6-Fluor-8-hydroksy-7-(1-imidazoyl)-l-(metylamino)-4-okso-1,4-dihydro-3-kinolinkarboksylsyre, etyl-6-fluor-8-hydroksy-7-(1-imidazoyl)-1-(metylamino)-4-okso-1,4-dihydro-3-kinolinkarboksy1at, benzyl-6-fluor-8-hydroksy-7-(l-imidazoyl)-1-(metylamino)-4— okso-1,4-diydro-3-kinolinkarboksylat, The starting materials represented by formula (V) can be exemplified as follows: 6-Fluoro-8-hydroxy-7-(1-imidazoyl)-1-(methylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, ethyl 6-fluoro-8-hydroxy-7-(1-imidazoyl)-1-(methylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylate, benzyl 6-fluoro-8-hydroxy-7- (1-imidazoyl)-1-(methylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylate,

6-fluor-1-[(2-fluoretyl)amino]-8-hydroksy-7-(1-imidazoyl)--4-okso-l,4-dihydro-3-kinolinkarboksylsyre, 6-fluoro-1-[(2-fluoroethyl)amino]-8-hydroxy-7-(1-imidazoyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid,

6- fluor-8-hydroksy-l-(metylamino)-7-(4-metyl-l-piperazinyl)--4-okso-l,4-dihydro-3-kinolinkarboksylsyre, 6-Fluoro-8-hydroxy-1-(methylamino)-7-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid,

7- (3,4-dimetyl-l-piperazinyl)-6-fluor-8-hydroksy-l-(metylamino) -4-okso-l,4-dihydro-3-kinolinkarboksylsyre, 7-(3,4-dimethyl-1-piperazinyl)-6-fluoro-8-hydroxy-1-(methylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid,

7-[3-(benzyloksykarbonyletylamino)metyl]-1-pyrrolidiny1]-6— fluor-8-hydroksy-l-(metylamino)-4-okso-l,4-dihydro-3-kinolin-karboksylsyre, 7-[3-(benzyloxycarbonylethylamino)methyl]-1-pyrrolidine]-6-fluoro-8-hydroxy-1-(methylamino)-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid,

7-[3-(benzyloksykarbonylamino)-1-pyrrolidinyl]-6-fluor-8— hydroksy-1-(metylamino)-4-okso-l,4-dihydro-3-kinolinkarbok-sy lsyre. 7-[3-(Benzyloxycarbonylamino)-1-pyrrolidinyl]-6-fluoro-8-hydroxy-1-(methylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid.

Eksempler på forbindelser som kan omsettes med en forbindelse med formel (V) er aldehyder med formel (VI), såsom formaldehyd, acetaldehyd ; deres polymere såsom paraformaldehyd, paracetal-dehyd, trioxan ; deres acetaler såsom dimetoksy-metan, 1,1-dimetoksyetan, 1,3-dioksolan, glykolaldehyd dimetylacetal, dimetylaminoacetaldehyd, dimetylacetal ; og deres enol-eter såsom 2-metoksypropen, 2-trimetyl-silyl-oksypropen. Examples of compounds that can be reacted with a compound of formula (V) are aldehydes of formula (VI), such as formaldehyde, acetaldehyde; their polymers such as paraformaldehyde, paracetal dehyde, trioxane; their acetals such as dimethoxymethane, 1,1-dimethoxyethane, 1,3-dioxolane, glycolaldehyde dimethyl acetal, dimethylaminoacetaldehyde, dimethyl acetal; and their enol ethers such as 2-methoxypropene, 2-trimethylsilyloxypropene.

Fremgangsmåte C: Method C:

Når det er ønsket å fremstille en forbindelse av formel I hvor radikalet R<5>R<6>N- er en piperazinring N-substituert som definert ovenfor, kan den ønskede forbindelse fremstilles ved å omsette en forbindelse med formel I hvor R<5>R<6>N- er N-substituert piperazinyl, med et middel som gir en slik N-substituent. Denne reaksjon, en N-alkylering eller en N-acylering, kan utføres f.eks. som følger: When it is desired to prepare a compound of formula I where the radical R<5>R<6>N- is a piperazine ring N-substituted as defined above, the desired compound can be prepared by reacting a compound of formula I where R<5 >R<6>N- is N-substituted piperazinyl, with an agent providing such an N-substituent. This reaction, an N-alkylation or an N-acylation, can be carried out e.g. as follows:

En forbindelse av den generelle formel A compound of the general formula

hvor R<1>, R<2> og R<3> er som definert tidligere, og piperazinyl-radikalet kan være substituert i 3-stilling med metyl eller fenyl, kan omsettes (i) med en forbindelse representert av den generelle formel where R<1>, R<2> and R<3> are as defined previously, and the piperazinyl radical may be substituted in the 3-position with methyl or phenyl, may be reacted (i) with a compound represented by the general formula

hvor Y er en avspaltbar-gruppe, og R<70> er metyl, etyl, acetyl eller nitrobenzyl, eller where Y is a leaving group, and R<70> is methyl, ethyl, acetyl or nitrobenzyl, or

for å erholde forbindelser hvor R<5>R<6>N- er 4-metylpiperazinyl (ii) med formaldehyd og maursyre. to obtain compounds where R<5>R<6>N- is 4-methylpiperazinyl (ii) with formaldehyde and formic acid.

Således kan den ønskede forbindelse fremstilles ved å omsette en forbindelse representert av formel (IX) med en forbindelse representert av formel (X). Som avspaltbar gruppe Y kan det nevnes f.eks. halogenatomer såsom klor, brom, jod, acyloksy-radikaletr såsom acyloksy, lavere alkan-sulfonyl-oksy-radikaletr, såsom metansulfonyloksy, arylsulfonyloksy-radikaletr såsom p-toluensulfonyloksy; valgfritt nitrerte fenoksy-radikaletr såsom fenoksy, 4-nitrofenoksy eller succinimidoksy eller phthalimidooksy. Thus, the desired compound can be prepared by reacting a compound represented by formula (IX) with a compound represented by formula (X). As cleavable group Y can be mentioned e.g. halogen atoms such as chlorine, bromine, iodine, acyloxy radical ethers such as acyloxy, lower alkane sulfonyloxy radical ethers such as methanesulfonyloxy, arylsulfonyloxy radical ethers such as p-toluenesulfonyloxy; optionally nitrated phenoxy radicals such as phenoxy, 4-nitrophenoxy or succinimidoxy or phthalimidoxy.

Dersom forbindelsene med formel (X) inneholder en aminosub-stituent kan nevnte substituent om ønsket beskyttes av et radikal såsom beskrevet ovenfor under R'• i formelene (G) og If the compounds of formula (X) contain an amino substituent, said substituent can, if desired, be protected by a radical as described above under R'• in the formulas (G) and

(H) . (H) .

Reaksjonen kan om nødvendig utføres i et oppløsningsmiddel If necessary, the reaction can be carried out in a solvent

såsom dimetylformamid, dimetylacetamid, dimetylsulfoksyd, N,N'-dimetyl-propylenurea, dioxan, tetrahydrofuran, pyridin . Blandinger av 2 eller flere oppløsningsmidler kan også bli brukt. such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N,N'-dimethylpropyleneurea, dioxane, tetrahydrofuran, pyridine. Mixtures of 2 or more solvents may also be used.

Reaksjonen utføres fortrinnsvis i nærvær av en syre-akseptor såsom trietylamin, pyridin, N,N-dimetylanilin, 1,4-diazabi-cyklo[2,2,2]octan, 1,8-diazabicyklo[5,4,0]undec-7-en, The reaction is preferably carried out in the presence of an acid acceptor such as triethylamine, pyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2,2,2]octane, 1,8-diazabicyclo[5,4,0]undec -7 one,

natriumhydrid, alkalimetall oksider, alkalimetall karbonater. sodium hydride, alkali metal oxides, alkali metal carbonates.

Reaksjonstemperaturen kan varieres innenfor et relativ bredt område. Generelt utføres reaksjonen ved en temperatur mellom ca. 0°C og 180°C, fortrinnsvis mellom 0°C og 110°C. Ved å utføre fremgangsmåten fremskaffet i henhold til foreliggende oppfinnelse anvendes 1 til 4 mol, fortrinnsvis 1 til 2 mol av forbindelsen av formel (X) basert på 1 mol av forbindelsen av formel (IX). The reaction temperature can be varied within a relatively wide range. In general, the reaction is carried out at a temperature between approx. 0°C and 180°C, preferably between 0°C and 110°C. In carrying out the method provided according to the present invention, 1 to 4 mol, preferably 1 to 2 mol of the compound of formula (X) based on 1 mol of the compound of formula (IX) are used.

Forbindelsen av formel (X) brukt i foreliggende oppfinnelse kan være iodometan, iodoetan, brometan, maursyreanhydrid, eddiksyreanhydrid, acetylklorid, 4-nitrobenzyl-bromid. The compound of formula (X) used in the present invention can be iodomethane, iodoethane, bromoethane, formic anhydride, acetic anhydride, acetyl chloride, 4-nitrobenzyl bromide.

Reaksjonen av forbindelsene (IX) med formaldehyd og maursyre (hvorved forbindelsene med formel I hvor R<5>R<6>N- er 4-metylpiperazinyl erholdes), utføres normalt ved noe øket temperatur, f.eks. ca. +50°C til +100°C. The reaction of the compounds (IX) with formaldehyde and formic acid (by which the compounds of formula I where R<5>R<6>N- is 4-methylpiperazinyl is obtained) is normally carried out at a somewhat elevated temperature, e.g. about. +50°C to +100°C.

Fremgangsmåte D: Procedure D:

Når det er ønsket å fremstille en forbindelse av formel I hvor R<5>R<6>N- er 1,1-dioksyd-tiomorfolin, kan disse forbindelser fremstilles ved å underkaste en tilsvarende forbindelse hvor R<5>R<6>N- er tiomorfolin, oksydering. When it is desired to prepare a compound of formula I where R<5>R<6>N- is 1,1-dioxide-thiomorpholine, these compounds can be prepared by subjecting a corresponding compound where R<5>R<6> N- is thiomorpholine, oxidation.

Oksydasjonen utføres ved behandling med et organisk eller uorganisk oksyderende middel. Forskjellige forbindelser som lett gir oksygen kan bli brukt som oksyderende middel, f.eks. organiske peroksyder såsom monosubstituerte organiske peroksyder (f.eks. C^-C^alkyl eller alkanoyl hydroperoksyder såsom t-butylhydroperoksyd) permaursyre og pered-diksyre, så vel som fenyl-substituerte derivater av disse hydroperoksyder, såsom cumenhydroperoksyd og perbenzo-syre. Fenyl-substituenten kan om ønsket ytterligere være en lavere gruppe (f.eks. en C1-C4-alkyl eller alkoksygruppe) et halogenatom eller en karboksygruppe (f.eks. 4-metylperbenzo-syre, 4-metoksyperbenzosyre, 3-klorperbenzosyre og monoper-phthalsyre). Forskjellige uorganiske oksyderende midler kan også bli brukt, som oksyderende middel, f.eks. hydrogen-peroksyd, ozon, permanganater såsom kalium- eller natrium-permanganat, hypokloritter, såsom natrium-, kalium-, ammonium hypokloritt, peroksymonosvovelsyre og peroksydisvovelsyre. Bruken av 3-klorperbenzosyre er foretrukket. Oksydasjonen utføres fortrinnsvis i et inært oppløsningsmiddel f.eks. i aprotisk inært løsningsmiddel, såsom tetrahydrofuran, dioxan, metylenklorid, kloroform eller etylacetat. Oksydasjonen utføres generelt ved romtemperatur i et område fra - 20°C til +50°C. Mengden av oksydasjonsmiddel bør være den dobbelte av den støkiometriske andel eller mer for å erholde den ønskede 1,1-dioksydtiomorfolinforbindelse. The oxidation is carried out by treatment with an organic or inorganic oxidizing agent. Various compounds that readily give oxygen can be used as oxidizing agents, e.g. organic peroxides such as monosubstituted organic peroxides (eg C 1 -C 4 alkyl or alkanoyl hydroperoxides such as t-butyl hydroperoxide) permauric acid and peracetic acid, as well as phenyl-substituted derivatives of these hydroperoxides such as cumene hydroperoxide and perbenzoic acid. The phenyl substituent can, if desired, further be a lower group (e.g. a C1-C4 alkyl or alkoxy group), a halogen atom or a carboxy group (e.g. 4-methylperbenzoic acid, 4-methoxyperbenzoic acid, 3-chloroperbenzoic acid and monoper -phthalic acid). Various inorganic oxidizing agents can also be used, as oxidizing agent, e.g. hydrogen peroxide, ozone, permanganates such as potassium or sodium permanganate, hypochlorites such as sodium, potassium, ammonium hypochlorite, peroxymonosulphuric acid and peroxydisulfuric acid. The use of 3-chloroperbenzoic acid is preferred. The oxidation is preferably carried out in an inert solvent, e.g. in aprotic inert solvent such as tetrahydrofuran, dioxane, methylene chloride, chloroform or ethyl acetate. The oxidation is generally carried out at room temperature in a range from - 20°C to +50°C. The amount of oxidizing agent should be twice the stoichiometric proportion or more to obtain the desired 1,1-dioxide thiomorpholine compound.

Fremgangsmåte E; Method E;

Når det er ønsket å fremstille en forbindelse av formel I hvor R<5>R<6>N- er en pyrrolidinring substituert med amino eller en piperidinring substituert med amino eller hydroksy, kan disse forbindelser fremstilles ved å avspalte den beskyttende gruppe fra en tilsavrende forbindelse som har en beskyttet amino- eller hydroksygruppe. When it is desired to prepare a compound of formula I where R<5>R<6>N- is a pyrrolidine ring substituted with amino or a piperidine ring substituted with amino or hydroxy, these compounds can be prepared by cleaving the protecting group from a compound having a protected amino or hydroxy group.

Amino-beskyttende grupper er f.eks. butoksykarbonyl eller etoksykarbonyl; en substituert alkoksykarbonylgruppe, f.eks. trikloreetoksykarbonyl, fenoksykarbonyl, benzyloksykarbonyl, p-nitrobenzyloksykarbonyl; en aralkylgruppe såsomtrityl eller benzhydryl eller en halogen-alkanoylgruppe såsom trifluoracetyl. Amino-protecting groups are e.g. butoxycarbonyl or ethoxycarbonyl; a substituted alkoxycarbonyl group, e.g. trichloroethoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl; an aralkyl group such as trityl or benzhydryl or a haloalkanoyl group such as trifluoroacetyl.

De aminobeskyttende grupper kan spaltes av ved sur hydrolyse (f.eks. t-butoksykarbonyl eller tritylgruppen) eller vd basisk hydrolyse (f.eks. trifluoracetylgruppen). Benzyloksykarbonyl og p-nitrobenzyloksykarbonyl fjernes ved hydrogenolyse. The amino-protecting groups can be split off by acid hydrolysis (eg t-butoxycarbonyl or the trityl group) or basic hydrolysis (eg the trifluoroacetyl group). Benzyloxycarbonyl and p-nitrobenzyloxycarbonyl are removed by hydrogenolysis.

Aminobeskyttende grupper som er spaltbare ved sur hydrolyse fjernes fortrinnsvis ved hjelp av en lavere alkankarboksyl-syre som kan være halogenert. Spesielt anvendes maursyre eller trifluoreddiksyre. Den sure hydrolyse utføres generelt ved romtemperatur selv om den kan utføres ved en noe høyere eller lavere temperatur (f.eks. en temperatur i området fra ca. 0°C til +4 0°C). Beskyttende grupper som er spaltbare under basiske betingelser blir generelt hydrolysert med fortynnet vanndig kaustisk alkali ved 0°C til 30°C. Amino-protecting groups which are cleavable by acid hydrolysis are preferably removed by means of a lower alkane carboxylic acid which may be halogenated. In particular, formic acid or trifluoroacetic acid is used. The acid hydrolysis is generally carried out at room temperature, although it can be carried out at a somewhat higher or lower temperature (eg a temperature in the range from about 0°C to +40°C). Protecting groups that are cleavable under basic conditions are generally hydrolyzed with dilute aqueous caustic alkali at 0°C to 30°C.

Karboksybeskyttende grupper er f.eks. de karboksybeskyttende radikaler behandlet under R3- ovenfor. Carboxy-protecting groups are e.g. the carboxy-protecting radicals treated under R3- above.

Fremgangsmåte F: Procedure F:

Når det er ønsket å fremstille en forbindelse av formel I hvor R<5>R<6>N- er kan denne forbindelse fremstilles ved å klorere en tilsvarende forbindelse R<5>R<6>N- er When it is desired to prepare a compound of formula I where R<5>R<6>N- is, this compound can be prepared by chlorinating a corresponding compound R<5>R<6>N- is

Kloreringsmiddelet er fortrinnsvis tionyl-klorid eller fosfortriklorid, fosforoksyklorid eller fosforpenta-klorid. The chlorinating agent is preferably thionyl chloride or phosphorus trichloride, phosphorus oxychloride or phosphorus pentachloride.

Reaksjonstemperaturen er fortrinnsvis mellom ca. 0°C The reaction temperature is preferably between approx. 0°C

og 80°C. Karboksygruppene som er tilstede er fortrinnsvis beskyttet f.eks. benzylert og etterfølgende om ønsket igjen satt fri, f.eks. hydrogenering (fjerning av benzyl). and 80°C. The carboxyl groups that are present are preferably protected, e.g. benzylated and subsequently, if desired, left free, e.g. hydrogenation (removal of benzyl).

Fremgangsmåte G; Method G;

Når det er ønsket å fremstille en forbindelse av formel I R<5>R<6>N- er When it is desired to prepare a compound of formula I R<5>R<6>N- is

kan denne forbindelsen fremstilles ved å redusere nitrogrup-pene av en tilsvarende nitro-substiuert forbindelse av formel I. Reduksjonen kan utføres ved hydrogenering i nærvær av en edelmetall-katalysator såsom palladium på trekull. Reaksjonen utføres passende i vann eller en lavere alkanol såsom metanol eller etanol, om ønsket i blanding med andre oppløsningsmid-ler som er løselige deri. Reaksjonstemperaturen ligger normalt mellom ca. 10°C og ca. 40°C, fortrinnsvis ved ca. romtemperatur. this compound can be prepared by reducing the nitro groups of a corresponding nitro-substituted compound of formula I. The reduction can be carried out by hydrogenation in the presence of a noble metal catalyst such as palladium on charcoal. The reaction is conveniently carried out in water or a lower alkanol such as methanol or ethanol, if desired in admixture with other solvents soluble therein. The reaction temperature is normally between approx. 10°C and approx. 40°C, preferably at approx. room temperature.

Fremgangsmåte H; Method H;

Fremstilling av estere av formel I, d.v.s. hvor R<1> er en karboksybeskyttende gruppe som definert ovenfor, kan utføres ved å omsette en karboksylsyre av formel I med tilsvarende halid, fortrinnsvis et iodid eller bromid, inneholdene den ønskede ester-gruppe. Reaksjonene kan akseleres ved hjelp av en base såsom et alkalimetall hydroksyd, et alkalimetall-karbonat eller et organisk amin såsom trietylamin. Esterifi-seringen utføres fortrinnsvis i et inært organisk løsnings-middel såsom dimetylacetamid, hexametylfosforsyre triamid, dimetyl-sulfoksyd eller spesielt dimetylformamid. Reaksjonen utføres fortrinnsvis ved en temperatur i området på ca. 0°C til 40°C. Preparation of esters of formula I, i.e. where R<1> is a carboxy protecting group as defined above, can be carried out by reacting a carboxylic acid of formula I with a corresponding halide, preferably an iodide or bromide, containing the desired ester group. The reactions can be accelerated by means of a base such as an alkali metal hydroxide, an alkali metal carbonate or an organic amine such as triethylamine. The esterification is preferably carried out in an inert organic solvent such as dimethylacetamide, hexamethylphosphoric acid triamide, dimethyl sulphoxide or especially dimethylformamide. The reaction is preferably carried out at a temperature in the range of approx. 0°C to 40°C.

Fremgangsmåte I: Procedure I:

Fremstillingen av de farmasøytiske akseptable salter av forbindelsen av formel I eller hydratene eller solvatene av nevnte salter kan utføres på i og for seg kjent måte f.eks. ved å omsette en karboksylsyre av formel I med en ekvivalent-mengde av den ønskede base eller omvendt en fri base av formel I med en organisk eller uorganisk syre. Reaksjonen utføres passende i et oppløsningsmiddel såsom vann eller et organisk oppløsningsmiddel (f.eks. etanol, metanol, aceton ). Temperaturen hvor saltdannelsen utføres er ikke kritisk. Saltdannelsen utføres generelt ved romtemperatur, men den kan utføres ved temperatur noe over eller under romtemperatur f.eks. i området fra 0°C til +50°C. The production of the pharmaceutically acceptable salts of the compound of formula I or the hydrates or solvates of said salts can be carried out in a manner known per se, e.g. by reacting a carboxylic acid of formula I with an equivalent amount of the desired base or, conversely, a free base of formula I with an organic or inorganic acid. The reaction is suitably carried out in a solvent such as water or an organic solvent (eg ethanol, methanol, acetone). The temperature at which the salt formation is carried out is not critical. The salt formation is generally carried out at room temperature, but it can be carried out at a temperature slightly above or below room temperature, e.g. in the range from 0°C to +50°C.

Eksempler på farmasøytisk akseptable syrer anvendelige i ovenfor nevnte fremgangsmåte er hydroklorid, hydrobromid, svovel, fosfor, nitro, maur, aceton, propion, succino, glykol, lactin, tartarin, citrin, ascorbin, malein, hydroksymalein, fenylaceton, benzo, 4-aminobenzo, arthrani-lic, 4-hydroksybenzo, salicylin, aminosalicylin, nicotin, metansulfon, etansulfon, hydroksyetansulfon, benzensulfon, p-toluensulfon, glucon, glucuron, galacturon, aspartin og glutamin syre; metionin, tryptophan, lysin, arginin . Examples of pharmaceutically acceptable acids usable in the above-mentioned method are hydrochloride, hydrobromide, sulphur, phosphorus, nitro, formic, acetone, propion, succino, glycol, lactin, tartarin, citrine, ascorbic, maleic, hydroxymaleic, phenylacetone, benzo, 4-aminobenzo , arthrani-lic, 4-hydroxybenzo, salicyline, aminosalicyline, nicotine, methanesulfone, ethanesulfone, hydroxyethanesulfone, benzenesulfone, p-toluenesulfone, glucone, glucurone, galacturone, aspartic and glutamic acid; methionine, tryptophan, lysine, arginine.

Syreaddisjonssaltene kan omdannes til en fri form ved behandling med base, såsom med et metalhydroksyd, ammoniakk. The acid addition salts can be converted to a free form by treatment with a base, such as with a metal hydroxide, ammonia.

De basiske salter av forbindelsen av formel I kan fremstilles ved å omsette en forbindelse av formel I med en metall-base eller amin såsom et alkali eller jordalkali metall-hydroksyd eller et organisk amin. Eksempler på metaller brukt som cationer er natrium, kalium, magnesium, kalsium. Eksempler på aminer er dietanolamin, N,N<1->dibenzyletylen- The basic salts of the compound of formula I can be prepared by reacting a compound of formula I with a metal base or amine such as an alkali or alkaline earth metal hydroxide or an organic amine. Examples of metals used as cations are sodium, potassium, magnesium, calcium. Examples of amines are diethanolamine, N,N<1->dibenzylethylene-

diamin, cholin, etylendiamin. diamine, choline, ethylenediamine.

Syreaddisjonssaltene eller base-saltene av forbindelsen av formel I er forskjellige fra den tilsvarende frie form i enkelte fysiske egenskaper såsom oppløselighet i vann. The acid addition salts or base salts of the compound of formula I differ from the corresponding free form in certain physical properties such as solubility in water.

Forbindelsen av formel I og deres farmasøytiske salter kan eksistere i uoppløst så vel som oppløst form innebefattende hydrerte former. Hydreringen kan utføres automatisk i løpet av fremstillingsprosessen eller kan opptre gradvis som et resultat av hydroscopiske egenskaper av et opprinnelig vannfritt produkt. For kontrollert fremstilling av et hydrat kan et fullstendig eller delvis vannfritt produkt utsettes for en fuktig atmosfære (f.eks. ved ca. +10°C til +40°C). Solvater med farmasøytisk akseptable løsningsmidler såsom etanol kan erholdes i løpet av f.eks. krystallisering. The compound of formula I and their pharmaceutical salts may exist in undissolved as well as dissolved form including hydrated forms. The hydration may be carried out automatically during the manufacturing process or may occur gradually as a result of hydroscopic properties of an initially anhydrous product. For controlled preparation of a hydrate, a completely or partially anhydrous product can be exposed to a moist atmosphere (eg at about +10°C to +40°C). Solvates with pharmaceutically acceptable solvents such as ethanol can be obtained during e.g. crystallization.

Enkelte forbindelser fremskaffet ved foreliggende oppfinnelse har asymmetriske sentre. Den rene D isomer, rene L isomer så vel som blandinger derav innebefattende racemiske blandinger er også innebefattet foreliggende oppfinnelse. Certain compounds provided by the present invention have asymmetric centers. The pure D isomer, pure L isomer as well as mixtures thereof including racemic mixtures are also included in the present invention.

Forbindelsene fremstilt i henhold til foreliggende oppfinnelse oppviser en bred antibakteriell aktivitet mot gram-positive og gram-negative organismer og Mycoplasma og kan bli brukt som midler for behandling og profylaxe av infek-sjonssykdommer. De in vitro og in vivo antibakterielle aktiviteter av forbindelsene i følge foreliggende oppfinnelse er vist som følger: The compounds produced according to the present invention exhibit a broad antibacterial activity against gram-positive and gram-negative organisms and Mycoplasma and can be used as agents for the treatment and prophylaxis of infectious diseases. The in vitro and in vivo antibacterial activities of the compounds of the present invention are shown as follows:

1. In vitro antibakterielle aktiviteter 1. In vitro antibacterial activities

De in vitro antibakterielle aktiviter av det representative pyrido[3.2.1-ij]-1,3,4-benzoksadiazinderivater i følge foreliggende oppfinnelse ble undersøkt ved standard agar-fortynningsmetode [se: Chemotherapy, 22., 1126 (1974) ] . Deres minimum inhibitoriske konsentrasjoner (MIC i jig/ml) er vist i tabell 1, tabell 2 og tabell 3. Forbindelsene som ble brukt her, ble fremstilt i de respektive eksempler beskrevet nedenfor. The in vitro antibacterial activities of the representative pyrido[3.2.1-ij]-1,3,4-benzoxadiazine derivatives according to the present invention were investigated by the standard agar dilution method [see: Chemotherapy, 22., 1126 (1974)]. Their minimum inhibitory concentrations (MIC in µg/ml) are shown in Table 1, Table 2 and Table 3. The compounds used herein were prepared in the respective examples described below.

2. In vivo terapeutisk effektivitet 2. In vivo therapeutic efficacy

De in vivo antibakterielle aktiviteter av pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-derivatene fremstilt i følge eksempel 5, eksempel 30, eksempel 65 og eksempel 66 som nevnt nedenfor ble undersøkt mot dødelig infeksjon av Escherichia coli ML4707, Pseudomonas aeruginosa 4au542 og Streptococcus pneumoniae 6-001. ICR-mus med vekt ca. 20 g ble infisert ved intraperitoneal injeksjon av en tilsvarende bakteriell supsensjon. Forsøksforbindelsen ble tilført oralt eller sub-cutant samtidig med injeksjonen. Dødeligheten ble observert over 5 dager. Den respektive 50% effektive dose (ED50, mg/kg) som beskytter 50% av dyrene fra død forårsaket ved infeksjon er vist i tabell 4. The in vivo antibacterial activities of the pyrido[3.2.1-ij]-1,3,4-benzoxadiazine derivatives prepared according to Example 5, Example 30, Example 65 and Example 66 as mentioned below were investigated against lethal infection of Escherichia coli ML4707 , Pseudomonas aeruginosa 4au542 and Streptococcus pneumoniae 6-001. ICR mice weighing approx. 20 g were infected by intraperitoneal injection of a corresponding bacterial suspension. The test compound was administered orally or subcutaneously at the same time as the injection. Mortality was observed over 5 days. The respective 50% effective dose (ED50, mg/kg) that protects 50% of the animals from death caused by infection is shown in Table 4.

3. Akutt toksisitet 3. Acute toxicity

De respektive LD50 verdier av de forbindelsene erholdt i eksemplene 5, 6, 7, 13, 14, 23, 28 og 40 som nevnt nedenfor er mer enn 2000 mg/kg. Den akutte toksisitet av disse forbindelser ble undersøkt ved oral tilførsel i ICR-mus. The respective LD50 values of the compounds obtained in examples 5, 6, 7, 13, 14, 23, 28 and 40 as mentioned below are more than 2000 mg/kg. The acute toxicity of these compounds was investigated by oral administration in ICR mice.

Forbindelsene fremstilt i henhold til foreliggende oppfinnelse oppviser et bredt antimikrobielt spektrum mot gram-positive og gram-negative bakterier og Mycoplasma, spesielt mot de som er motstandsdyktige for forskjellige antibiotika, såsom penicilliner, cephalosporiner, aminoglykosider, tetra-cykliner . The compounds produced according to the present invention exhibit a broad antimicrobial spectrum against gram-positive and gram-negative bacteria and Mycoplasma, especially against those resistant to various antibiotics, such as penicillins, cephalosporins, aminoglycosides, tetracyclines.

Videre har forbindelsene fremstilt i henhold til foreliggende oppfinnelse lav toksisitet og en kraftig og bred antimikrobiell effektivitet. De beskyttende effekter av forbindelsene i følge foreliggende oppfinnelse på systemiske bakterielle infeksjoner i mus, er større enn de til synte-tiske antibakterielle midler som er tilgjengelige konver-sjonelt. Derfor kan forbindelsene i følge foreliggende oppfinnelse effektivt anvendes for forhindring eller behandling av sykdommer forårsaket av gram-positive og gram-negative bakterier og bakterioide mikroorganismer i mennesker eller dyr. Furthermore, the compounds produced according to the present invention have low toxicity and a strong and broad antimicrobial effectiveness. The protective effects of the compounds according to the present invention on systemic bacterial infections in mice are greater than those of synthetic antibacterial agents which are available conversionally. Therefore, the compounds according to the present invention can be effectively used for the prevention or treatment of diseases caused by gram-positive and gram-negative bacteria and bacteroid microorganisms in humans or animals.

For eksempel kan sykdommer forårsaket av de følgende mikroorganismer eller av blandinger av de følgende mikroorganismer bli behandlet og/eller forhindret: Staphylococcus, Streptococcus, Aerococcus, Enterococcus, Micrococcus, Laktobasillus, Bifidobacterium, Clostridium, Eubakterium, Peptococcus, Peptostreptococcus, Propionbacte-rium, Escherichia, Citrobacter, Campylbacter, Enterbacter, Klebsiella, Proteus, Pseudomonas, Serratia, Salmonella, Shigella, Vibrio, Aeromonas, Haemophilus, Neisseria, Acinetobacter, Alcaligenes, Bordetella, Bcteroider, Fuso-bacterium, Mycoplasma og andre mikroorganismer. For example, diseases caused by the following microorganisms or by mixtures of the following microorganisms can be treated and/or prevented: Staphylococcus, Streptococcus, Aerococcus, Enterococcus, Micrococcus, Lactobacillus, Bifidobacterium, Clostridium, Eubacterium, Peptococcus, Peptostreptococcus, Propionbacterium, Escherichia , Citrobacter, Campylbacter, Enterbacter, Klebsiella, Proteus, Pseudomonas, Serratia, Salmonella, Shigella, Vibrio, Aeromonas, Haemophilus, Neisseria, Acinetobacter, Alcaligenes, Bordetella, Bcteroids, Fuso-bacterium, Mycoplasma and other microorganisms.

Foreliggende oppfinnelse omhandler videre farmasøytiske blandinger inneholdene en eller flere forbindelser i følge foreliggende oppfinnelse. Forbindelsene i følge foreliggende oppfinnelse kan tilføres oralt eller ikke-oralt til mennesker eller dyr ved forskjellige vanlige tilføringsmetoder. The present invention further relates to pharmaceutical mixtures containing one or more compounds according to the present invention. The compounds according to the present invention can be administered orally or non-orally to humans or animals by various common administration methods.

Videre blir forbindelsene i henhold til foreliggende oppfinnelse brukt enkeltvis eller sammen med hjelpestoff, flytende fortynningsmidler, bindemidler, smøremidler, fuktningsmidler osv. f.eks i form av generelle medisinske blandinger såsom tabletter, granuler, sukkerbelagte tabletter, pulver-kapsler, geler, tørre siruper, sirup-ampuller, suspensjoner, væsker, emulsjoner, salver, pasta, kremer, Furthermore, the compounds according to the present invention are used individually or together with excipients, liquid diluents, binders, lubricants, wetting agents, etc., for example in the form of general medicinal mixtures such as tablets, granules, sugar-coated tablets, powder capsules, gels, dry syrups , syrup ampoules, suspensions, liquids, emulsions, ointments, pastes, creams,

suppositorer og lignende. suppositories and the like.

Videre kan oppløsningsforsinkende midler, absorpsjons akselerende midler, overflate-aktive midler bli brukt som andre tilsetningsstoffer for sammensetningen d.v.s. en hver form som er farmasøytisk akseptable kn bli brukt. Furthermore, dissolution delaying agents, absorption accelerating agents, surface-active agents can be used as other additives for the composition, i.e. Any form that is pharmaceutically acceptable can be used.

Forbindelsene i henhold til foreliggende oppfinnelse kan bli brukt alene eller som blandinger av to eller flere forskjellige typer av forbindelser og mengden av forbindelsene er ca. 0,1 til 99,5%, fortrinnsvis 0,5 til 95% basert på vekten av den totale medisinelle blanding. The compounds according to the present invention can be used alone or as mixtures of two or more different types of compounds and the amount of the compounds is approx. 0.1 to 99.5%, preferably 0.5 to 95% based on the weight of the total medicinal mixture.

Den medisinelle blanding i henhold til foreliggende oppfinnelse kan fremstilles i en kombinasjon av forbindelsene i følge foreliggende oppfinnelse eller blandingen derav med andre vanlige forbindelser som er farmasøytisk aktive. The medicinal mixture according to the present invention can be prepared in a combination of the compounds according to the present invention or the mixture thereof with other common compounds which are pharmaceutically active.

En dose pr. dag til en pasient av den nye forbindelse i henhold til foreliggende oppfinnelse kan varieres avhengig . av individet, dyretypen, vekten og tilstanden som skal avhjelpes, men ligger generelt i området 0,5 til 500 mg pr. kg kroppsvekt, fortrinnsvis ca. 1 til 300 mg pr. kg kroppsvekt. One dose per day to a patient of the new compound according to the present invention can be varied depending. of the individual, the type of animal, the weight and the condition to be remedied, but is generally in the range of 0.5 to 500 mg per kg body weight, preferably approx. 1 to 300 mg per kg body weight.

De følgende eksempler illustrerer de foretrukne metoder for fremstilling av forbindelsen i følge foreliggende oppfinnelse. The following examples illustrate the preferred methods for producing the compound according to the present invention.

Fremstilling av utgangsmaterialer Production of starting materials

Referanse eksempel Reference example

Fremstillin<g> av dietyl N- ( 3 , 4- difluor- 2- hydroksyfenyl)-aminometylenmalonat. (a) En oppløsning av 2,3-difluor-6-nitrofenol (500 mg) i metanol (7 ml) ble hydrogenert over 5% Pd/C (60 mg) i 6 timer. Reaksjonsblandingen ble filtrert under nitrogen-strøm og filtratet ble inndampet under redusert trykk for å gi 414 mg av rå 2-amino-5,6-difluorfenol. (b) En blanding av ovenfor nevnte amin (414 mg) og dietyl-etoksymetylenmalonat (618 mg) ble oppvarmet ved 130°C under nitrogen-atmosfære i 5 minutter. Det resulterende krystallinske residium ble triturert med etanol og filtrert for å gi 590 mg av dietyl N-(3,4-difluor-2-hydroksyfenyl)-amino-metylenmalonat , smeltepunkt 178-180°C, MS m/z 315 (M<+>). Ytterligere 59 mg av krystallene ble erholdt etter silica-gel kolonne-kromatografi av moderluten ved å bruke CHC13/-aceton (20:1) som eluent. Preparation<g> of diethyl N-(3,4-difluoro-2-hydroxyphenyl)-aminomethylene malonate. (a) A solution of 2,3-difluoro-6-nitrophenol (500 mg) in methanol (7 mL) was hydrogenated over 5% Pd/C (60 mg) for 6 h. The reaction mixture was filtered under a stream of nitrogen and the filtrate was evaporated under reduced pressure to give 414 mg of crude 2-amino-5,6-difluorophenol. (b) A mixture of the above amine (414 mg) and diethyl ethoxymethylene malonate (618 mg) was heated at 130°C under a nitrogen atmosphere for 5 minutes. The resulting crystalline residue was triturated with ethanol and filtered to give 590 mg of diethyl N-(3,4-difluoro-2-hydroxyphenyl)-amino-methylene malonate, mp 178-180°C, MS m/z 315 (M< +>). A further 59 mg of the crystals were obtained after silica gel column chromatography of the mother liquor using CHCl 3 /-acetone (20:1) as eluent.

Fremstillin<g> av etyl- 8- benzvloksy- 6, 7- difluor- 4- hydroksy- 3-kinolinkarboksylat (Rute 1). (c) Til en blanding av dietyl N-(3,4-difluor-2-hydroksy-fenyl)aminometylenmalonat (80 mg) og vannfritt kaliumkarbonat (70 mg) i tørr dimetylformamid (1,5 ml) ble det tilsatt benzylbromid (3 0 pl). Blandingen ble omrørt ved romtemperatur i 2 timer. Etter fjerning av oppløsningsmid-delet under redusert trykk ble residiet igjen oppløst i diklormetan og utfellingen ble filtrert av. Filtratet ble vasket med vann, tørket over vannfri natriumsulfat og inndampet. Det krystallinske residium ble vasket med n-hexan og rekrystallisert fra metanol for å di dietyl N-(2-benzyl-oksy-3,4-difluorfenyl)aminometylenmalonat (90 mg), smeltepunkt 87°C, MS m/z 405 (M<+>). (d) En oppløsning av det ovenfor nevnte malonat (280 mg) i difenyleter (2,8 ml) ble oppvarmet til 250°C i 30 minutter under nitrogen-atmosfære. Reaksjonsblandingen ble avkjølt, Preparation<g> of ethyl-8-benzvloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylate (Route 1). (c) To a mixture of diethyl N-(3,4-difluoro-2-hydroxy-phenyl)aminomethylene malonate (80 mg) and anhydrous potassium carbonate (70 mg) in dry dimethylformamide (1.5 mL) was added benzyl bromide (3 0 pl). The mixture was stirred at room temperature for 2 hours. After removal of the solvent under reduced pressure, the residue was again dissolved in dichloromethane and the precipitate was filtered off. The filtrate was washed with water, dried over anhydrous sodium sulfate and evaporated. The crystalline residue was washed with n-hexane and recrystallized from methanol to give diethyl N-(2-benzyl-oxy-3,4-difluorophenyl)aminomethylene malonate (90 mg), mp 87°C, MS m/z 405 (M <+>). (d) A solution of the above malonate (280 mg) in diphenyl ether (2.8 ml) was heated to 250°C for 30 minutes under a nitrogen atmosphere. The reaction mixture was cooled,

og etanolen generert i reaksjonsmediet ble fjernet under redusert trykk. Den mørkebrune oppløsning ble anvendt på en kolonne silica-gel (10 g) fulgt av suksessiv eluering med benzen, diklormetan og diklormetan/-aceton (30:1). De råe fraksjonene ble kombinert og oppløsningsmiddelet ble fjernet under redusert trykk for å gi et krystallinsk residum. Residiet ble vasket med med en blanding av n-hexan og etylacetat for å gi 90 mg av etyl 8-benzyloksy-6,7-difluor-4-hydroksy-3-kinolinkarboksylat. En analystisk prøve, smeltepunkt 220-201'C; MS m/z 359 (M<+>), ble fremstilt ved omkrystallisering fra metanol. and the ethanol generated in the reaction medium was removed under reduced pressure. The dark brown solution was applied to a column of silica gel (10 g) followed by successive elution with benzene, dichloromethane and dichloromethane/acetone (30:1). The crude fractions were combined and the solvent was removed under reduced pressure to give a crystalline residue. The residue was washed with a mixture of n-hexane and ethyl acetate to give 90 mg of ethyl 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylate. An analytical sample, melting point 220-201'C; MS m/z 359 (M<+>), was prepared by recrystallization from methanol.

Fremstilling av et<y>l 8- benzvloksv- 6, 7- difluor- 4- hvdroksy- 3-kinolinkarboksylat (Rute 2) Preparation of et<y>1 8-benzoxyl-6,7-difluoro-4-hydroxy-3-quinolinecarboxylate (Route 2)

Til en omrørt oppløsning av etyl 6,7-difluor-4,8-dihydroksy-3-kinolinkarboksylat (3 00 mg) i tørr dimetylformamid (6 ml) ble det tilsatt vannfri kaliumkarbonat (308 mg) og så benzylklorid (145 jjI) . Blandingen ble omrørt ved 55-65°C i 11 timer. Reaksjonsblandingen ble fortynnet med vann (30 ml) og ekstrahert med kloroform. Ekstrakten ble tørket over vannfri natriumsulfat og konsentrert under redusert gtrykk. Residiet ble kromatografert på silica-gel (7 g) ved å bruke aceton/kloroform (1:20) som en eluent for å gi 113 g etyl-8-benzyloksy-6,7-difluor-4-hydroksy-3-kinolinkarboksylat, smeltepunkt 200-201°C; MS m/z 359 (M<+>) etter omkrystallisering fra metanol. To a stirred solution of ethyl 6,7-difluoro-4,8-dihydroxy-3-quinolinecarboxylate (300 mg) in dry dimethylformamide (6 ml) was added anhydrous potassium carbonate (308 mg) and then benzyl chloride (145 µl). The mixture was stirred at 55-65°C for 11 hours. The reaction mixture was diluted with water (30 mL) and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel (7 g) using acetone/chloroform (1:20) as an eluent to give 113 g of ethyl 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinoline carboxylate, melting point 200-201°C; MS m/z 359 (M<+>) after recrystallization from methanol.

Fremstillin<g> av etyl- benzvloksy- 6, 7- difluor- 1- fformyl-metvlamino)- 4- okso- l, 4- dihvdro- 3- kinolinkarboksvlat Preparation of ethyl-benzvloxy-6,7-difluoro-1-formyl-methylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylate

(e) etter at en blanding av etyl 8-benzyloksy-6,7-difluor-4--hydroksy-3-kinolinkarboksylat (410 mg) og vannfritt kaliumkarbonat (315 mg) i tørr dimetylformamid (10 ml) ble omrørt i 3 timer ble det tilsatt 0-(2,4-dinitrofenyl)hydroksylamin (2 60 mg). Blandingen ble omrørt ved romtemperatur i ytterli- (e) after a mixture of ethyl 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylate (410 mg) and anhydrous potassium carbonate (315 mg) in dry dimethylformamide (10 ml) was stirred for 3 hours O-(2,4-dinitrophenyl)hydroxylamine (260 mg) was added. The mixture was stirred at room temperature in the outer

gere 6,5 timr. Etter fjerning av oppløsningsmiddelet under rdusert trykk ble det tilsatt vann (12 ml) og blandingen ble omrørt vd romtemperatur i 3 timer. Utfellingen ble samlet opp ved filtrering og vasket med kaldt vann og så med eter for å gi 405 mg etyl l-amino-8-benzyloksy-6,7-difluor-4--okso-1,4-dihydro-3-kinolinkarboksylat. En analytisk prøve, smeltepunkt 143-144°C; MS m/z 374 (M<+>), ble fremstilt ved omkrystallisering fra metanol. (f) 98% maursyre (0,60 ml) til tilsatt eddikanhyrid (1,51 ml) ved 0°C. Blandingen ble omrørt ved 0°C i 15 minutter, ved 50°C i 15 minutter og så avkjølt til 0'C. Til denne oppløsning ble det tilsatt dråpevis den ovenfor nevnte amin (400 mg) i 98% maursyre (2,1 ml). Blandingen ble omrørt ved romtemperatur i 2 dager. Reaksjonsblandingen ble inndampet under redusert trykk for å gi den krystalliniske residium, som ble rekrystallisert fra etanol for å gi 410 mg etyl 8-benzyloksy-6,7-difluor-1-(formylamino)-4-okso-l,4— dihydro-3-kinolinkarboksylat, smeltepunkt 188-190°C; gere 6.5 hrs. After removal of the solvent under reduced pressure, water (12 ml) was added and the mixture was stirred at room temperature for 3 hours. The precipitate was collected by filtration and washed with cold water and then with ether to give 405 mg of ethyl 1-amino-8-benzyloxy-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate. An analytical sample, melting point 143-144°C; MS m/z 374 (M<+>), was prepared by recrystallization from methanol. (f) 98% formic acid (0.60 ml) to added acetic anhydride (1.51 ml) at 0°C. The mixture was stirred at 0°C for 15 minutes, at 50°C for 15 minutes and then cooled to 0°C. To this solution was added dropwise the above-mentioned amine (400 mg) in 98% formic acid (2.1 ml). The mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated under reduced pressure to give the crystalline residue, which was recrystallized from ethanol to give 410 mg of ethyl 8-benzyloxy-6,7-difluoro-1-(formylamino)-4-oxo-1,4- dihydro- 3-quinoline carboxylate, melting point 188-190°C;

MS m/z 402 (M<+>) MS m/z 402 (M<+>)

(g) En blanding av det ovenfor nevnte formamid (400 mg), vannfritt kaliumkarbonat (275 mg) og vannfritt dimetylformamid (17 ml) ble omrørt i romtemperatur i 1,5 timer. Metyl-jod (0,19 ml) ble tilsatt blandingen og omrøringen fortsatte i 2,5 timer. Oppløsningsmiddelet ble fjernet under redusert trykk og residiet ble adskilt mellom kloroform og vann. Det organiske lag ble tørket over vannfritt natriumsulfat og konsentrert til tørrhet under redusert trykk. Residiet ble rekrystallisert fra etanol for å gi 335 g etyl 8-benzyloksy-6,7-difluor-1-(formylmetylamino)-4-okso-l,4-dihydro-3-kinolinkarboksylat, smeltepunkt 180-181°C; (g) A mixture of the above-mentioned formamide (400 mg), anhydrous potassium carbonate (275 mg) and anhydrous dimethylformamide (17 ml) was stirred at room temperature for 1.5 hours. Methyl iodide (0.19 mL) was added to the mixture and stirring was continued for 2.5 hours. The solvent was removed under reduced pressure and the residue was separated between chloroform and water. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was recrystallized from ethanol to give 335 g of ethyl 8-benzyloxy-6,7-difluoro-1-(formylmethylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylate, mp 180-181°C;

MS m/z 416 (M<+>) MS m/z 416 (M<+>)

Fremstilling av 6, 7- difluor- 8- hydroksy- l-( metylamino)- 4-- okso- l, 4- dihydro- 3- kinolinkarboksvlatsvre Preparation of 6,7-difluoro-8-hydroxyl-1-(methylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid

(h) Etyl 8-benzyloksy-6,7-difluor-1-(formylmetylamino)-4- (h) Ethyl 8-benzyloxy-6,7-difluoro-1-(formylmethylamino)-4-

-okso-1,4-dihydro-3-kinolinkarboksylat (330 mg) ble hydrogenert over 5% Pd/C (50 mg) i kloroform (14 ml) i 4 timer. Reaksjonsblandingen ble fortynnet med metanol (14 ml) og filtrert. Den filtrerte kake ble vasket med kloroform/- metanol (1:1). De kombinerte filtrater ble inndampet og residiet ble rekrystallisert fra etanol for å i 239 m etyl 6,7-difluor-1-(formylmetylamino)-8-hydroksy-4-okso-l,4— dihydro-3-kinolinkarboksylat, smeltepunkt 221-225°C (dec); MS m/z 326 (M<+>). (i) Blandingen nevnt ovenfor med ester (210 mg) og 0,5N natriumhydroksyd (5,2 ml) ble oppvarmet til 100°C i 2 timer under nitrogen-atmosfære. Reaksjonsblandinen ble gjort sur med eddiksyre (0,16 ml). Utfellingen som ble separert fra ble filtrert, vasket med vann og tørket under redusert trykk for å gi 168 mg 6,7-difluor-8-hydroksy-l-(metylamino)-4— okso-1,4-dihydro-3-kinolinkarboksysyre. En analytisk prøve, smeltepunkt 248-250°C (dec); MS m/z 270 (M<+>), ble fremstilt ved omkrystallisering fra etanol. -oxo-1,4-dihydro-3-quinolinecarboxylate (330 mg) was hydrogenated over 5% Pd/C (50 mg) in chloroform (14 mL) for 4 h. The reaction mixture was diluted with methanol (14 mL) and filtered. The filtered cake was washed with chloroform/methanol (1:1). The combined filtrates were evaporated and the residue recrystallized from ethanol to give 239 m of ethyl 6,7-difluoro-1-(formylmethylamino)-8-hydroxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate, mp 221- 225°C (dec); MS m/z 326 (M<+>). (i) The mixture mentioned above with ester (210 mg) and 0.5N sodium hydroxide (5.2 ml) was heated to 100°C for 2 hours under nitrogen atmosphere. The reaction mixture was acidified with acetic acid (0.16 mL). The precipitate separated from was filtered, washed with water and dried under reduced pressure to give 168 mg of 6,7-difluoro-8-hydroxy-1-(methylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid . An analytical sample, melting point 248-250°C (dec); MS m/z 270 (M<+>), was prepared by recrystallization from ethanol.

Eksempel 1 Example 1

Fremstillin<g> av 9, 10- difluor- 3- metvl- 7- okso- 2, 3- diydro- 7H-pyrido f 3. 2. 1- ii1- 1, 3, 4- benzoksadin- 6- karboksylsyre Preparation<g> of 9, 10- difluoro- 3- methyl- 7- oxo- 2, 3- dihydro- 7H-pyrido f 3. 2. 1- ii1- 1, 3, 4- benzoxadine- 6- carboxylic acid

En blanding av 6,7-difluor-8-hydroksy-l-(metylamino)-4-okso--1,4-dihydro-3-kinolinkarboksylsyre (105 mg) erholdt i referanse eksempel (i), paraformaldehyd (150 mg) og tørr dioxan (5 ml) ble oppvarmet til 100°C i 3 timer under nitrogen-atmosfære. Etter fjerning av oppløsningsmiddelet under redusert trykk ble dimetylformamid (20 ml) tilsatt til residiet og blandingen ble omrørt i 20 minutter og så filtrert. Den filtrerte kake ble vasket med dimetylformamid og det kombinerte filtrat ble inndampet under redusert trykk. Residiet ble triturert med vann og filtrert for å gi 97 mg av 9,10-difluor-3-metyl-7-okso-2,3-dihydro-7H-pyrido-[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre. En analytisk prøve, smeltepunkt 290-292°C (dec); MS m/z 282 (M<+>) ble fremstilt ved omkrystallisering fra dimetylformamid. A mixture of 6,7-difluoro-8-hydroxy-1-(methylamino)-4-oxo--1,4-dihydro-3-quinolinecarboxylic acid (105 mg) obtained in reference example (i), paraformaldehyde (150 mg) and dry dioxane (5 mL) was heated to 100°C for 3 hours under a nitrogen atmosphere. After removal of the solvent under reduced pressure, dimethylformamide (20 mL) was added to the residue and the mixture was stirred for 20 minutes and then filtered. The filtered cake was washed with dimethylformamide and the combined filtrate was evaporated under reduced pressure. The residue was triturated with water and filtered to give 97 mg of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido-[3.2.1-ij]-1,3,4 -benzoxadiazine-6-carboxylic acid. An analytical sample, mp 290-292°C (dec); MS m/z 282 (M<+>) was prepared by recrystallization from dimethylformamide.

Eksempel 2 Example 2

Fremstilling av 9, 10- difluor- 2, 3- dimetyl- 7- okso- 2, 3- dihydro-- 7H- pyrido r 3. 2. 1- ii]- 1, 3. 4- benzoksadiazin- 6- karboksylsyre Preparation of 9, 10- difluoro- 2, 3- dimethyl- 7- oxo- 2, 3- dihydro-- 7H- pyrido r 3. 2. 1- ii]- 1, 3. 4- benzoxadiazine- 6- carboxylic acid

En blanding av 6,7-difluor-8-hydroksy-1-(metylamino)-4-okso--1,4-dihydro-3-kinolinkarboksylsyre (50 mg) erholdt i referanse eksempel (i), 90% acetaldeyd (1 ml) og dioxan (5 ml) ble varmet til 100°C i 3 timer under nitrogen-atmosfære. Reaksjonsblandingen ble inndampet under redusert trykk for å gi 52 mg av 9,10-difluor-2,3-dimetyl-7-okso-2,3-dihydro-7H--pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre, smeltepunkt 285-289<'C; MS m/z 296 (M+) . A mixture of 6,7-difluoro-8-hydroxy-1-(methylamino)-4-oxo--1,4-dihydro-3-quinolinecarboxylic acid (50 mg) obtained in reference example (i), 90% acetaldehyde (1 ml) and dioxane (5 ml) were heated to 100°C for 3 hours under a nitrogen atmosphere. The reaction mixture was evaporated under reduced pressure to give 52 mg of 9,10-difluoro-2,3-dimethyl-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3, 4-benzoxadiazine-6-carboxylic acid, m.p. 285-289°C; MS m/z 296 (M+).

Eksempel 3 Example 3

Fremstilling av 9. 10- difluor- 2- fhydroksvmetyl)- 3- metvl- 7-- okso- 2, 3- dihydro- 7H- pyrido f 3. 2♦ 1- ii1- 1, 3. 4- benzoksadiazin-6- karboksylsyre Preparation of 9. 10- difluoro- 2- fhydroxymethyl)- 3- methyl- 7-- oxo- 2, 3- dihydro- 7H- pyrido f 3. 2♦ 1- ii1- 1, 3. 4- benzoxadiazine-6- carboxylic acid

En suspensjon av 6,7-difluor-8-hydroksy-l-(metylamino)-4— okso-1,4-dihydro-3-kinolinkarboksylsyre (50 mg) erholdt i referanse eksempel (i), glykolaldehyd dietylacetal (45 pl) og pyridinium p-toluensulfonat (7 mg) i tørr dioxan (2 ml) ble varmet til 110'C i 5 timer under nitrogen-atmosfære. Etter at oppløsningsmiddelet var fjernet under redusert trykk ble det krystalliniske residium vasket med vann og metanol for å gi 52 mg av 9,10-difluor-2-(hydroksymetyl)-3--metyl-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre, smeltepunkt 254-258°C (dec); MS m/z 312 (M<+>). A suspension of 6,7-difluoro-8-hydroxy-1-(methylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (50 mg) obtained in reference example (i), glycolaldehyde diethyl acetal (45 µl) and pyridinium p-toluenesulfonate (7 mg) in dry dioxane (2 ml) was heated to 110°C for 5 hours under a nitrogen atmosphere. After the solvent was removed under reduced pressure, the crystalline residue was washed with water and methanol to give 52 mg of 9,10-difluoro-2-(hydroxymethyl)-3-methyl-7-oxo-2,3-dihydro- 7H-pyrido[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid, mp 254-258°C (dec); MS m/z 312 (M<+>).

Eksempel 4 Example 4

Fremstillin<g> av 9, 10- difluor- 2- r( dimetylamino) metyll- 3— metvl- 7- oksc— 7H- pyrido r 3. 2. 1- ii1- 1, 3, 4- benzoksadiazin- 6-- karboksvlsyre p- toluensulfonat Preparation<g> of 9, 10- difluoro- 2- r( dimethylamino) methyl- 3- methyl- 7- oxc- 7H- pyrido r 3. 2. 1- ii1- 1, 3, 4- benzoxadiazine- 6-- carboxylic acid p-toluenesulfonate

En suspensjon av 6,7-difluor-8-hydroksy-l-(metylamino)-4--okso-1,4-dihydro-3-kinolinkarboksylsyre (50 mg) erholdt i referanse eksempel (i), dimetylaminoacetaldehyd dimetylacetal (37 mg) og p-toluensulfonsyre monohydrat (53 mg) i tørr dioxan (2 ml) ble varmet til 110°C i 17 timer under nitrogen-atmosfære. Etter at oppløsningsmiddelet var fjernet under redusert trykk ble residiet rekrystallisert fra metanol for å gi 61 mg av 9,10-difluor-2-[(dimetylamino)metyl]-3-metyl— 7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre p-toluensulfonat, smeltepunkt 232-236°C (dec), FAB-MS m/z 340 (M+) . A suspension of 6,7-difluoro-8-hydroxy-1-(methylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (50 mg) obtained in reference example (i), dimethylaminoacetaldehyde dimethyl acetal (37 mg ) and p-toluenesulfonic acid monohydrate (53 mg) in dry dioxane (2 mL) were heated to 110°C for 17 h under a nitrogen atmosphere. After the solvent was removed under reduced pressure, the residue was recrystallized from methanol to give 61 mg of 9,10-difluoro-2-[(dimethylamino)methyl]-3-methyl—7-oxo-2,3-dihydro-7H- pyrido[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid p-toluenesulfonate, mp 232-236°C (dec), FAB-MS m/z 340 (M+).

Eksempel 5 Example 5

Fremstillin<g> av 9- fluor- 3- metyl- 10-( 4- metvl- l- piperazinvl)-- 7- okso- 2, 3- dihvdro- 7H- pyridor3. 2. 1- ii1- 1, 3, 4- benzoksadiazin- 6- karboksylsyre Preparation of 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyridor3. 2. 1- ii1- 1, 3, 4- benzoxadiazine- 6- carboxylic acid

En blanding av 9,10-difluor-3-metyl-7-okso-2,3-dihydro-7H--pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre (30 mg) erholdt i eksempel 1, N-metylpiperazin (47 pl) og tørr pyridin (3 ml) ble varmet til 100-110°C i 9 timer under nitrogen-atmosfære. Pyridin ble fjernet under redusert trykk og residiet ble rekrystallisert fra metanol for å gi 23 mg av 9-fluor-3-metyl-10-(4.metyl-l-piperazinyl)-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre, smeltepunkt 268-269°C (dec); MS m/z 362 (M<+>). A mixture of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H--pyrido[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid (30 mg) obtained in Example 1, N-methylpiperazine (47 µl) and dry pyridine (3 ml) were heated to 100-110°C for 9 hours under a nitrogen atmosphere. Pyridine was removed under reduced pressure and the residue was recrystallized from methanol to give 23 mg of 9-fluoro-3-methyl-10-(4.methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H- pyrido[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid, mp 268-269°C (dec); MS m/z 362 (M<+>).

De følgende forbindelser ble erholdt i henhold til en tilsvarende fremgangsmåte som den i eksempel 5: The following compounds were obtained according to a similar procedure to that of Example 5:

De følgende eksempler ble fremstilt fra forbindelsene beskrevet i eksempel 2, 3 og 4 tilsvarende fremgangsmåten i eksempel 5. The following examples were prepared from the compounds described in examples 2, 3 and 4 corresponding to the method in example 5.

Eksempel 22 Example 22

Fremstilling av 10- r3-( benzvloksykarbonvlamino)- 1- pyrrolidinyl 1- 9- fluor- 3- metvl- 7- okso- 2, 3- dihydro- 7H- pyrido- f3. 2.1-- ii1- 1. 3, 4- benzoksadiazin- 6- karboksylsvre Preparation of 10-r3-(benzoyloxycarbonylamino)-1-pyrrolidinyl 1-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido-f3. 2.1-- ii1- 1. 3, 4- benzoxadiazine- 6- carboxylic acid

En blanding av 9,10-difluor-3-metyl-7-okso-2,3-dihydro-7H--pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre (28 mg) erholdt i følge eksempel 1, 3-(benzyloksykarbonylamino)--pyrrolidin (94 mg) og tørr pyridin (3 ml) ble varmet opp til 100'C i 3 timer under nitrogen-atmosfære. Pyridin ble fjernet under redusert trykk og residiet ble rekrystallisert fra metanol for å gi 3 6 mg av 10-[3-(benzyloksykarbonyl-amino) -1-pyrrolidinyl]-9-fluor-3-metyl-7-okso-2,3-dihydro— 7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre, smeltepunkt 227-230°C; MS m/z 482 (M<+>). A mixture of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H--pyrido[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid (28 mg) obtained according to Example 1, 3-(benzyloxycarbonylamino)-pyrrolidine (94 mg) and dry pyridine (3 ml) were heated to 100°C for 3 hours under a nitrogen atmosphere. Pyridine was removed under reduced pressure and the residue was recrystallized from methanol to give 36 mg of 10-[3-(benzyloxycarbonyl-amino)-1-pyrrolidinyl]-9-fluoro-3-methyl-7-oxo-2,3 -dihydro— 7H-pyrido[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid, melting point 227-230°C; MS m/z 482 (M<+>).

Eksempel 23 Example 23

Fremstillin<g> av 10-( 3- amino- l- pyrrolidinyl)- 9- fluor- 3- metyl-- 7- okso- 2, 3- dihvdro- 7H- pvrido f 3. 2. 1- ii]- 1. 3, 4- benzoksadiazin- 6- karboksylsvre Preparation of 10-(3-amino-1-pyrrolidinyl)-9-fluoro-3-methyl--7-oxo-2,3-dihydro-7H-pyrido f 3.2.1-ii]-1 3, 4- benzoxadiazine- 6- carboxylic acid

10-[3-(benzyloksykarbonylamino)-1-pyrrolidinyl]-9-fluor-3--metyl-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzo-oksadiazin-6-karboksylsyre (30 mg) erholdt i eksempel 21 ble hydrogenert over 5% Pd/C (10 mg) i dimetylformamid (2 ml) i 4,5 timer. Etter fjerning av katalysatoren ved filtrering ble filtratet konsentrert under redusert trykk. Residiet ble rekrystallisert fra metanol for å gi 10-(3-amino-l-pyrrolidinyl) -9-f luor-3-metyl-7-okso-2 ,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre, smeltepunkt 230-234 "C (dec); MS m/z 348 (M+) . 10-[3-(benzyloxycarbonylamino)-1-pyrrolidinyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4- benzo-oxadiazine-6-carboxylic acid (30 mg) obtained in Example 21 was hydrogenated over 5% Pd/C (10 mg) in dimethylformamide (2 ml) for 4.5 hours. After removal of the catalyst by filtration, the filtrate was concentrated under reduced pressure. The residue was recrystallized from methanol to give 10-(3-amino-1-pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij]- 1,3,4-Benzoxadiazine-6-carboxylic acid, mp 230-234 °C (dec); MS m/z 348 (M+).

De følgende forbindelser ble erholdt tilsvarende fremgangsmåten i følge eksemplene 22 og 23: The following compounds were obtained corresponding to the procedure according to examples 22 and 23:

Eksempel 28 Example 28

Fremstilling av 10-( 3, 4- dimetyl- l- piperazinyl)- 9- fluor- 3-- metyl- 7- okso- 2. 3- dihydro- 7H- pyrido r 3. 2. 1- ii1- 1, 3, 4- benzoksadiazin- 6- karboksylsvre Preparation of 10-(3,4-dimethyl-1-piperazinyl)-9-fluoro-3--methyl-7-oxo-2.3-dihydro-7H-pyrido r3.2.1-ii1-1,3 , 4- benzoxadiazine- 6- carboxylic acid

En blanding av 9-fluor-3-metyl-10-(3-metyl-l-piperazinyl)-7--okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre (60 mg) erholdt i eksempel 7, 98% maursyre (1 ml) og 35% formalin (1 ml) ble omrørt ved lOO-IWC. Etter oppvarming i 2 timer, ble blandingen inndampet under redusert trykk. Residiet ble oppløst i vann, nøytralisert med IN natriumhydroksyd og ekstrahert med kloroform. Ekstraktet ble vasket med vann og tørket over vannfri natriumsulfat. Etter at oppløsningsmiddelet ble fjernet under redusert trykk ble det krystallinske residium rekrystallisert fra metanol for å gi 43 mg av 10-(3,4-dimetyl-l— piperazinyl)-9-fluor-3-metyl-7-okso-2,3-dihydro-7H-pyrido-[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre, smeltepunkt 257-259°C; FAB-MS m/z 377 (MH<+>). A mixture of 9-fluoro-3-methyl-10-(3-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4 -benzoxadiazine-6-carboxylic acid (60 mg) obtained in Example 7, 98% formic acid (1 ml) and 35% formalin (1 ml) were stirred at lOO-IWC. After heating for 2 hours, the mixture was evaporated under reduced pressure. The residue was dissolved in water, neutralized with 1N sodium hydroxide and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. After the solvent was removed under reduced pressure, the crystalline residue was recrystallized from methanol to give 43 mg of 10-(3,4-dimethyl-1-piperazinyl)-9-fluoro-3-methyl-7-oxo-2,3 -dihydro-7H-pyrido-[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid, melting point 257-259°C; FAB-MS m/z 377 (MH<+>).

Eksempel 29 Example 29

Fremstilling av 9- fluor- 10-( 3- metoksy- l- pyrrolidinyl)- 3-- metyl- 7- okso- 2. 3- dihvdro- 7H- pvrido r 3. 2. 1- ii1- 1. 3. 4- benzoksadiazin- 6- karboksylsyre Preparation of 9- fluoro- 10-(3- methoxy-l- pyrrolidinyl)- 3-- methyl- 7- oxo- 2. 3- dihydro- 7H- pvrido r 3. 2. 1- ii1- 1. 3. 4 - benzoxadiazine-6-carboxylic acid

Til en suspensjon av 9-fluor-10-(3-hydroksy-l-pyrrolidinyl)--3-metyl-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre (100 mg) erholdt i eksempel 16, i tørr dimetylformamid (10 ml) ble det tilsatt 60% natriumhydrid i olje (30 mg) og metyl-jodid (40 pl). Etter omrøring av blandingen ved romtemperatur i 2 timer, ble det tilsatt 60% natriumhydrid (30 mg) og metyl-jodid (40 pl) og blandingen ble så omrørt ved 45 °C i 3 timer. Oppløsningsmiddelet ble så fjernet under redusert trykk. Residiet ble tilsatt kaldt vann (2 ml) og 0,5N natriumhydroksyd (2,3 ml) og den resulterende suspensjon ble varmet opp til 100°C i 2 timer. Reaksjonsblandingen ble så avkjølt til romtemperatur, nøytralisert med eddiksyre og fortynnet med vann. Blandingen ble ekstrahert med kloroform og ekstraktet ble vasket med vann, tørket over vannfritt natriumsulfat og konsentrert under redusert trykk for å gi den krystallinske residium, som ble kromatografert på silica-gel ved å bruke aceton/- kloroform (1:9) som eluent. 42 mg av 9-fluor-10-(3-metoksy--1-pyrrolidinyl)-3-metyl-7-okso-2,3-dihydro-7H-pyrido-[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre, smeltepunkt 233-234<*>C; FAB-MS m/z 364 (MH<+>) ble erholdt etter omkrystallisering fra metanol. To a suspension of 9-fluoro-10-(3-hydroxy-1-pyrrolidinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3, 4-Benzoxadiazine-6-carboxylic acid (100 mg) obtained in Example 16, in dry dimethylformamide (10 ml) was added 60% sodium hydride in oil (30 mg) and methyl iodide (40 µl). After stirring the mixture at room temperature for 2 hours, 60% sodium hydride (30 mg) and methyl iodide (40 µl) were added and the mixture was then stirred at 45 °C for 3 hours. The solvent was then removed under reduced pressure. To the residue was added cold water (2 ml) and 0.5N sodium hydroxide (2.3 ml) and the resulting suspension was heated to 100°C for 2 hours. The reaction mixture was then cooled to room temperature, neutralized with acetic acid and diluted with water. The mixture was extracted with chloroform and the extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crystalline residue, which was chromatographed on silica gel using acetone/chloroform (1:9) as eluent. 42 mg of 9-fluoro-10-(3-methoxy--1-pyrrolidinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido-[3.2.1-ij]-1,3, 4-benzoxadiazine-6-carboxylic acid, melting point 233-234<*>C; FAB-MS m/z 364 (MH<+>) was obtained after recrystallization from methanol.

Eksempel 30 Example 30

Fremstillin<g> av 9- f luor- 10-( 4- metoksy- l- piperidyl)- 3- metyl-- 7- okso- 2, 3- dihvdro- 7H- pvrido[ 3. 2. 1- ii]- 1. 3. 4- benzoksadiazin- 6- karboksylsvre Preparation of 9-fluoro-10-(4-methoxy-1-piperidyl)-3-methyl--7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ii]- 1. 3. 4- benzoxadiazine- 6- carboxylic acid

9-Fluor-10-(4-metoksy-l-piperidyl)-3-metyl-7-okso-2,3— dihydro-7H-pyrido[3.2.1-ij]-l,3,4-benzoksadiazin-6-karboksylsyre ble fremstilt fra 9-fluor-10-(4-hydroksy-l-piperidyl)-3-metyl-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4--benzoksadiazin-6-karboksylsyre erholdt i eksempel 12 analogt med eksempel 29, og ble erholdt som krystaller, smeltepunkt 229-233°C (dec); MS m/z 377 (M<+>), etter omkrystallisering fra kloroform/n-hexan. 9-Fluoro-10-(4-methoxy-1-piperidyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoxadiazine-6 -carboxylic acid was prepared from 9-fluoro-10-(4-hydroxy-1-piperidyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3, 4-Benzoxadiazine-6-carboxylic acid obtained in Example 12 analogously to Example 29, and was obtained as crystals, melting point 229-233°C (dec); MS m/z 377 (M<+>), after recrystallization from chloroform/n-hexane.

Eksempel 31 Example 31

Fremstilling av 10-( 1, l- dioksid- 4- tiomorfolinyl)- 9- fluor- 3-- metvl- 7- okso- 2. 3- dihvdro- 7H- pvrido r 3. 2. 1- ii1- 1. 3. 4- benzoksadiazin- 6- karboksylsyre Preparation of 10-(1,1-dioxide-4-thiomorpholinyl)-9-fluoro-3--methyl-7-oxo-2.3-dihydro-7H-pyrido r 3.2.1-ii1-1.3 4- benzoxadiazine- 6- carboxylic acid

Til en suspensjon av 9-fluor-3-metyl-7-okso-l0-(4-tiomorfo-linyl)-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin--6-karboksylsyre (50 mg) erholdt i eksempel 10 i diklormetan (5 ml) ble det tilsatt m-klorperbenzosyre (70% renhet, 74 mg). Blandingen ble omrørt ved romtemperatur i 18 timer. Oppløsningsmiddelet ble så fjernet under redusert trykk. Residiet ble vasket med eter, diklormetan og en blanding av kloroform og metanol og omkrystallisert fra dimetylformamid for å gi 22 mg av 10-(l,l-dioksid-4-tiomorfolinyl)-9-fluor--3-metyl-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre, smeltepunkt >300°C; MS m/z 397 For a suspension of 9-fluoro-3-methyl-7-oxo-10-(4-thiomorpholinyl)-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoxadiazine --6-carboxylic acid (50 mg) obtained in Example 10 in dichloromethane (5 ml) was added m-chloroperbenzoic acid (70% purity, 74 mg). The mixture was stirred at room temperature for 18 hours. The solvent was then removed under reduced pressure. The residue was washed with ether, dichloromethane and a mixture of chloroform and methanol and recrystallized from dimethylformamide to give 22 mg of 10-(1,1-dioxide-4-thiomorpholinyl)-9-fluoro-3-methyl-7-oxo -2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid, melting point >300°C; MS m/z 397

(M+) . (M+).

Eksempel 3 2 Example 3 2

Fremstilling av 9- fluor- 3- metyl- 7- okso- 10- f4-( 2- okso- n-- propyl)- 1- piperazinyl1- 2, 3- dihydro- 7H- pyridof3. 2. 1- ii1-1. 3. 4- benzoksadiazin- 6- karboksylsvre Preparation of 9-fluoro-3-methyl-7-oxo-10-f4-(2-oxo-n--propyl)-1-piperazinyl1-2,3-dihydro-7H-pyridof3. 2. 1- ii1-1. 3. 4- benzoxadiazine- 6- carboxylic acid

En blanding av 9-fluor-3-metyl-7-okso-10-(1-piperazinyl)--2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6--karboksylsyre (50 mg) erholdt i eksempel 6, kloraceton (17 pl), trietylamin (40 pl) og tørr dimetylformamid (1 ml) ble oppvarmet til 80°C i 3,5 timer. De flyktige komponenter ble så fjernet under redusert trykk og residiet ble suspendert i vann. Utfellingen ble samlet opp ved filtrering og omkrystallisert fra en blanding av diklormetan og metanol for å gi 32 g 9-fluor-3-metyl-7-okso-10-[4-(2-okso-n—propyl)-l-piperazinyl]-2,3-dihydro-7H-pyrido[3.2.1-ij]-l,3,4-benzoksadiazin-6-karboksylsyre, smeltepunkt 225-229°C (dec), FAB-MS m/z 405 (MH<+>). A mixture of 9-fluoro-3-methyl-7-oxo-10-(1-piperazinyl)-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoxadiazine-6 --carboxylic acid (50 mg) obtained in Example 6, chloroacetone (17 µl), triethylamine (40 µl) and dry dimethylformamide (1 ml) were heated to 80°C for 3.5 hours. The volatile components were then removed under reduced pressure and the residue was suspended in water. The precipitate was collected by filtration and recrystallized from a mixture of dichloromethane and methanol to give 32 g of 9-fluoro-3-methyl-7-oxo-10-[4-(2-oxo-n-propyl)-1-piperazinyl ]-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid, mp 225-229°C (dec), FAB-MS m/z 405 (MH <+>).

De følgende eksempler ble erholdt i henhold til en tilsvarende fremgangsmåte som den i eksempel 32. The following examples were obtained according to a similar method to that in example 32.

Eksempel 3 5 Example 3 5

Fremstillin<g> av 10-[ 4-( 3- karboksylpropionyl)- 1- piperazinyl1-- 9- fluor- 3- metvl- 7- okso- 2, 3- dihvdro- 7H- pyrido f 3. 2. 1- ii1-- 1, 3. 4- benzoksadiazin- 6- karboksylsyre Preparation<g> of 10-[ 4-( 3- carboxylpropionyl)- 1- piperazinyl1-- 9- fluoro- 3- methyl- 7- oxo- 2, 3- dihydro- 7H- pyrido f 3. 2. 1- ii1 -- 1, 3. 4- Benzoxadiazine- 6- carboxylic acid

En blanding v 9-fluor-3-metyl-7-okso-10-(1-piperazinyl)-2,3--dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre (50 mg) erholdt i eksempel 6 succinianhydrid (21,6 mg), trietylamin (40 pl) og tørr dimetylformamid (4 ml) ble varmet opp til 80°C i 2 timer. Oppløsningsmiddelet ble så fjernet under redusert trykk og residiet ble suspendert i vann. Utfellingen ble samlet opp ved filtrering og omkrystallisert fra en blanding av diklormetan og metanol for å gi 50 mg av 10-[4-(3-karboksylpropionyl)-1-piperazinyl]-9--fluor-3-metyl-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]--1,3,4-benzoksadiazin-6-karboksylsyre, smeltepunkt 257-259"C (dec); FAB-MS m/z 449 (MH+) . A mixture v 9-fluoro-3-methyl-7-oxo-10-(1-piperazinyl)-2,3--dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoxadiazine-6 -carboxylic acid (50 mg) obtained in Example 6 succinic anhydride (21.6 mg), triethylamine (40 µl) and dry dimethylformamide (4 ml) were heated to 80°C for 2 hours. The solvent was then removed under reduced pressure and the residue suspended in water. The precipitate was collected by filtration and recrystallized from a mixture of dichloromethane and methanol to give 50 mg of 10-[4-(3-carboxylpropionyl)-1-piperazinyl]-9-fluoro-3-methyl-7-oxo- 2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid, mp 257-259"C (dec); FAB-MS m/z 449 (MH+) .

Eksempel 36 Example 36

Fremstilling av 10-( 4- acetvl- l- piperazinvl^- 9- fluor- 3- metyl-- 7- okso- 2. 3- dihvdro- 7H- pyrido[ 3. 2. 1- ii1- 1. 3, 4- benzoksadiazin- 6- karboksylsyre 10-(4-acetyl-l-piperazinyl)-9-fluor-3-metyl-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre ble fremstil fra 9-fluor-3-metyl-7-okso-10-(1-piperazinyl)-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre erholdt i eksempel 6 og eddikanhydrid, analogt med eksempel 35, og ble erholdt som krystaller, smeltepunkt 294-296°C (dec); FAB-MS m/z 391 (MH<+>) etter omkrystallisering fra diklormetan/metanol. Preparation of 10-( 4- acetvl- 1- piperazinvl^- 9- fluoro- 3- methyl-- 7- oxo- 2. 3- dihydro- 7H- pyrido[ 3. 2. 1- ii1- 1. 3, 4 - benzoxadiazine-6-carboxylic acid 10-(4-acetyl-1-piperazinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3 ,4-Benzoxadiazine-6-carboxylic acid was prepared from 9-fluoro-3-methyl-7-oxo-10-(1-piperazinyl)-2,3-dihydro-7H-pyrido[3.2.1-ij]-1, 3,4-Benzoxadiazine-6-carboxylic acid obtained in Example 6 and acetic anhydride, analogous to Example 35, and was obtained as crystals, mp 294-296°C (dec); FAB-MS m/z 391 (MH<+>) after recrystallization from dichloromethane/methanol.

Eksempel 3 7 Example 3 7

Fremstilling av 10- r4-( 4- aminobenzvl)- 1- piperazinvl]- 9-fluor- 3- metyl- 7- okso- 2, 3- dihydro- 7H- pyrido[ 3. 2. 1- ii]- 1. 3. 4-- benzoksadiazin- 6- karboksvlsyre Preparation of 10- r4-(4-aminobenzyl)-1- piperazinyl]- 9-fluoro- 3- methyl- 7- oxo- 2, 3- dihydro- 7H- pyrido[ 3. 2. 1- ii]- 1. 3. 4-- Benzoxadiazine- 6- carboxylic acid

9- Fluor-3-metyl-10-[4-(4-nitrobenzyl)-1-piperazinyl]-7-okso--2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6— karboksylsyre (100 m) erholdt i eksempel 34 ble hydrogenert over 5% Pd/c (10 mg) i diklormetan/metanol (1:1) i 2 timer. Etter fjerning av katalysatoren ved filtratet ble filtratet konsentrert til tørrhet under redusert trykk. Residiet ble omkrystallisert fra etanol for å gi 69 mg fremstilling av 10- [4-(4-aminobenzyl)-1-piperazinyl]-9-fluor-3-metyl-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4—benzoksadiazin-6-karboksylsyre, smeltepunkt 237-238°C (dec); FAB-MS m/z 454 (MH<+>). 9- Fluoro-3-methyl-10-[4-(4-nitrobenzyl)-1-piperazinyl]-7-oxo--2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3, 4-Benzoxadiazine-6-carboxylic acid (100 m) obtained in Example 34 was hydrogenated over 5% Pd/c (10 mg) in dichloromethane/methanol (1:1) for 2 hours. After removing the catalyst from the filtrate, the filtrate was concentrated to dryness under reduced pressure. The residue was recrystallized from ethanol to give 69 mg of 10-[4-(4-aminobenzyl)-1-piperazinyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[ 3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid, mp 237-238°C (dec); FAB-MS m/z 454 (MH<+>).

Eksempel 3 8 Example 3 8

Fremstilling av 10- f3-( aminometyl)- 1- pyrrolidinyl1- 9- fluor-- 3- metvl- 7- okso- 2. 3- dihydro- 7H- pyrido[ 3. 2. 1- ii1- 1. 3. 4— benzoksadiazin- 6- karboksvlsyre Preparation of 10-f3-(aminomethyl)-1-pyrrolidinyl1-9-fluoro-3-methyl-7-oxo-2.3-dihydro-7H-pyrido[3.2.1-ii1-1.3.4 — benzoxadiazine-6-carboxylic acid

En blanding av 10-[3-(aminometyl)-1-pyrrolidinyl]-9-fluor--3-metyl-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre (40 mg) erholdt i eksempel 14a og IN natriumhydroksid (2,5 ml) ble varmet opp til 100"C i 3 timer. Etter avkjøling til romtemperatur ble reaksjonsblandingen nøytralisert med eddiksyre og utfellingen som ble separert ble oppsamlet ved filtrering og omkrystallisering fra metanol for å gi 15 mg av 10-[3-(aminometyl)-1-pyrrolidinyl ]-9-fluor-3-metyl-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre, smeltepunkt 177-180°C (dec); FAB-MS m/z 363 (MH+) . A mixture of 10-[3-(aminomethyl)-1-pyrrolidinyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3 ,4-Benzoxadiazine-6-carboxylic acid (40 mg) obtained in Example 14a and 1N sodium hydroxide (2.5 ml) were heated to 100°C for 3 hours. After cooling to room temperature, the reaction mixture was neutralized with acetic acid and the precipitate which was separated was collected by filtration and recrystallization from methanol to give 15 mg of 10-[3-(aminomethyl)-1-pyrrolidinyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[ 3.2.1-ij]-1,3,4-Benzoxadiazine-6-carboxylic acid, mp 177-180°C (dec); FAB-MS m/z 363 (MH + ).

Eksempel 3 9 Example 3 9

Fremstillin<g> av 6- fluor- 8- hydroksy- 7-( 1- imidazoylyl)- 1--( metylamino)- 4- okso- l, 4- dihvdro- 3- kinolinkarboksylsyre Preparation of 6-fluoro-8-hydroxy-7-(1-imidazoylyl)-1-(methylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid

Karbonyldiimidazol (32 mg) ble tilsatt til en omrørt oppløsning av 6,7-difluor-8-hydroksy-l-(metylamino)-4-okso--l,4-dihydro-3-kinolinkarboksylsyre (50 mg) erholdt i referanse eksempel (i) i tørr dimetylformamid (2 ml). Omrøringen fortsatte ved romtemperatur i 2 timer og så ved 80°C i 5 timer. Oppløsningsmiddelet ble fjernet under redusert trykk og residiet ble suspendert i vann og pH ble justert til 5 med eddiksyre. Utfellingen som ble separert ble filtrert og vasket med metanol for å gi 35 mg 6-fluor-8-hydroksy-7-(1-imidazoylyl)-1-(metylamino)-4-okso-l,4-dihydro-3-kinolinkarboksylsyre som et blekt gul pulver. FAB-MS m/z 319 (MH<+>); ^H-NMR (d6-DMS0) S: 2,82 (3H,s), 7,10 (1H, d, J=10,7 Hz), 7,61 (1H, d), 7,75 (1H, d), 8,62 (lH,s), 8,92 (1H,S) 15,33 (1H, br.s). Carbonyldiimidazole (32 mg) was added to a stirred solution of 6,7-difluoro-8-hydroxy-1-(methylamino)-4-oxo--1,4-dihydro-3-quinolinecarboxylic acid (50 mg) obtained in Reference Example (i) in dry dimethylformamide (2 mL). Stirring was continued at room temperature for 2 hours and then at 80°C for 5 hours. The solvent was removed under reduced pressure and the residue was suspended in water and the pH was adjusted to 5 with acetic acid. The precipitate that separated was filtered and washed with methanol to give 35 mg of 6-fluoro-8-hydroxy-7-(1-imidazoylyl)-1-(methylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid as a pale yellow powder. FAB-MS m/z 319 (MH<+>); ^H-NMR (d6-DMSO) S: 2.82 (3H,s), 7.10 (1H, d, J=10.7 Hz), 7.61 (1H, d), 7.75 (1H , d), 8.62 (1H,s), 8.92 (1H,S) 15.33 (1H, br.s).

Eksempel 40 Example 40

Fremstilling av 9- fluor- 10-( l- imidazovl)- 3- metvl- 7- okso- 2. 3-- dihvdro- 7H- pvrido r 3. 2. 1- ii1- 1. 3. 4- benzoksadiazin- 6- karbok-svisvre Preparation of 9- fluoro- 10-(1- imidazovl)- 3- methyl- 7- oxo- 2. 3-- dihydro- 7H- pvrido r 3. 2. 1- ii1- 1. 3. 4- benzoxadiazine- 6 - karbok-svisvre

En oppløsning av 6-fluor-8-hydroksy-7-(1-imidazolyl)-1--metylamino)-4-okso-l,4-dihydro-3-kinolinkarboksylsyre (15 mg) erholdt i eksempel 39 i en blanding av 35% formalin (1 ml) og dioxan (1 ml) ble varmet opp til lOO-llCC i 1,5 timer under nitrogen-atmosfære. Oppløsningsmiddelet ble fjernet under redusert trykk og det krystallinske residiet ble vasket med metanol for å gi 9-fluor-10-(1-imidazoyl)-3-metyl-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre som et blekt rosa pulver. En analytisk prøve, smeltepunkt >300°C; FAB-MS m/z 331 (MH<+>) ble fremstilt ved omkrystallisering fra dimetylformamid og eter. A solution of 6-fluoro-8-hydroxy-7-(1-imidazolyl)-1-methylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (15 mg) obtained in Example 39 in a mixture of 35% formalin (1 ml) and dioxane (1 ml) were heated to 100-110°C for 1.5 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure and the crystalline residue was washed with methanol to give 9-fluoro-10-(1-imidazoyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3.2.1 -ij]-1,3,4-Benzoxadiazine-6-carboxylic acid as a pale pink powder. An analytical sample, melting point >300°C; FAB-MS m/z 331 (MH<+>) was prepared by recrystallization from dimethylformamide and ether.

9-fluor-10-(1-imidazoyl)-3-metyl-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre ble altså fremstilt fra 9-10-difluor-3-metyl-7-okso-2,3-dihydro--7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre og imidazol i dimetylsulfoksid analogisk til eksempel 5 9-Fluoro-10-(1-imidazoyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid thus became prepared from 9-10-difluoro-3-methyl-7-oxo-2,3-dihydro--7H-pyrido[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid and imidazole in dimethylsulfoxide analogously to example 5

Eksempel 41 Example 41

Fremstilling av benzyl 9- fluor- 10- f3- hvdroksv- l- pyrroli-dinvl)- 3- metyl- 7- okso- 2, 3- dihydro- 7H- pyridof 3. 2. 1- ij1- 1, 3, 4-- benzoksadiazin- 6- karboksylat Preparation of benzyl 9- fluoro- 10- f3- hydroxy- 1- pyrroli-dinvl)- 3- methyl- 7- oxo- 2, 3- dihydro- 7H- pyridof 3. 2. 1- ij1- 1, 3, 4 -- benzoxadiazine-6-carboxylate

En blanding av 9-fluor-10-(3-hydroksy-1-pyrrolidinyl)-3— metyl-7-okso-2,3-dihydro-7H-pyridin[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre (10 mg) erholdt i eksempel 16, vannfritt kaliumkarbonat (8 mg) og dimetylformamid (0,5) ble omrørt ved romtemperatur i 1,5 timer og så ble det tilsatt benzylbromid )10,8 mg). Denne blandingen ble omrørt ved romtemperatur i 3 timer og inndampet under redusert trykk. A mixture of 9-fluoro-10-(3-hydroxy-1-pyrrolidinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyridine[3.2.1-ij]-1,3,4- Benzoxadiazine-6-carboxylic acid (10 mg) obtained in Example 16, anhydrous potassium carbonate (8 mg) and dimethylformamide (0.5) were stirred at room temperature for 1.5 hours and then benzyl bromide (10.8 mg) was added. This mixture was stirred at room temperature for 3 hours and evaporated under reduced pressure.

Residiet ble suspendert i vann og ekstrahert med kloroform. Ekstraktet ble konsentrert til tørrhet under redusert trykk. Residiet ble triturert med eter for å gi 11 mg benzyl 9-fluor-10-(3-hydroksy-l-pyrrolidinyl)-3-metyl-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4—benzoksadiazin-6-karboksylat, smeltepunkt 196-198°C (dec); FAB-MS m/z 440 (MH<+>). The residue was suspended in water and extracted with chloroform. The extract was concentrated to dryness under reduced pressure. The residue was triturated with ether to give 11 mg of benzyl 9-fluoro-10-(3-hydroxy-1-pyrrolidinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij ]-1,3,4-benzoxadiazine-6-carboxylate, mp 196-198°C (dec); FAB-MS m/z 440 (MH<+>).

Eksempel 42 Example 42

Fremstilling av benzyl 10-( 3- klor- l- pvrrolidinvl)- 9- fluor- 3-- metvl- 7- okso- 2. 3- dihYdro- 7H- pyrido[ 3. 2. 1- ii1- 1, 3. 4- bensok-sadiazin- 6- karboksvlat Preparation of benzyl 10-(3-chloro-1-pyrrolidinyl)-9-fluoro-3--methyl-7-oxo-2.3-dihydro-7H-pyrido[3.2.1-ii1-1,3. 4- benzoc-sadiazin- 6- carboxvlat

Benzyl 9-fluor-10-(3-hydroksy-l-pyrrolidinyl)-3-metyl-7--okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin--6-karboksylat (8 mg) erholdt i eksempel 41 ble oppløst i 0,2 ml tionylklorid og omrørt ved 60'C i 15 minutter. Reaksjonsblandingen ble fortynnet med vann og ekstrahert med kloroform. Benzyl 9-fluoro-10-(3-hydroxy-1-pyrrolidinyl)-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoxadiazine --6-carboxylate (8 mg) obtained in Example 41 was dissolved in 0.2 ml of thionyl chloride and stirred at 60°C for 15 minutes. The reaction mixture was diluted with water and extracted with chloroform.

Ekstraktet ble konsentrert under redusert trykk. Residiet The extract was concentrated under reduced pressure. The residence

ble kromatografert på silica-gel (2 g) med kloroform for å was chromatographed on silica gel (2 g) with chloroform to

gi 2,8 mg benzyl 10-(3-klor-l-pyrrolidinyl)-9-fluor-3--metyl-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-bens-oksadiazin-6-karboksylat, smeltepunkt >300<0>C; FAB-MS m/z 458 give 2.8 mg of benzyl 10-(3-chloro-1-pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij]-1, 3,4-benz-oxadiazine-6-carboxylate, melting point >300<0>C; FAB-MS m/z 458

(MH<+>), 460 (MH+2)<+.>(MH<+>), 460 (MH+2)<+.>

Eksempel 43 Example 43

Fremstilling av 10-( 3- klor- l- pvrrolidinyl)- 9- fluor- 3- metyl-- 7- okso- 2, 3- dihvdro- 7H- pvrido[ 3. 2. 1- ii]- l, 3. 4- benzoksadiazin- 6- karboksvlsvre Preparation of 10-(3-chloro-1-pyrrolidinyl)-9-fluoro-3-methyl--7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ii]-1,3. 4- benzoxadiazine- 6- carboxylic acid

Benzyl 10-(3-klor-l-pyrrolidinyl)-9-fluor-3-metyl-7-okso— 2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylat (2,5 mg) erholdt i eksempel 42 ble hydrogenert over 5% Pd/C (1 mg) i kloroform. Benzyl 10-(3-chloro-1-pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoxadiazine- The 6-carboxylate (2.5 mg) obtained in Example 42 was hydrogenated over 5% Pd/C (1 mg) in chloroform.

Etter fjerning av katalysatoren ved filtrering ble filtratet konsentrert til tørrhet under redusert trykk. Residiet ble omkrystallisert fra etanol for å gi 1,0 mg av 10-(3-klor-l--pyrrolidinyl)-9-fluor-3-metyl-7-okso-2,3-dihydro-7H— pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-3-karboksylsyre, After removal of the catalyst by filtration, the filtrate was concentrated to dryness under reduced pressure. The residue was recrystallized from ethanol to give 1.0 mg of 10-(3-chloro-1-pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3.2. 1-ij]-1,3,4-benzoxadiazine-3-carboxylic acid,

smeltepunkt 269-272°C (dec); FAB-MS m/z 368 (MH<+>), 370 mp 269-272°C (dec); FAB-MS m/z 368 (MH<+>), 370

(MH+2)<+>. (MH+2)<+>.

Eksempel 44 Example 44

Fremstillin<g> av 9- fluor- 3- metyl- 10-( 4- metyl- l- piperazinyl) -- 7- okso- 2. 3- dihydro- 7H- pyrido f 3. 2. 1- ii1- 1, 3, 4- benzoksadiazin- 6- karboksvlsyre via fluorboran- intermediat Preparation of 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl) -- 7-oxo-2.3-dihydro-7H-pyrido f 3.2.1-ii1-1, 3, 4- Benzoxadiazine- 6- carboxylic acid via fluoroborane intermediate

(a) En blanding av 9,10-difluor-3-metyl-7-okso-2,3-dihydro--7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre (100 mg) eroldt i eksempel 1 og 60% vannfritt fluorborsyre (1 ml) ble oppvarmet til 90°C i 12 timer. Etter at reaksjonsblandingen ble avkjølt til romtemperatur ble utfellingen samlet opp ved filtrering, vasket med metanol og tørket under redusert trykk for å gi 100 mg ren 9,10-difluor-6--[[(difluorboryl)oksy]karbonyl]-3-metyl-2,3-dihydro-7H--pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-7-one; FAB-MS m/z 331 (a) A mixture of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid ( 100 mg) dissolved in Example 1 and 60% anhydrous hydroboric acid (1 ml) were heated to 90°C for 12 hours. After the reaction mixture was cooled to room temperature, the precipitate was collected by filtration, washed with methanol and dried under reduced pressure to give 100 mg of pure 9,10-difluoro-6-[[(difluoroboryl)oxy]carbonyl]-3-methyl -2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoxadiazin-7-one; FAB-MS m/z 331

(MH<+>). (MH<+>).

(b) Til en omrørt oppløsning av det ovenfor nevnte boran-intermediat (33 mg) i dimetylsulfoksid (1 ml) ble det tilsatt N-metylpiperazin (15 pl) og trietylamin (20 pl). Etter omrøring ved romtemperatur i 3 timer ble reaksjonsblandingen lyofilisert. Residiet ble omkrystallisert fra metanol for å gi 28 mg av 6-[[(difluorboryl)oksy]karbonyl]--9-fluor-3-metyl-10-(4-metyl-l-piperazinyl)-2,3-dihydro--7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-7-one som gule krystaller, smeltepunkt 228-230°C (dec); FAB-MS m/z 411 (b) To a stirred solution of the above borane intermediate (33 mg) in dimethylsulfoxide (1 ml) was added N-methylpiperazine (15 µl) and triethylamine (20 µl). After stirring at room temperature for 3 hours, the reaction mixture was lyophilized. The residue was recrystallized from methanol to give 28 mg of 6-[[(difluoroboryl)oxy]carbonyl]-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-2,3-dihydro- -7H-pyrido[3.2.1-ij]-1,3,4-benzoxadiazin-7-one as yellow crystals, mp 228-230°C (dec); FAB-MS m/z 411

(MH<+>). (MH<+>).

(c) Til en oppløsning av det ovenfor nevnte boran-intermediat (5 mg) i 95% etanol (1 ml) ble det tilsatt trietylamin (3 pl). Etter oppvarming under tilbakeløp i 4 timer ble reaksjonsblandingen avkjølt til romtemperatur. Utfellingen som ble separerte ble samlet opp ved filtrering for å gi 9--fluor-3-metyl-10-(4-metyl-l-piperazinyl)-7-okso-2,3— dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre, smeltepunkt 268-269°C (dec). (c) To a solution of the above-mentioned borane intermediate (5 mg) in 95% ethanol (1 ml) was added triethylamine (3 µl). After heating under reflux for 4 hours, the reaction mixture was cooled to room temperature. The precipitate which separated was collected by filtration to give 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[3.2.1 -ij]-1,3,4-benzoxadiazine-6-carboxylic acid, mp 268-269°C (dec).

Eksempel 45 Example 45

Fremstilling av 9- fluor- 3- metvl- 10-( 4- metyl- l- piperazinvl)-- 7- okso- 2, 3- dihydro- 7H- pvrido[ 3. 2. 1- ii1- 1, 3, 4- benzoksadiazin- 6- karboksvlsyre via acetoksyborn- intermediat Preparation of 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)--7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ii1-1,3,4 - benzoxadiazine-6-carboxylic acid via acetoxyborn intermediate

(a) En blanding av 9,10-difluor-3-metyl-7-okso-2,3-dihydro--7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre (100 mg) erholdt i eksempel 1, eddikanhydrid (1 ml) og triacetoksyboran (100 mg) ble oppvarmet til 140 °C i 15 (a) A mixture of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid ( 100 mg) obtained in Example 1, acetic anhydride (1 ml) and triacetoxyborane (100 mg) were heated to 140 °C for 15

minutter. Reaksjonsblandingen ble inndampet under redusert trykk. Residiet ble trituratert med aceton og filtrert for å minutes. The reaction mixture was evaporated under reduced pressure. The residue was triturated with acetone and filtered to

gi 138 mg av 6-[[(diacetoksyboryl)oksy]karbonyl]-9,10--difluor-3-metyl-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-7-one; FAB-MS m/z 411 (MH<+>). give 138 mg of 6-[[(diacetoxyboryl)oxy]carbonyl]-9,10--difluoro-3-methyl-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4- benzoxadiazin-7-one; FAB-MS m/z 411 (MH<+>).

(b) Til en blanding av det ovenfor nevnte boran-intermediat (41 mg) i dimetylsulfoksid (1 ml) ble det tilsatt N-metylpiperazin (15 pl) og trietylamin (20 pl). Etter at blandin- (b) To a mixture of the above borane intermediate (41 mg) in dimethylsulfoxide (1 ml) was added N-methylpiperazine (15 µl) and triethylamine (20 µl). After mixing

gen ble omrørt ved romtemperatur i 2 timer, ble reaksjonsblandingen lyofilisert. Residiet ble omkrystallisert fra metanol/eter for å gi 34 mg av 6-[[(diacetoksyboryl)oksy]--karbonyl]-9-fluor-3-metyl-10-(4-metyl-l-piperazinyl)-2,3--dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-7-one som gule krystaller; smeltepunkt 156-157°C (dec); FAB-MS m/z 491 (MH<+>). was stirred at room temperature for 2 hours, the reaction mixture was lyophilized. The residue was recrystallized from methanol/ether to give 34 mg of 6-[[(diacetoxyboryl)oxy]--carbonyl]-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-2,3 --dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoxadiazin-7-one as yellow crystals; mp 156-157°C (dec); FAB-MS m/z 491 (MH<+>).

(c) Det ovenfor nevnte boran-intermediat (5 mg) ble suspen- (c) The above-mentioned borane intermediate (5 mg) was suspended

dert i aceton (0,1 ml) og tilsatt konsentrert HC1 (2,5 pl). in acetone (0.1 mL) and added concentrated HCl (2.5 µl).

Reaksjonsblandingen ble omrørt ved romtemperatur i 30 The reaction mixture was stirred at room temperature for 30

minutter og avkjølt i isbad. Utfellingen ble separert og samlet opp ved filtrering og utfellingen ble oppløst i 95% minutes and cooled in an ice bath. The precipitate was separated and collected by filtration and the precipitate was dissolved in 95%

etanol (0,1 ml). Til oppløsningsmiddelet ble det tilsatt trietylamin (2 pl) og blandingen ble kokt under tilbakeløp i 1 time. Etter at oppløsningsmiddelet ble avkjølt til romtemperatur, utfellingen som ble separert ble samlet opp ved filtrering for å gi 9-fluor-3-metyl-10-(4-metyl-l-piperazinyl) -7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4--benzoksadiazin-6-karboksylsyre, smeltepunkt 268-269"C (dec.). ethanol (0.1 mL). To the solvent was added triethylamine (2 µl) and the mixture was refluxed for 1 hour. After the solvent was cooled to room temperature, the precipitate that separated was collected by filtration to give 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro- 7H-pyrido[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid, mp 268-269°C (dec.).

Eksempel 4 6 Example 4 6

Fremstilling av pivalovloksymetyl 10- f3-( benzyloksykarbonyl-amino) - 1- pvrrolidinvl]- 9- fluor- 3- metyl- 7- okso- 2, 3- dihydro— 7H- pvridor3. 2. 1- ii]- 1, 3. 4- benzoksadiazin- 6- karboksylat Preparation of pivalovloxymethyl 10-[3-(benzyloxycarbonyl-amino)-1-pyrrolidinyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro—7H- pvridor3. 2. 1- ii]- 1, 3. 4- benzoxadiazine- 6- carboxylate

En blanding 10-[3-(benzyloksykarbonyl-amino)-1-pyrrolidinyl] -9-fluor-3-metyl-7-okso-2,3-dihydro—7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylat (290 mg) erholdt i eksempel 22, pivaloyloksymetylklorid (130 pl), vannfritt kaliumkarbonat (166 mg) og tørr dimetylformamid (10 ml) ble omrørt ved 45"C i 8 timer. Oppløsningsmiddelet ble så fjernet under redusert trykk. Residiet ble oppløst i diklormetan. Diklormetan-oppløsningen ble vasket med vann og tørket over vannfritt natriumsulfat. Oppløsningsmiddelet ble fordampet av under redusert trykk og residiet ble omkrystallisert fra etylacetat for å gi 325 mg av pivaloyloksymetyl 10-[3-(benzyloksykarbonyl-amino)-1-pyrrolidinyl]-9-fluor-3-metyl-7-okso-2,3-dihydro—7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylat, smeltepunkt 185-188°C? FAB-MS m/z 597 A mixture 10-[3-(benzyloxycarbonyl-amino)-1-pyrrolidinyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3 ,4-benzoxadiazine-6-carboxylate (290 mg) obtained in Example 22, pivaloyloxymethyl chloride (130 µl), anhydrous potassium carbonate (166 mg) and dry dimethylformamide (10 ml) were stirred at 45°C for 8 hours. The solvent was then removed under reduced pressure. The residue was dissolved in dichloromethane. The dichloromethane solution was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure and the residue was recrystallized from ethyl acetate to give 325 mg of pivaloyloxymethyl 10-[3-(benzyloxycarbonyl) -amino)-1-pyrrolidinyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylate, mp 185-188°C?FAB-MS m/z 597

(MH<+>). (MH<+>).

Eksempel 47 Example 47

Fremstilling pivaloyloksymetyl 10-( 3- amino- l- pyrrolidinvl)-- 9- fluor- 3- mtyl- 7- okso- 2, 3- dihvdro- 7H- pvrido F 3. 2. 1- ii] — 1. 3. 4- benzoksadiazin- 6- karboksylat Preparation pivaloyloxymethyl 10-(3- amino-l- pyrrolidinyl)-- 9- fluoro- 3- methyl- 7- oxo- 2, 3- dihydro- 7H- pvrido F 3. 2. 1- ii] — 1. 3. 4- benzoxadiazine- 6- carboxylate

Pivaloyloksymetyl 10-(3-amino-l-pyrrolidinyl)--9-fluor-3-mtyl-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]— 1,3,4-benzoksadiazin-6-karboksylat ble fremstilt av pivaloyloksymetyl 10-[3-(benzyloksykarbonylamino)-1-pyrrolidinyl]--9-fluor-3-metyl-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]— 1,3,4-benzoksadiazin-6-karboksylat (200 mg) erholdt i eksempel 46, analogt med eksempel 23, og som ble erholdt som blekt, brunt pulver etter utfelling fra en blanding av etylacetat og n-hexan; ^-H NMR (CDC13) 5: 1,22 (9H, s), 1,6-2,4 (2H, m), 2,99 (3H, s), 3,3-4,0 (5H, m), 4,98 (2H, s), 5,96 (2H, s), 7,64 (1H, d, J=14,4 Hz), 8,37 (1H, s); FAB-MS m/Z 463 (MH<+>). Pivaloyloxymethyl 10-(3-amino-1-pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij]— 1,3,4-benzoxadiazine -6-carboxylate was prepared from pivaloyloxymethyl 10-[3-(benzyloxycarbonylamino)-1-pyrrolidinyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij ]— 1,3,4-benzoxadiazine-6-carboxylate (200 mg) obtained in Example 46, analogously to Example 23, and which was obtained as a pale brown powder after precipitation from a mixture of ethyl acetate and n-hexane; 1 H NMR (CDCl 3 ) δ: 1.22 (9H, s), 1.6-2.4 (2H, m), 2.99 (3H, s), 3.3-4.0 (5H, m), 4.98 (2H, s), 5.96 (2H, s), 7.64 (1H, d, J=14.4 Hz), 8.37 (1H, s); FAB-MS m/Z 463 (MH<+>).

Eksempel 48 Example 48

Fremstillin<g> av etyl 10- f3- Cbenzyloksykarbonvlamino)- 1-- pyrrolidinyll- 9- fluor- 3- metvl- 7- okso- 2, 3- dihydro- 7H- pyrido-[ 3. 2. 1- ii1- 1, 3, 4- benzoksadiazin- 6- karboksylat En blanding 10-[3-(benzyloksykarbonylamino)-1-pyrrolidinyl]--9-fluor-3-metyl-7-okso-2,3-dihydro-7H-pyrido-[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre (337 mg) erholdt i eksempel 22, etyljodid (84 pl), vannfritt kaliumkarbonat (193 mg) og tørr dimetylformamid (12 ml) ble omrørt ved 45°C i 6 timer. Oppløsningsmiddlet ble fjernet under redusert trykk og residit ble oppløst i diklormetan. Diklormetan-oppløsningen ble vasket med vann, tørket over vannfritt natriumsulfat og konsentrert under redusert trykk. Residiet ble så anvendt på en silica-gel kolonne og eluert med en blanding av kloroform og aceton (20:1). De rene fraksjoner ble kombinert, konsentrert til tørrhet under redusert trykk og residiet ble omkrystallisert fra etylacetat for å gi 271 mg av etyl 10-[3-(benzyloksykarbonylamino)-1—pyrrolidinyl]-9-fluor-3-metyl-7-okso-2,3-dihydro-7H-pyrido-[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylat, smeltepunkt 204-207"C; FAB-MS m/z 511 (MH<+>). Preparation<g> of ethyl 10- (3- Cbenzyloxycarbonylamino)- 1-- pyrrolidinyl- 9- fluoro- 3- methyl- 7- oxo- 2, 3- dihydro- 7H- pyrido-[ 3. 2. 1- ii1- 1 , 3, 4- benzoxadiazine- 6- carboxylate A mixture 10-[3-(benzyloxycarbonylamino)-1-pyrrolidinyl]--9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido-[ 3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid (337 mg) obtained in Example 22, ethyl iodide (84 µl), anhydrous potassium carbonate (193 mg) and dry dimethylformamide (12 ml) were stirred at 45 °C for 6 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. The dichloromethane solution was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was then applied to a silica-gel column and eluted with a mixture of chloroform and acetone (20:1). The pure fractions were combined, concentrated to dryness under reduced pressure and the residue recrystallized from ethyl acetate to give 271 mg of ethyl 10-[3-(benzyloxycarbonylamino)-1-pyrrolidinyl]-9-fluoro-3-methyl-7-oxo -2,3-dihydro-7H-pyrido-[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylate, mp 204-207"C; FAB-MS m/z 511 (MH<+> ).

Eksempel 49 Example 49

Fremstilling av etyl 10-( 3- amino- l- pyrrolidinvl)- 9- fluor- 3-- metyl- 7- okso- 2, 3- dihvdro- 7H- pvrido[ 3. 2. 1- ii1- 1. 3, 4- benzoksadiazin- 6- karboksvlat Preparation of ethyl 10-(3-amino-1-pyrrolidine)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ii1-1.3, 4- benzoxadiazine- 6- carboxylate

Etyl 10-[3-(benzyloksykarbonylamino)-1-pyrrolidinyl]-9--fluor-3-metyl-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4--benzoksadiazin-6-karboksylat (200 mg) erholdt i eksempel 48 ble hydrogenert over 5% Pd/C (12 0 mg) i en blanding av kloroform (25 ml) og metanol (10 ml) i 23 timer. Etter fjerning av katalysatoren ved filtrering, ble filtratet konsentrert under redusert trykk. Residiet ble så anvendt på en silica-gel kolonne og eluert med en blanding av kloroform og metanol (4:1). De rene fraksjoner ble konsentrert til tørrhet under redusert trykk. Residiet ble videre renset ved preparert TLC (silica gel; CHCl3/MeOH, 3:1) og omkrystallisert fra eanol for å gi 71 mg av etyl 10-(3-amino-l-pyrrolidinyl)-9-fluor-3-metyl-7-okso-2,3-dihydro-7H-pyrido-[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylat, smeltepunkt 187-192°C (dec); FAB-MS m/z 377 (MH+) . Ethyl 10-[3-(benzyloxycarbonylamino)-1-pyrrolidinyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4 --benzoxadiazine-6-carboxylate (200 mg) obtained in Example 48 was hydrogenated over 5% Pd/C (120 mg) in a mixture of chloroform (25 ml) and methanol (10 ml) for 23 hours. After removal of the catalyst by filtration, the filtrate was concentrated under reduced pressure. The residue was then applied to a silica-gel column and eluted with a mixture of chloroform and methanol (4:1). The pure fractions were concentrated to dryness under reduced pressure. The residue was further purified by preparative TLC (silica gel; CHCl3/MeOH, 3:1) and recrystallized from ethanol to give 71 mg of ethyl 10-(3-amino-1-pyrrolidinyl)-9-fluoro-3-methyl- 7-oxo-2,3-dihydro-7H-pyrido-[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylate, mp 187-192°C (dec); FAB-MS m/z 377 (MH + ).

Eksempel 50 Example 50

Fremstilling av 10-( S- amino- l- pyrrolidinyl)- 9- fluor- 3- metyl-- 7- okso- 2, 3- dihydro- 7H- pvrido[ 3. 2. 1- ii1- 1, 3, 4- benzoksadiazin- 6- karboksylsvre hvdroklorid Preparation of 10-(S-amino-1-pyrrolidinyl)-9-fluoro-3-methyl--7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ii1-1,3,4 - benzoxadiazine-6-carboxylic acid hydrochloride

pH til et oppløsningsmiddel av 10-(3-amino-l-pyrrolidinyl)-9- fluor-3-met<y>l—7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre (20 mg), erholdt i eksempel 23, i vann (1 ml) ble justert til 1,0 med 6N-NC1. Det klare oppløsningsmiddelet ble lyofilisert og residiet ble krystallisert fra vann/etanol (1:2) for å gi 19 mg av 10- (3-amino-l-pyrrolidinyl)-9-fluor-3-metyl-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre hydroklorid, smeltepunkt 226-228°C (dec). pH of a solvent of 10-(3-amino-1-pyrrolidinyl)-9-fluoro-3-meth<y>1-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij]- 1,3,4-Benzoxadiazine-6-carboxylic acid (20 mg), obtained in Example 23, in water (1 ml) was adjusted to 1.0 with 6N-NC1. The clear solvent was lyophilized and the residue crystallized from water/ethanol (1:2) to give 19 mg of 10-(3-amino-1-pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2, 3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid hydrochloride, mp 226-228°C (dec).

Eksempel 51 Example 51

Fremstilling av 9- fluor- 3- metyl- 10-( 4- metyl- l- piperazinvl)-- 7- okso- 2. 3- dihydro- 7H- pvridor3. 2. 1- ii]- 1. 3, 4- benzoksadizin-- 6- karboksylsvre hvdroklorid Preparation of 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)--7-oxo-2.3-dihydro-7H-pvridor3. 2. 1- ii]- 1. 3, 4- benzoxadizine-- 6- carboxylic acid hydrochloride

9-fluor-3-metyl-10-(4-metyl-l-piperazinyl)-7-okso-2,3— dihydro-7H-pyrido[3.2.l-ij]-1,3,4-benzoksadizin-6-karbok- 9-Fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoxadizin-6 -karbok-

sylsyre hydroklorid ble erholdt analogisk til eksempel 50, smeltepunkt 264-266°C (dec). syllic acid hydrochloride was obtained analogously to example 50, melting point 264-266°C (dec).

Eksempel 52 Example 52

Fremstilling av natrium 9- fluor- 3- metyl- 10- morfolino- 7- okso-- 2. 3- dihvdro- 7H- pyrido r 3. 2. 1- ii1- 1, 3, 4- benzoksadiazin- 6-- karboksvlat Preparation of sodium 9- fluoro- 3- methyl- 10- morpholino- 7- oxo-- 2. 3- dihydro- 7H- pyrido r 3. 2. 1- ii1- 1, 3, 4- benzoxadiazine- 6-- carboxvlate

9-fluor-3-metyl-10-morfolino-7-okso-2,3-dihydro-7H-pyrido-[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre (14 mg) erholdt i eksempel 9 ble suspendert i vann (0,4 ml) og IN natriumhydroksid (40 pl) ble tilsatt ved omrøring. Det klare oppløsningsmiddelet ble lyofilsert og residiet ble krystallisert fra vann/etanol (1:4) for å gi 12 mg av natrium 9-fluor-3-metyl-10-morfolino-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylat, smeltepunkt >300°C. 9-Fluoro-3-methyl-10-morpholino-7-oxo-2,3-dihydro-7H-pyrido-[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid (14 mg) obtained in Example 9 was suspended in water (0.4 mL) and 1N sodium hydroxide (40 µl) was added with stirring. The clear solvent was lyophilized and the residue crystallized from water/ethanol (1:4) to give 12 mg of sodium 9-fluoro-3-methyl-10-morpholino-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylate, melting point >300°C.

Eksempel 53 Example 53

Fremstilling av 9- fluor- 3-( 2- fluoretyl)- 10-( 4- metvl- l- piper-azinvl)- 7- okso- 2, 3- dihydro- 7H- pvridor3. 2♦ 1- ii1- 1. 3. 4— benzoksadiazin- 6- karboksylsvre Preparation of 9-fluoro-3-(2-fluoroethyl)-10-(4-methyl-1-piperazine)-7-oxo-2,3-dihydro-7H-pvridor3. 2♦ 1- ii1- 1. 3. 4— benzoxadiazine- 6- carboxylic acid

9-Fluor-3-(2-fluoretyl)-10-(4-metyl-l-piperazinyl)-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4—benzoksadiazin-6-karboksylsyre ble fremstilt fra etyl 8-benzyloksy-6,7--difluor-1-(formylamino)-4-okso-l,4-dihydro-3-kinolinkarbok-sylat erholdt i referanse eksempel (f), fulgt av fremgangs-måteseriene i referanse eksempel (g, h og i) (ved å bruke 1--brom-2-fluoretan i stedet for metyl jodid), eksempel 1 og eksempel 5, og ved å erholdes som krystaller, smeltepunkt 220-224'C; MS m/z 394 (M<+>) etter omkrystallisering fra metanol. 9-Fluoro-3-(2-fluoroethyl)-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4 —benzoxadiazine-6-carboxylic acid was prepared from ethyl 8-benzyloxy-6,7-difluoro-1-(formylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylate obtained in reference example (f), followed by the series of procedures in Reference Example (g, h and i) (using 1-bromo-2-fluoroethane instead of methyl iodide), Example 1 and Example 5, and obtaining as crystals, melting point 220- 224°C; MS m/z 394 (M<+>) after recrystallization from methanol.

Eksempel 54 og 55 Examples 54 and 55

De ble erholdt fra de følgende utgangsforbindelser They were obtained from the following output compounds

fra forbindelsen erholdt i eksempel 1 ved å bruke analog måte til de beskrevet i eksempel 5 eller eksempel 22/23. from the compound obtained in example 1 using an analogous method to those described in example 5 or example 22/23.

Eksempel 56 Example 56

Fremstilling av natrium 9- fluor- 3- metvl- 10- f4- metyl- l-piperazinvl)- 7- okso- 2, 3- dihvdro- 7H- pyridor3. 2. 1- ii]- 1, 3, 4-- benzoksadiazin- 6- karboksylat Preparation of sodium 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H- pyridor3. 2. 1- ii]- 1, 3, 4-- benzoxadiazine- 6- carboxylate

9- Fluor-3-metyl-10-(4-metyl-l-piperazinyl)-7-okso-2,3-dihydro-7H-pyrido[3,2,1-ij]-1.3.4-benzoksadiazin-6-karboksylat ble oppløst i 0,5N natriumydroksid (2,88 ml). Det klare oppløsningsmiddelet ble inndampet under redusert trykk for å gi 555 mg av et blekt, gult pulver som ble omkrystallisert fra etanol for å gi 475 mg natrium 9-fluor-3-metyl-10- (4-metyl-l-piperazinyl)-7-okso-2,3-dihydro-7H-pyrido-[3.2.1-ij]-l,3,4-benzoksadiazin-6-karboksylat etter tørking i våkum ved 80°C i 2 dager, smeltepunkt 252-254°C (dec), FAB-MS m/z 385. 9- Fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6 -carboxylate was dissolved in 0.5N sodium hydroxide (2.88 mL). The clear solvent was evaporated under reduced pressure to give 555 mg of a pale yellow powder which was recrystallized from ethanol to give 475 mg of sodium 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)- 7-oxo-2,3-dihydro-7H-pyrido-[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylate after drying in vacuum at 80°C for 2 days, melting point 252-254° C (dec), FAB-MS m/z 385.

Claims (12)

1. Analogifremgangsmåte ved fremstilling av terapeutisk aktive 10-substituerte 9-fluor-7-okso-2,3-dihydro-7H-pyrido-[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyrederivater med den generelle formel hvor R<1> er et hydrogenatom eller et karboksy-beskyttende radikal valgt fra laverealkyl, benzyl og lavere alkanoylok-sylalkyl; R<2> er et lavere alkyl-radikal som kan være substituert med et fluoratom; R<3> er et hydrogenatom eller et lavere alkyl-radikal som kan være substituert med et hydroksy-radikal eller med et dilavere alkylamino-radikal; R<5> er et lavere alkylradikal, og R<6> er et di-lavere alkyl-aminolavere alkylradikal, eller R<5> og R<6> tatt sammen med det hosliggende nitrogenatom kan danne - en piperazinring som kan være substituert i 3-stilling med metyl eller fenyl og/eller N-substituert med lavere metyl, etyl, acetyl aminobenzyl; - en morfolinring; - en 1,1-dioksydtiomorfolinring; - en pyrrolidinring som er substituert i 3-stilling med amino, metylamino, etylamino, aminometyl, metylaminometyl, etylaminometyl, metoksy eller klor eller i 4-stilling med metyl eller metoksy; - en imidazolring som kan være substituert med metyl i 4-stilling; eller - en piperidinring som kan være substituert med aminometyl, hydroksy, amino, metylamino eller metoksy; så vel som farmasøytisk akseptable salter derav og hydrater eller solvater av forbindelsene med formel I eller deres salter, karakterisert ved at fremgangsmåten omfatter: (a) å omsette en forbindelse representert av den generelle formel hvor R<1>, R<2> og R<3> er som definert ovenfor, og X<1> er et halogenatom; og amino-, hydroksy- og/eller karboksygrupper som er tilstede, kan være beskyttet, med et amin representert av den generelle formel hvor R5 og R<6> er som definert ovenfor, etterfulgt av, om nødvendig, fjerning av et beskyttende radikal, eller (b) å omsette en forbindelse representert av den generelle formel hvor R<1>, R<2>, R<5> og R<6> er som definert ovenfor, og amino, hydroksy og/eller karboksygrupper som er tilstede kan være beskyttet, med et aldehyd representert av den generelle formel hvor R<3> er som definert ovenfor, eller dets polymer, acetal eller enol-eter, etterfulgt om nødvendig av fjerning av et beskyttelsesradikal, eller (c) for fremstilling av en forbindelse med formel I hvor R<5>R<6>N- er en N-substituert piperazinring som definert ovenfor, å omsette en forbindelse med formel I hvor R<5>R<6>n-er N-usubstituert piperazinyl, med er et middel som gir en slik N-substituent; eller (d) for fremstilling av en forbindelse med formel I hvor R<5>R<6>N- er 1,1-dioksyd-tiomorfolino ved å la en tilsvarende forbindelse hvor R<5>R<6>N- er tiomorfolino, undergå oksydasjon; eller (e) for fremstilling av en forbindelse av formel I hvor R<5>R<6>N- er en pyrrolidinring substituert med amino eller en piperidinring substituert med amino eller hydroksy, å avspalte den beskyttende gruppe fra en tilsvarende forbindelse som har en beskyttet amino- eller hydroksygruppe; eller (f) for fremstilling av en forbindelse med formel I hvor R<5>R<6>N- er en klorpyrrolidinring, å klorere en tilsvarende hydroksypyrrolidinforbindelse med formel I hvor R<1> er et karboksybeskyttende radikal som definert ovenfor og hvis ønsket å avspalte nevnte beskyttende radikal R<1>; eller (g) for fremstilling av en forbindelse med formel I hvor R<5>R<6>N- er en aminobenzyl-piperazinring, å redusere nitro-gruppen i en tilsvarende nitrobenzyl-piperazinforbindelse med formel I, eller (h) for fremstilling av en forbindelse med formel I hvor R<1 >er et karboksy-beskyttende radikal som definert ovenfor, å underkaste en karboksylsyre av formel I en tilsvarende esterifisering, og hvis ønsket for fremstilling av farmasøytisk akseptable salter, hydrater eller solvater av en forbindelse av formel I eller hydrater eller solvater av nevnte salter, å omdanne en forbindelse av formel I til et salt, hydrat eller solvat eller til et hydrat eller solvat av nevnte salt.1. Analogy method for the preparation of therapeutically active 10-substituted 9-fluoro-7-oxo-2,3-dihydro-7H-pyrido-[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid derivatives with the general formula where R<1> is a hydrogen atom or a carboxy-protecting radical selected from lower alkyl, benzyl and lower alkanoyloxylalkyl; R<2> is a lower alkyl radical which may be substituted with a fluorine atom; R<3> is a hydrogen atom or a lower alkyl radical which may be substituted with a hydroxy radical or with a dilower alkylamino radical; R<5> is a lower alkyl radical, and R<6> is a di-lower alkyl-amino lower alkyl radical, or R<5> and R<6> taken together with the adjacent nitrogen atom can form - a piperazine ring which can be substituted in 3-position with methyl or phenyl and/or N-substituted with lower methyl, ethyl, acetyl aminobenzyl; - a morpholine ring; - a 1,1-dioxidethiomorpholine ring; - a pyrrolidine ring which is substituted in the 3-position with amino, methylamino, ethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, methoxy or chlorine or in the 4-position with methyl or methoxy; - an imidazole ring which may be substituted with methyl in the 4-position; or - a piperidine ring which may be substituted with aminomethyl, hydroxy, amino, methylamino or methoxy; as well as pharmaceutically acceptable salts thereof and hydrates or solvates of the compounds of formula I or their salts, characterized in that the method comprises: (a) reacting a compound represented by the general formula where R<1>, R<2> and R<3> are as defined above, and X<1> is a halogen atom; and amino, hydroxy and/or carboxy groups present may be protected, with an amine represented by the general formula wherein R5 and R<6> are as defined above, followed, if necessary, by removal of a protecting radical, or (b) reacting a compound represented by the general formula where R<1>, R<2>, R<5> and R<6> are as defined above, and amino, hydroxy and/or carboxy groups present may be protected, with an aldehyde represented by the general formula wherein R<3> is as defined above, or its polymer, acetal or enol ether, followed if necessary by removal of a protecting radical, or (c) for the preparation of a compound of formula I wherein R<5>R<6> N- is an N-substituted piperazine ring as defined above, reacting a compound of formula I wherein R<5>R<6>n-is N-unsubstituted piperazinyl, with is an agent which gives such an N-substituent; or (d) for the preparation of a compound of formula I wherein R<5>R<6>N- is 1,1-dioxide-thiomorpholino by adding a corresponding compound wherein R<5>R<6>N- is thiomorpholino , undergo oxidation; or (e) for the preparation of a compound of formula I wherein R<5>R<6>N- is a pyrrolidine ring substituted with amino or a piperidine ring substituted with amino or hydroxy, cleaving the protecting group from a corresponding compound having a protected amino or hydroxy group; or (f) for the preparation of a compound of formula I wherein R<5>R<6>N- is a chloropyrrolidine ring, to chlorinate a corresponding hydroxypyrrolidine compound of formula I wherein R<1> is a carboxy protecting radical as defined above and if desired cleaving said protecting radical R<1>; or (g) for the preparation of a compound of formula I where R<5>R<6>N- is an aminobenzyl-piperazine ring, to reduce the nitro group in a corresponding nitrobenzyl-piperazine compound of formula I, or (h) for the preparation of a compound of formula I where R<1 >is a carboxy-protecting radical as defined above, subjecting a carboxylic acid of formula I to a corresponding esterification, and if desired for the preparation of pharmaceutically acceptable salts, hydrates or solvates of a compound of formula I or hydrates or solvates of said salts, converting a compound of formula I into a salt, hydrate or solvate or into a hydrate or solvate of said salt. 2. Fremgangsmåte ved fremstilling av en forbindelse ifølge krav 17hvilken forbindelse er 9-fluor-3-metyl-10-(4-metyl-l- -piperazinyl)-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4- -benzoksadiazin-6-karboksylsyre eller et farmasøytisk akseptabelt salt derav eller et hydrat eller et solvat av denne forbindelse eller av nevnte salt ;karakterisert ved at tilsvarende substituerte utgangsmaterialer anvendes.2. Process for the preparation of a compound according to claim 17, which compound is 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[3.2. 1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrate or a solvate of this compound or of said salt; characterized in that correspondingly substituted starting materials are used. 3. Fremgangsmåte ved fremstilling av en forbindelse ifølge krav ljhvilken forbindelse er 9-fluor-3-metyl-7-okso-10-(1-piperazinyl)-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre eller et farmasøytisk akseptabelt salt derav eller et hydrat eller et solvat av denne forbindelse eller av nevnte salt ^karakterisert ved at tilsvarende substituerte utgangsmaterialer anvendes.3. Process for the preparation of a compound according to claim ljwhich compound is 9-fluoro-3-methyl-7-oxo-10-(1-piperazinyl)-2,3-dihydro-7H-pyrido[3.2.1-ij]- 1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrate or a solvate of this compound or of said salt ^ characterized in that correspondingly substituted starting materials are used. 4. Fremgangsmåte ved fremstilling av en forbindelse ifølge krav 1, hvilken forbindelse er 9-fluor-3-mety1-10-(3-metyl-1-piperazinyl)-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre eller et farmasøytisk akseptabelt salt derav eller et hydrat eller et solvat av denne forbindelse eller av nevnte salt ^karakterisert ved at tilsvarende substituerte utgangsmaterialer anvendes.4. Process for the preparation of a compound according to claim 1, which compound is 9-fluoro-3-methyl-10-(3-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[3.2 .1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrate or a solvate of this compound or of said salt ^characterized in that correspondingly substituted starting materials are used. 5. Fremgangsmåte ved fremstilling av en forbindelse ifølge krav l, hvilken forbindelse er 9-fluor-3-metyl-7-okso-10-(3-fenyl-l-piperazinyl)-2,3-dihydro-7H-pyrido[3.2.1-ij]-l,3,4-benzoksadiazin-6-karboksylsyre eller et farmasøytisk akseptabelt salt derav eller et hydrat eller et solvat av denne forbindelse eller av nevnte salt^, karakterisert ved at tilsvarende substituerte utgangsmaterialer anvendes.5. Process for the preparation of a compound according to claim 1, which compound is 9-fluoro-3-methyl-7-oxo-10-(3-phenyl-1-piperazinyl)-2,3-dihydro-7H-pyrido[3.2 .1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrate or a solvate of this compound or of said salt^, characterized in that correspondingly substituted starting materials are used. 6. Fremgangsmåte ved fremstilling av en forbindelse ifølge krav lj hvilken forbindelse er 9-fluor-3-metyl-10-morfolin-7-okso-2,3-dihydro-7H-pyrido-[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre eller et farmasøytisk akseptabelt salt derav eller et hydrat eller et solvat av denne forbindelse eller av nevnte salt, karakterisert ved at det anvendes tilsvarende substituerte utgangsmaterialer.6. Process for the preparation of a compound according to claim lj which compound is 9-fluoro-3-methyl-10-morpholine-7-oxo-2,3-dihydro-7H-pyrido-[3.2.1-ij]-1, 3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrate or a solvate of this compound or of said salt, characterized in that correspondingly substituted starting materials are used. 7. Fremgangsmåte ved fremstilling av en forbindelse ifølge krav 1, hvilken forbindelse er 10-[3-[etylamino)metyl]-l-pyrrolidinyl)-9-fluor-3-metyl-7-okso-2,3-dihydro-7H-pyrido-[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre eller et farmasøytisk akseptabelt salt derav eller et hydrat eller solvat av denne forbindelse eller av nevnte salt^ k a r a k terisert ved at tilsvarende substituerte utgangsforbindelser anvendes.7. Process for the preparation of a compound according to claim 1, which compound is 10-[3-[ethylamino)methyl]-1-pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H -pyrido-[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt^ characterized in that similarly substituted starting compounds are used. 8. Fremgangsmåte ved fremstilling av en forbindelse ifølge krav 1, hvilken forbindelse er 10-(3-amino-l-pyrrolidinyl)-9-fluor-3-metyl-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre eller et farmasøytisk akseptabelt salt derav eller et hydrat eller et solvat av denne forbindelse eller av nevnte salt^ karakterisert ved at det anvendes tilsvarende substituerte utgangsmaterialer.8. Process for the preparation of a compound according to claim 1, which compound is 10-(3-amino-1-pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[3.2 .1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrate or a solvate of this compound or of said salt^ characterized in that similarly substituted starting materials are used. 9. Fremgangsmåte ved fremstilling av en forbindelse ifølge krav 1, hvilken forbindelse er 9-fluor-3-metyl-10-[3-(metylamino)-1-pyrrolidinyl]-7-okso-2,3-dihydro-7H-pyrido-[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre eller et farmasøytisk akseptabelt salt derav eller et hydrat eller solvat av denne forbindelse eller av nevnte salt, karakterisert ved at tilsvarende substituerte utgangsforbindelser anvendes.9. Process for the preparation of a compound according to claim 1, which compound is 9-fluoro-3-methyl-10-[3-(methylamino)-1-pyrrolidinyl]-7-oxo-2,3-dihydro-7H-pyrido -[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt, characterized in that correspondingly substituted starting compounds are used. 10. Fremgangsmåte ved fremstilling av en forbindelse ifølge krav 1, hvilken forbindelse er 10-[4-(4-aminobenzyl)-1-piperazinyl]-9-fluor-3-metyl-7-okso-2,3-dihydro-7H-pyrido-[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre eller et farmasøytisk akseptabelt salt derav eller et hydrat eller solvat av denne forbindelse eller av nevnte salt; karakterisert ved at tilsvarende substituerte utgangsforbindelser anvendes.10. Process for the preparation of a compound according to claim 1, which compound is 10-[4-(4-aminobenzyl)-1-piperazinyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H -pyrido-[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt; characterized in that correspondingly substituted starting compounds are used. 11. Fremgangsmåte ved fremstilling av en forbindelse ifølge krav 1, hvilken forbindelse er 10-(trans-3-amino-4-metyl-l-pyrrolidinyl)-9-fluor-3-metyl-7-okso-2,3-dihydro-7H-pyrido-[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre eller et farmasøytisk akseptabelt salt derav eller et hydrat eller solvat av denne forbindelse eller av nevnte salt, karakterisert ved at tilsvarende substituerte utgangsforbindelser anvendes.11. Process for the preparation of a compound according to claim 1, which compound is 10-(trans-3-amino-4-methyl-1-pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro -7H-pyrido-[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt, characterized in that correspondingly substituted starting compounds are used . 12. Fremgangsmåte ved fremstilling av en forbindelse ifølge krav 1, hvilken forbindelse er 10-(trans-3-amino-4-metoksy-1-pyrrolidinyl)-9-fluor-3-metyl-7-okso-2,3-dihydro-7H-pyrido[3.2.1-ij]-1,3,4-benzoksadiazin-6-karboksylsyre eller et farmasøytisk akseptabelt salt derav eller et hydrat eller solvat av denne forbindelse eller av nevnte salt^ karakterisert ved at tilsvarende substituerte utgangsforbindelser anvendes.12. Process for the preparation of a compound according to claim 1, which compound is 10-(trans-3-amino-4-methoxy-1-pyrrolidinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro -7H-pyrido[3.2.1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof or a hydrate or solvate of this compound or of said salt^ characterized in that correspondingly substituted starting compounds are used.
NO873816A 1986-09-12 1987-09-11 ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 10-SUBSTITUTED 9-FLUOR-7-OXO-2,3-DIHYDRO-7H-PYRIDO (3.2.1-IJ) -1,3,4-BENZOXADIAZINE-6-CARBOXYLSYL NO169125C (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
NO894109A NO174926C (en) 1986-09-12 1989-10-13 Hydroxyamino oksodihydrokinolinderivater
NO894108A NO171162C (en) 1986-09-12 1989-10-13 Pyrido BENZOKSADIAZINDERIVATER

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP86112619 1986-09-12

Publications (4)

Publication Number Publication Date
NO873816D0 NO873816D0 (en) 1987-09-11
NO873816L NO873816L (en) 1988-03-14
NO169125B true NO169125B (en) 1992-02-03
NO169125C NO169125C (en) 1992-05-13

Family

ID=8195410

Family Applications (1)

Application Number Title Priority Date Filing Date
NO873816A NO169125C (en) 1986-09-12 1987-09-11 ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 10-SUBSTITUTED 9-FLUOR-7-OXO-2,3-DIHYDRO-7H-PYRIDO (3.2.1-IJ) -1,3,4-BENZOXADIAZINE-6-CARBOXYLSYL

Country Status (22)

Country Link
JP (3) JPH0696578B2 (en)
KR (1) KR960002857B1 (en)
CN (1) CN1017800B (en)
AT (1) AT389119B (en)
AU (1) AU602534B2 (en)
CA (1) CA1336905C (en)
CZ (1) CZ281195B6 (en)
DK (1) DK173330B1 (en)
DZ (1) DZ1124A1 (en)
FI (1) FI86428C (en)
HU (1) HU199481B (en)
IE (1) IE61624B1 (en)
IL (1) IL83814A (en)
MC (1) MC1850A1 (en)
MX (1) MX8302A (en)
NO (1) NO169125C (en)
NZ (1) NZ221681A (en)
PH (1) PH23930A (en)
PT (1) PT85686B (en)
SK (1) SK660487A3 (en)
ZA (1) ZA876636B (en)
ZW (1) ZW16387A1 (en)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZW16387A1 (en) * 1986-09-12 1988-05-25 Hoffmann La Roche Tricyclic compounds
JP4820290B2 (en) * 2004-05-13 2011-11-24 第一三共株式会社 Substituted pyrrolidine derivatives
US7563805B2 (en) * 2005-05-19 2009-07-21 Daiichi Pharmaceutical Co., Ltd. Tri-, tetra-substituted-3-aminopyrrolidine derivative
CN101443314B (en) 2006-03-13 2014-04-09 杏林制药株式会社 Aminoquinolones as GSK-3 inhibitors
CN101855228B (en) 2007-09-11 2012-10-24 杏林制药株式会社 Cyanoaminoquinolones and tetrazoloaminoquinolones as GSK-3 inhibitors
EP2203459B1 (en) 2007-09-12 2016-03-16 Kyorin Pharmaceutical Co., Ltd. Spirocyclic aminoquinolones as gsk-3 inhibitors
FR2928150A1 (en) * 2008-02-29 2009-09-04 Vetoquinol Sa Sa NOVEL 7-SUBSTITUTED 3-CARBOXY-OXADIAZINO-QUINOLONES DERIVATIVES, THEIR PREPARATION AND APPLICATION AS ANTI-BACTERIANS
EP2145891A1 (en) * 2008-07-09 2010-01-20 Vetoquinol S.A. 9-substituted-5-carboxy-oxadiazino-quinolone derivatives, their preparation and their application as anti-bacterials
EP2406266B1 (en) 2009-03-11 2013-12-25 Kyorin Pharmaceutical Co., Ltd. 7-cycloalkylaminoquinolones as gsk-3 inhibitors
CN107522718B (en) * 2017-09-14 2019-11-08 浙江国邦药业有限公司 A kind of synthetic method of Marbofloxacin

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZW16387A1 (en) * 1986-09-12 1988-05-25 Hoffmann La Roche Tricyclic compounds

Also Published As

Publication number Publication date
AU602534B2 (en) 1990-10-18
JPH0819120B2 (en) 1996-02-28
NO873816D0 (en) 1987-09-11
HUT47294A (en) 1989-02-28
KR960002857B1 (en) 1996-02-27
NZ221681A (en) 1990-12-21
AU7811487A (en) 1988-03-17
PH23930A (en) 1990-01-23
FI86428C (en) 1992-08-25
PT85686A (en) 1987-10-01
FI873940A (en) 1988-03-13
JPH07138256A (en) 1995-05-30
DK477287A (en) 1988-03-13
CA1336905C (en) 1995-09-05
CN87106838A (en) 1988-05-11
MX8302A (en) 1993-12-01
IL83814A (en) 1991-09-16
IE872444L (en) 1988-03-12
JPH0696578B2 (en) 1994-11-30
CZ660487A3 (en) 1996-04-17
KR880003954A (en) 1988-06-01
FI86428B (en) 1992-05-15
PT85686B (en) 1990-05-31
MC1850A1 (en) 1988-09-30
DK477287D0 (en) 1987-09-11
FI873940A0 (en) 1987-09-11
ATA263887A (en) 1989-03-15
ZA876636B (en) 1988-07-27
NO873816L (en) 1988-03-14
DZ1124A1 (en) 2004-09-13
HU199481B (en) 1990-02-28
CZ281195B6 (en) 1996-07-17
DK173330B1 (en) 2000-07-24
CN1017800B (en) 1992-08-12
NO169125C (en) 1992-05-13
IE61624B1 (en) 1994-11-16
SK278990B6 (en) 1998-05-06
AT389119B (en) 1989-10-25
ZW16387A1 (en) 1988-05-25
JPH07138262A (en) 1995-05-30
JPS63132891A (en) 1988-06-04
SK660487A3 (en) 1998-05-06
JPH0826030B2 (en) 1996-03-13

Similar Documents

Publication Publication Date Title
US4801584A (en) Pyrido(3,2,1-IJ)-1,3,4 benzoxadiazine derivatives
US5371090A (en) Naphthyridonecarboxylic acid derivatives
CA1168241A (en) Naphthyridine derivatives, intermediates thereof and processes for preparation thereof
EP0132845B1 (en) Novel 1,8-naphthyridine derivatives, and process for preparation thereof
AU617735B2 (en) Derivatives of 7-(1-azetidinyl)-1,4-dihydro-4-oxo-3- guinolinecarboxylic acids, their preparation and application as medicines
KR870001693B1 (en) Process for preparing 1,4-dihydro-4-oxo-naphthyridine derivatives
JP2008528604A (en) Antibacterial agent
NO169125B (en) ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 10-SUBSTITUTED 9-FLUOR-7-OXO-2,3-DIHYDRO-7H-PYRIDO (3.2.1-IJ) -1,3,4-BENZOXADIAZINE-6-CARBOXYLSYL
US4473568A (en) Antibacterial thiazolidine or thiomorpholine substituted quinolines
NO862042L (en) ANTIBACTERYLY EFFECTIVE CHINOLONCARBOXYLIC ACID ESTERS.
US4616019A (en) Naphthyridine antibacterial compounds
US4864023A (en) Pyrido(3,2,1-IJ)-1,3,4-benzoxadiazine derivatives
JPH0673056A (en) Quinolinecarboxylic acid derivative and salt thereof
JP2704428B2 (en) Quinolonecarboxylic acid derivative or salt thereof
EP0911336B1 (en) Pyridonecarboxylic acid derivatives and intermediates for the synthesis thereof
US5990122A (en) Quinolone- and naphthyridonecarboxylic acid derivatives
US5703094A (en) Quinolone- and naphthyridonecarboxylic acid derivatives
NO171162B (en) Pyrido BENZOKSADIAZINDERIVATER
JPH05255319A (en) New quinolone derivative or its salt and antibacterial agent containing the compound
CS235545B2 (en) Method of 1-ethyl or vinyl-6-halogen-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine derivatives preparation