NO173547B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE QUINOLONCARBOXYLIC ACID DERIVATIVES - Google Patents

ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE QUINOLONCARBOXYLIC ACID DERIVATIVES Download PDF

Info

Publication number
NO173547B
NO173547B NO90901274A NO901274A NO173547B NO 173547 B NO173547 B NO 173547B NO 90901274 A NO90901274 A NO 90901274A NO 901274 A NO901274 A NO 901274A NO 173547 B NO173547 B NO 173547B
Authority
NO
Norway
Prior art keywords
cyclopropyl
dihydro
oxo
methyl
acid
Prior art date
Application number
NO90901274A
Other languages
Norwegian (no)
Other versions
NO901274D0 (en
NO173547C (en
NO901274L (en
Inventor
Michael Schriewer
Klaus Grohe
Andreas Krebs
Uwe Petersen
Thomas Schenke
Ingo Haller
Karl Georg Metzger
Rainer Endermann
Hans-Joachim Zeiler
Original Assignee
Bayer Ag
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 Bayer Ag filed Critical Bayer Ag
Publication of NO901274D0 publication Critical patent/NO901274D0/en
Publication of NO901274L publication Critical patent/NO901274L/en
Publication of NO173547B publication Critical patent/NO173547B/en
Publication of NO173547C publication Critical patent/NO173547C/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Landscapes

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

Description

Foreliggende oppfinnelse vedrører fremstilling av nye, terapeutisk aktive kinolonkarboksylsyrederivater som i 5-stilling "bærer en metylrest. The present invention relates to the production of new, therapeutically active quinolone carboxylic acid derivatives which carry a methyl residue in the 5-position.

Det er funnet at kinolonkarboksylsyrederivater med formelen It has been found that quinolone carboxylic acid derivatives with the formula

(I) (IN)

hvori in which

R<1> står for cyklopropyl eller 2,4-difluorfenyl, A betyr hydrogen eller fluor, og R<1> stands for cyclopropyl or 2,4-difluorophenyl, A means hydrogen or fluorine, and

R<4> står for R<4> stands for

eller or

og deres farmasøytisk anvendbare salter oppviser en høy antibakteriell virkning, spesielt i det grampositive området. and their pharmaceutically usable salts exhibit a high antibacterial activity, especially in the gram-positive range.

De egner seg følgelig som virksomme stoffer for human- og veterinærmedisin, hvorved det som veterinærmedisin også regnes behandlingen av fisk for behandling eller forebyggelse av bakterielle infeksjoner. They are therefore suitable as active substances for human and veterinary medicine, whereby the treatment of fish for the treatment or prevention of bacterial infections is also considered veterinary medicine.

Ifølge oppfinnelsen oppnår man forbindelsene med formel (I) når man omsetter forbindelsene med formel (II) According to the invention, the compounds of formula (I) are obtained when the compounds of formula (II) are reacted

hvori in which

R<1> og A har betydningen angitt ovenfor, og R<1> and A have the meanings given above, and

X<4> står for halogen, spesielt fluor eller klor, med forbindelser med formel (III) X<4> stands for halogen, especially fluorine or chlorine, with compounds of formula (III)

hvori in which

R<4> har den ovenfor angitte betydningen, R<4> has the meaning given above,

eventuelt i nærvær av syreoppfangende midler og eventuelt avspalter beskyttelsesgrupper som inneholder R<4>, og eventuelt omdanner oppnådde forbindelser til farmasøytisk akseptable salter ved i og for seg kjente fremgangsmåter. optionally in the presence of acid scavengers and optionally cleaves off protective groups containing R<4>, and optionally converts obtained compounds into pharmaceutically acceptable salts by methods known per se.

Anvender man eksempelvis l-cyklopropyl-6,7,8-trifluor-1,4-dihydro-5-metyl-4-okso-3-kinolinkarboksylsyre og 1-metyl-oktahydropyrrolo[3,4-b]pyridin som utgangsstoffer, så kan reaksjonsforløpet gjengis ved følgende formelskjema: Anvender man eksempelvis l-cyklopropyl-7-(2,7-diaza-bicyklo-[3,3,0]okt-7-yl)-6-fluor-l, 4-dihydro-5-metyl-4-okso-3-kinolinkarboksylsyre og etanol/hydrogenklorid som utgangsstoffer, så kan reaksjonsforløpet gjengis ved følgende formel skjema: If, for example, 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid and 1-methyl-octahydropyrrolo[3,4-b]pyridine are used as starting materials, then the course of the reaction can be reproduced by the following formula: For example, 1-cyclopropyl-7-(2,7-diaza-bicyclo-[3,3,0]oct-7-yl)-6-fluoro-1,4-dihydro-5 -methyl-4-oxo-3-quinoline carboxylic acid and ethanol/hydrogen chloride as starting materials, the course of the reaction can be reproduced by the following formula:

De som utgangsstoffer anvendte forbindelsene med formel II er kjente eller kan fremstilles ved kjente fremgangsmåter. Som eksempler kan nevnes: 1-cyklopropyl-6 ,7 ,8-trifluor-1, 4-dihydro-5-metyl-4-okso-3-kinolinkarboksylsyre, The compounds of formula II used as starting materials are known or can be prepared by known methods. Examples include: 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid,

1-cyklopropyl - 6 ,7,8-trifluor-l, 4-dihydro-5-metyl-4-okso-3-kinolinkarboksylsyreetylester, 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid ethyl ester,

6,7-difluor-l-( 4-f luor-f enyl )-l ,4-dihydro-5-metyl-4-okso-3-kinolinkarboksylsyre, 6,7-difluoro-1-(4-fluoro-phenyl)-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid,

6,7-difluor-l-(2, 4-difluor-fenyl)-l,4-dihydro-5-metyl-4-okso-3-kinolinkarboksylsyre. 6,7-difluoro-1-(2,4-difluoro-phenyl)-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid.

7-klor-l-cyklopropyl-6,8-difluor-1,4-dihydro-5-metyl-4-okso-3-kinolinkarboksylsyren er ikke kjent. Den kan fremstilles ifølge følgende reaksjonsskjema: The 7-chloro-1-cyclopropyl-6,8-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid is not known. It can be produced according to the following reaction scheme:

DABCO = 1,4-diazabicyklo[2,2,2]oktan. DABCO = 1,4-diazabicyclo[2,2,2]octane.

Omsetningen av (II) med (III), hvorved forbindelsene (III) også kan anvendes i form av deres hydroklorider, foretas fortrinnsvis i et fortynningsmiddel som dimetylsulfoksyd, N,N-dimetylformamid, N-metylpyrrolidin, heksametyl-fosfor-syretriamid, sulfolan, acetonitril, vann, en alkohol som metanol, etanol, n-propanol, isopropanol, glykolmonometyleter eller pyridin. Videre kan blandinger av disse fortyn-ningsmidlene anvendes. The reaction of (II) with (III), whereby the compounds (III) can also be used in the form of their hydrochlorides, is preferably carried out in a diluent such as dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidine, hexamethyl-phosphoric acid triamide, sulfolane, acetonitrile, water, an alcohol such as methanol, ethanol, n-propanol, isopropanol, glycol monomethyl ether or pyridine. Furthermore, mixtures of these diluents can be used.

Som syrebindende middel kan alle vanlige uorganiske og organiske syrebindingsmidler anvendes. Hertil hører fortrinnsvis alkalihydroksydene, alkalikarbonatene, organiske aminer og amidiner. Som spesielt egnede skal nevnes: trietylamin, 1,4-diazabicyklo[2,2,2]oktan (DABCO), 1,8-diazabicyklo[5,4,0]undec-7-en (DBU) eller overskytende amin As an acid-binding agent, all common inorganic and organic acid-binding agents can be used. These preferably include the alkali hydroxides, alkali carbonates, organic amines and amidines. As particularly suitable should be mentioned: triethylamine, 1,4-diazabicyclo[2,2,2]octane (DABCO), 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) or excess amine

(III). (III).

Reaksjonstemperaturene kan varieres innen et vidt område. Generelt arbeider man mellom 20 og 200°C, fortrinnsvis mellom 80 og 180°C. The reaction temperatures can be varied within a wide range. In general, you work between 20 and 200°C, preferably between 80 and 180°C.

Omsetningen kan gjennomføres ved normaltrykk, eller også ved forhøyet trykk. Generelt arbeider man ved trykk mellom 1 og 100 bar, fortrinnsvis mellom 1 og 10 bar. The turnover can be carried out at normal pressure, or also at elevated pressure. In general, you work at pressures between 1 and 100 bar, preferably between 1 and 10 bar.

Ved gjennomføring av fremgangsmåten ifølge oppfinnelsen anvender man til 1 mol av karboksylsyren (II) 1 til 15, fortrinnsvis 1 til 6 mol av forbindelsen (III). When carrying out the method according to the invention, 1 to 15, preferably 1 to 6, mol of the compound (III) is used for 1 mol of the carboxylic acid (II).

Frie hydroksygrupper kan under omsetningen være beskyttet med en egnet hydroksybeskyttelsesgruppe, f.eks. med tetrahydropy-ranylresten, og etter avslutning av reaksjonen igjen settes fri (se J.F.W. McOmie, "Protective Groups in Organic Chemistry" (1973), side 104). During the reaction, free hydroxy groups can be protected with a suitable hydroxy protecting group, e.g. with the tetrahydropyranyl residue, and after completion of the reaction again set free (see J.F.W. McOmie, "Protective Groups in Organic Chemistry" (1973), page 104).

Frie aminofunksjoner kan under omsetningen være beskyttet med en egnet aminobeskyttelsesgruppe, f.eks. med etoksykarbonyl-eller tert.-butoksykarbonylresten og etter avslutning av reaksjonen igjen settes fri ved behandling med en egnet syre som saltsyre eller trifluoreddiksyre (se Houben-Weyl, "Methoden der organischen Chemie", bind E4 , side 144 (1983); J.F.W. McOmie, "Protective Groups in Organic Chemistry" During turnover, free amino functions can be protected with a suitable amino protecting group, e.g. with the ethoxycarbonyl or tert.-butoxycarbonyl residue and after completion of the reaction is set free again by treatment with a suitable acid such as hydrochloric acid or trifluoroacetic acid (see Houben-Weyl, "Methoden der organischen Chemie", volume E4, page 144 (1983); J.F.W. McOmie , "Protective Groups in Organic Chemistry"

(1973), side 43). (1973), page 43).

Fremstillingen av syreaddisjonssalter av forbindelsene fremstilt ifølge oppfinnelsen foregår på vanlig måte f.eks. ved oppløsning av betainet i overskytende vandig syre og utfelling av saltet med et med vann blandbart organisk oppløsningsmiddel som metanol, etanol, aceton, acetonitril. Man kan også oppvarme ekvivalente mengder betain og syre i vann eller en alkohol som glykolmonometyleter og deretter inndampe til tørrhet eller fra det frasugede utfelte saltet. Som farmasøytisk anvendbare salter forstås eksempelvis saltene av saltsyre, svovelsyre, eddiksyre, glykolsyre, melkesyre, ravsyre, sitronsyre, vinsyre, metansulfonsyre, 4-toluensulfonsyre, galakturonsyre, glukonsyre, embonsyre, glutaminsyre eller asparaginsyre. The preparation of acid addition salts of the compounds prepared according to the invention takes place in the usual way, e.g. by dissolving the betaine in excess aqueous acid and precipitation of the salt with a water-miscible organic solvent such as methanol, ethanol, acetone, acetonitrile. One can also heat equivalent amounts of betaine and acid in water or an alcohol such as glycol monomethyl ether and then evaporate to dryness or from the aspirated precipitated salt. Pharmaceutically applicable salts include, for example, the salts of hydrochloric acid, sulfuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, methanesulfonic acid, 4-toluenesulfonic acid, galacturonic acid, gluconic acid, embonic acid, glutamic acid or aspartic acid.

Alkali- eller jordalkalisaltene av karboksylsyrene fremstilt ifølge oppfinnelsen oppnås eksempelvis ved oppløsning av betainet i underskudd alkali- eller jordalkalilut, filtrering av uoppløst betain og inndampning av filtratet til tørrhet. Farmasøytisk egnede er natrium-, kalium- eller kalsiumsalter. Ved omsetning av et alkali- eller jordalkalisalt med et egnet sølvsalt som sølvnitrat oppnås de tilsvarende sølvsaltene. The alkali or alkaline earth salts of the carboxylic acids produced according to the invention are obtained, for example, by dissolving the betaine in deficit alkali or alkaline earth solution, filtering undissolved betaine and evaporating the filtrate to dryness. Pharmaceutically suitable are sodium, potassium or calcium salts. By reacting an alkali or alkaline earth salt with a suitable silver salt such as silver nitrate, the corresponding silver salts are obtained.

Forbindelsene fremstilt ifølge oppfinnelsen viser ved lav toksisitet et bredt antibakterielt spektrum mot gram-positive og gram-negative kim, spesielt mot enterobakteriaser; fremfor alt mot slike som er resistente mot forskjellige antibiotika, som f.eks. penicilliner, cefalosporiner, aminoglykosider, sulfonamider, tetracykliner. The compounds produced according to the invention show, at low toxicity, a broad antibacterial spectrum against gram-positive and gram-negative germs, especially against enterobacteriases; above all against those that are resistant to various antibiotics, such as e.g. penicillins, cephalosporins, aminoglycosides, sulfonamides, tetracyclines.

Disse verdifulle egenskapene muliggjør deres anvendelse som kjemoterapeutiske virksomme stoffer innen medisinen. These valuable properties enable their use as chemotherapeutic active substances in medicine.

Forbindelsene fremstilt ifølge oppfinnelsen er virksomme mot et meget bredt spektrum av mikroorganismer. Ved deres hjelp kan gram-negative og gram-positive bakterier og bakterielignende mikroorganismer bekjempes samt de sykdommene som fremkalles av disse sykdomsfremkallerene forebygges, forbedres og/eller helbredes. The compounds produced according to the invention are effective against a very broad spectrum of microorganisms. With their help, gram-negative and gram-positive bacteria and bacteria-like microorganisms can be combated and the diseases caused by these pathogens can be prevented, improved and/or cured.

Spesielt virksomme er forbindelsene fremstilt ifølge oppfinnelsen mot bakterier og bakterielignende mikroorganismer. De er følgelig spesielt godt egnede for profylakse og kjemoterapi av lokale og systemiske infeksjoner innenfor human- og veterinærmedisin, som er fremkalt av disse sykdomsfremkallerene. The compounds produced according to the invention are particularly effective against bacteria and bacteria-like microorganisms. They are therefore particularly well suited for the prophylaxis and chemotherapy of local and systemic infections in human and veterinary medicine, which are caused by these pathogens.

Eksempelvis kan lokale og/eller systemiske sykdommer behandles og/eller forhindres, som er forårsaket av følgende sykdomsfremkallere eller av blandinger av følgende syk-domsf remkallere : Gram-positive kokker, f.eks. stafylokokker (Staph. aureus, Staph. epidermidis), og streptokokker (Strept. agalactiae, Strept. faecalis, Strept. pneumoniae, Strept. pyogenes); gram-negative kokker (Neisseria gonorrhoeae) samt gram-negative staver som enterobakteriaser, f.eks. Escheriachia coli, Haemophilus influenzae, Citrobacter (Citrob. freundii, Citrob. divernis), Salmonella og Shigella; videre klebsieller (Klebs. pneumoniae, Klebs. oxytoca), enterobakter (Ent. aerogenes, Ent. agglomerans), Hafnia, Serratia (Serr. marcescens), Proteus (Pr. mirabilis, Pr. rettgeri, Pr. vulgaris), Providencia, Yersinia, samt slekten Acinetobacter. Videre omfatter det antibakterielle spekteret slekten Pseudomonas (Ps. aeruginosa, Ps. maltophilia) samt strengt anaerobe bakterier som f.eks. Bacteroides fragilis, represen-tanter for stammen Peptococcus, Peptostreptococcus samt slekten Clostridium; videre Mykoplasmer (M. pneumoniae, M. hominis, M. urealyticum) samt Mykobakterier, f.eks. Mycobac-terium tuberculosis. For example, local and/or systemic diseases can be treated and/or prevented, which are caused by the following pathogens or by mixtures of the following pathogens: Gram-positive cocci, e.g. staphylococci (Staph. aureus, Staph. epidermidis), and streptococci (Strept. agalactiae, Strept. faecalis, Strept. pneumoniae, Strept. pyogenes); gram-negative cocci (Neisseria gonorrhoeae) as well as gram-negative rods such as enterobacteriases, e.g. Escheriachia coli, Haemophilus influenzae, Citrobacter (Citrob. freundii, Citrob. divernis), Salmonella and Shigella; further klebsiels (Klebs. pneumoniae, Klebs. oxytoca), enterobacters (Ent. aerogenes, Ent. agglomerans), Hafnia, Serratia (Serr. marcescens), Proteus (Pr. mirabilis, Pr. rettgeri, Pr. vulgaris), Providencia, Yersinia , as well as the genus Acinetobacter. Furthermore, the antibacterial spectrum includes the genus Pseudomonas (Ps. aeruginosa, Ps. maltophilia) as well as strictly anaerobic bacteria such as e.g. Bacteroides fragilis, representatives of the tribe Peptococcus, Peptostreptococcus and the genus Clostridium; further Mycoplasmas (M. pneumoniae, M. hominis, M. urealyticum) as well as Mycobacteria, e.g. Mycobacterium tuberculosis.

Listen ovenfor av sykdomsfremkallere er ment som eksempler og må ikke oppfattes som begrensende. Som sykdommer som kan forårsakes ved de nevnte sykdomsfremkallerene eller blan-dingsinfeksjoner og som kan forhindres, forbedres eller helbredes ved hjelp av forbindelsene fremstilt ifølge oppfinnelsen skal eksempelvis nevnes: Infeksjonssykdommer hos mennesker som f.eks. otitis, pharyngitis, pneumonie, peritonitis, pyelonephritis, cystitis, endocarditis, systemiske infeksjoner, bronkitt (akutt, kronisk), septiske infeksjoner, sykdommer i de øvre luftveiene, diffuse Panbronkeolitter, pulmonaert emfysem, dysenteri, enterit, leverabsesser, uretritt, prostatitt, epididymit, gastrointestinale infeksjoner, knoke- og leddinfeksjoner, systisk fibrose, hudinfeksjoner, postopera-tive sårinfeksjoner, absesser, flegmoner, sårinfeksjoner, infiserte forbrenninger, brannsår, infeksjoner i munnområdet, infeksjoner etter tannoperasjoner, osteomylit, septisk artrit, kolesystit, peritonitis med appendicitis, intra-adominale absesser, pankreatitis, sinusitis, mastoiditis, mastitis, tonsillitis, tyfus, meningit og infeksjoner i nervesystemet, salpingnit, endometrit, genitalinfeksjoner, pelveoperitonitis og øyeninfeksjoner. The above list of pathogens is intended as examples and must not be taken as limiting. As diseases which can be caused by the aforementioned pathogens or mixed infections and which can be prevented, improved or cured with the help of the compounds produced according to the invention, the following should be mentioned, for example: Infectious diseases in humans such as e.g. otitis, pharyngitis, pneumonia, peritonitis, pyelonephritis, cystitis, endocarditis, systemic infections, bronchitis (acute, chronic), septic infections, diseases of the upper respiratory tract, diffuse panbronchiolitis, emphysema pulmonary, dysentery, enteritis, liver abscesses, urethritis, prostatitis, epididymitis , gastrointestinal infections, joint and joint infections, cystic fibrosis, skin infections, postoperative wound infections, abscesses, phlegmons, wound infections, infected burns, burns, infections in the mouth area, infections after dental surgery, osteomyelitis, septic arthritis, cholecystitis, peritonitis with appendicitis, intra -abdominal abscesses, pancreatitis, sinusitis, mastoiditis, mastitis, tonsillitis, typhus, meningitis and infections of the nervous system, salpingitis, endometritis, genital infections, pelvic peritonitis and eye infections.

I tillegg til mennesker kan det også behandles bakterielle infeksjoner hos andre spesies. Eksempelvis kan nevnes: Svin: Coli-diarre, enterotoksemi, sepsis, dysenteri, salmonellose, mastitis-metritis-agalaktie-syndron, mastitis; drøvtyggere (okse, sau, geit): diarre, sepsis, bronkoneumoni, salmonellose, pasteurellose, mykoplasmose, genitalinfeksjoner ; In addition to humans, bacterial infections in other species can also be treated. Examples include: Pigs: Coli diarrhoea, enterotoxaemia, sepsis, dysentery, salmonellosis, mastitis-metritis-agalactia syndrome, mastitis; ruminants (ox, sheep, goat): diarrhoea, sepsis, bronchopneumonia, salmonellosis, pasteurellosis, mycoplasmosis, genital infections;

Hest: bronkopneumonier, folelammelse, puerperale og postperpurale infeksjoner, salmonellose; Horse: bronchopneumonias, foal paralysis, puerperal and post-puerperal infections, salmonellosis;

Hund og katt: bronkopneumoni, diarre, dermatit, otitis, urinveisinfeksjoner, prostatit; Dog and cat: bronchopneumonia, diarrhoea, dermatitis, otitis, urinary tract infections, prostatitis;

Fjærfe (høne, kalkun, vaktel, due, prydfugler o.a.): mycoplasmoser, E. coli-infeksjoner, kroniske luftveissykdom-mer, salmonellose, pasteurellose, psittakose. Poultry (hen, turkey, quail, pigeon, ornamental birds etc.): mycoplasmosis, E. coli infections, chronic respiratory diseases, salmonellosis, pasteurellosis, psittacosis.

Videre kan bakterielle infeksjoner ved oppdretts- og hold av nytte- og akvariefisk behandles, hvorved det antibakterielle spekteret i tillegg til de ovenfor nevnte sykdomsfremkallere også kan utvides med fremkallere som f.eks. Pasteurella, Brucella, Campylobacter, Listeria, Erysipelothrix, Corynebak-terien, Borrelia, Treponema, Nocardia, Rickettsien, Yesinia. Furthermore, bacterial infections during the farming and keeping of commercial and aquarium fish can be treated, whereby the antibacterial spectrum can be expanded in addition to the above-mentioned pathogens with pathogens such as e.g. Pasteurella, Brucella, Campylobacter, Listeria, Erysipelothrix, Corynebacteria, Borrelia, Treponema, Nocardia, Rickettsien, Yesinia.

Forbindelsene fremstilt ifølge oppfinnelsen kan følgelig anvendes i farmasøytiske preparater som ved siden av ikke-toksiske, inerte farmasøytisk egnede bærerstoffer inneholder en eller flere av forbindelsene fremstilt ifølge oppfinnelsen, eller som består av et eller flere av de virksomme stoffene fremstilt ifølge oppfinnelsen. The compounds produced according to the invention can consequently be used in pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable carrier substances, contain one or more of the compounds produced according to the invention, or which consist of one or more of the active substances produced according to the invention.

Under ikke-toksiske, inerte farmasøytisk egnede bærerstoffer forstås faste, halvfaste eller flytende fortynningsmidler, fyllstoffer og formuleringshjelpemidler av en hver type. Non-toxic, inert pharmaceutically suitable carriers are understood to mean solid, semi-solid or liquid diluents, fillers and formulation aids of each type.

Som fordelaktige farmasøytiske preparater skal nevnes tabletter, drageer, kapsler, piller, granulater, suppositorer, oppløsninger, suspensjoner og emulsjoner, pastaer, salver, geler, kremer, lotions, pudder og spray. Advantageous pharmaceutical preparations include tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays.

Tabletter, drageer, kapsler, piller og granulater kan ved siden av det eller de virksomme stoffene inneholde de vanlige bærerstoffene som (a) fyll- og drøyemidler, f.eks. stivelse, melkesukker, rørsukker, glukose, mannit og kiselsyre, (b) bindemidler, f.eks. karboksymetylcellulose, alginater, gelatiner, polyvinylpyrrolidon, (c) midler som holder på fuktigheten, f.eks. glyserin, (d) sprengmidler, f.eks. agar-agar, kalsiumkarbonat og natriumkarbonat, (e) oppløsningsfor-sinkere, f.eks. paraffin og (f) resorpsjonsakseleratorer, f.eks. kvaternære ammoniumforbindelser, (g) fuktemidler, f.eks. cetylalkohol, glyserinmonostearat, (h) adsorpsjonsmid-ler, f.eks. kaolin og bentonitt og (i) glidemidler, f.eks. talkum, kalsium- og magnesiumstearat og faste polyetylengly-koler eller blandinger av de under (a) til (i) oppførte stoffene. Tablets, dragées, capsules, pills and granules may, in addition to the active substance(s), contain the usual carrier substances such as (a) fillers and thickeners, e.g. starch, milk sugar, cane sugar, glucose, mannitol and silicic acid, (b) binders, e.g. carboxymethylcellulose, alginates, gelatins, polyvinylpyrrolidone, (c) humectants, e.g. glycerin, (d) explosives, e.g. agar-agar, calcium carbonate and sodium carbonate, (e) dissolution retarders, e.g. paraffin and (f) resorption accelerators, e.g. quaternary ammonium compounds, (g) wetting agents, e.g. cetyl alcohol, glycerin monostearate, (h) adsorbents, e.g. kaolin and bentonite and (i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).

Tablettene, drageene, kapslene, pillene og granulatene kan være utstyrt med de vanlige, eventuelt opakiseringsmiddel-holdige overtrekkene eller omhyllingene og også være slik sammensatt at de avgir det eller de virksomme stoffene bare, eller fortrinnsvis, i en bestemt del av intestinalkanalen eventuelt med forsinkelse, hvorved det som innstøpningsmasser f.eks. kan anvendes polymerstoffer og vokser. The tablets, dragees, capsules, pills and granules can be equipped with the usual, possibly opacifying agent-containing coatings or casings and also be composed in such a way that they release the active substance(s) only, or preferably, in a specific part of the intestinal tract, possibly with a delay , whereby as embedding compounds e.g. polymer substances and waxes can be used.

Det eller de virksomme stoffene kan eventuelt også foreligge i mikroinnkapslet form med et eller flere av de ovenfor angitte bærerstoffene. The active substance(s) may optionally also be available in microencapsulated form with one or more of the carrier substances specified above.

De terapeutisk virksomme forbindelsene skal fortrinnsvis være tilstede i de ovenfor angitte farmasøytiske preparatene i en konsentrasjon på 0,1 til 99,5, fortrinnsvis fra 0,5 til 95 vekt-# av den samlede blandingen. The therapeutically active compounds should preferably be present in the above-mentioned pharmaceutical preparations in a concentration of 0.1 to 99.5, preferably from 0.5 to 95% by weight of the total mixture.

De ovenfor angitte farmasøytiske preparatene kan ved siden av forbindelsene fremstilt ifølge oppfinnelsen også inneholde ytterligere farmasøytisk virksomme stoffer. In addition to the compounds produced according to the invention, the above-mentioned pharmaceutical preparations may also contain further pharmaceutically active substances.

Fremstillingen av de ovenfor angitte farmasøytiske preparatene foregår på vanlig måte ved kjente fremgangsmåter, f.eks. ved blanding av det eller de virksomme stoffene med bærer-stof f ene . The production of the above-mentioned pharmaceutical preparations takes place in the usual way by known methods, e.g. by mixing the active substance(s) with the carrier substance.

Generelt har det både innenfor human- og også innenfor veterinærmedisinen vist seg fordelaktig å administrere det eller de virksomme stoffene i samlede mengder på 0,5 til 500, fortrinnsvis 5 til 100 mg/kg kroppsvekt, i løpet av 24 timer, eventuelt i form av flere enkeltadministreringer, for å oppnå de ønskede resultatene. Enkeltadministreringene inneholder det eller de virksomme stoffene i mengder på fortrinnsvis 1 til 80, spesielt 3 til 30 mg/kg kroppsvekt. Det kan imidlertid være påkrevet å avvike fra de angitte doseringene, avhengig av type og kroppsvekt for behandlings-objektet, typen og alvoret av sykdomstilstanden, typen preparat og tilførsel av legemidlet samt det tidsrommet hhv. intervallet hvorunder administreringen foregår. In general, both within human and also within veterinary medicine, it has proven advantageous to administer the active substance(s) in total amounts of 0.5 to 500, preferably 5 to 100 mg/kg body weight, within 24 hours, possibly in the form of several single administrations, to achieve the desired results. The single administrations contain the active substance or substances in amounts of preferably 1 to 80, especially 3 to 30 mg/kg body weight. However, it may be necessary to deviate from the indicated dosages, depending on the type and body weight of the treatment object, the type and severity of the disease state, the type of preparation and administration of the medicine as well as the time period or the interval during which the administration takes place.

Følgelig kan det i noen tilfelle være tilstrekkelig å anvende mindre enn de ovenfor angitte mengdene virksomt stoff, mens i andre tilfeller de ovenfor angitte mengdene virksomt stoff må overskrides. Fastleggelsen av den i et hvert tilfelle påkrevede optimale doseringen og tilførselsmåten for det virksomme stoffet kan lett utføres av en hver fagmann på bakgrunn av hans fagkunnskap. Consequently, in some cases it may be sufficient to use less than the amounts of active substance indicated above, while in other cases the amounts of active substance indicated above must be exceeded. The determination of the optimal dosage required in each case and the method of delivery for the active substance can easily be carried out by each expert on the basis of his professional knowledge.

De nye forbindelsene kan tilføres i vanlige konsentrasjoner og preparater sammen med foret hhv. med forpreparatene eller med drikkevannet. Derved kan en infeksjon med gram-negative eller gram-positive bakterier forhindres, forbedres og/eller helbredes og det kan derved oppnås en fremmelse av veksten og en forbedring av utnyttelsen av foret. The new compounds can be added in usual concentrations and preparations together with the feed or with the preparations or with the drinking water. Thereby, an infection with gram-negative or gram-positive bacteria can be prevented, improved and/or cured and growth promotion and an improvement in the utilization of the feed can thereby be achieved.

Den minimale hemmekonsentrasjonen (MHK) ble bestemt ved rekkefortynningsfremgangsmåten på iso-sensitest Agar (oksoid). For hvert undersøkt stoff ble det fremstilt en rekke agarplater som inneholdt den dobbelte fortynningen, dvs. avtagende konsentrasjoner av det virksomme stoffet. Agarplatene ble podet med en Multipoint-inokulator (Denley). For poding ble det anvendt kulturer av fremkallere som hadde stått over natten som på forhånd var fortynnet på en slik måte at hvert podepunkt inneholdt ca. IO<4> kolonidannende partikler. De podede agarplatene ble dyrket ved 37°C, og kimveksten ble avlest etter ca. 20 timer. MEK-verdien The minimal inhibitory concentration (MIC) was determined by the serial dilution method on iso-sensitest Agar (oxoid). For each investigated substance, a number of agar plates containing the double dilution, i.e. decreasing concentrations of the active substance, were prepared. The agar plates were inoculated with a Multipoint inoculator (Denley). For inoculation, cultures of developers that had stood overnight were used, which had previously been diluted in such a way that each inoculation point contained approx. IO<4> colony-forming particles. The inoculated agar plates were grown at 37°C, and the germ growth was read after approx. 20 hours. The MEK value

(pg/ml) gir den laveste konsentrasjonen av virksomt stoff, hvorved ingen kimvekst kan observeres med det blotte øye. (pg/ml) gives the lowest concentration of active substance, whereby no germ growth can be observed with the naked eye.

Eksempel A Example A

7-klor-l-cyklopropyl-6,8-difluor-1,4-dihydro-5-metyl-4-okso-3-kinolinkarboksylsyre 7-chloro-1-cyclopropyl-6,8-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid

8,0 g l-cyklopropyl-5,6,7-8-tetrafluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyre og 7,9 ml tionylklorid ble kokt inntil ingen gass oppsto lenger. Deretter ble det inndampet i vakuum. Resten ble tilsatt 50 ml etanol og kokt i 2 timer. Det ble avkjølt ved romtemperatur og det utfelte faste stoffet ble isolert. 8.0 g of 1-cyclopropyl-5,6,7-8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 7.9 ml of thionyl chloride were boiled until no more gas was produced. It was then evaporated in vacuo. The residue was added to 50 ml of ethanol and boiled for 2 hours. It was cooled at room temperature and the precipitated solid was isolated.

Utbytte: 8,6 g 7-klor-l-cyklopropyl-5,6,8-trifluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyreetylester Smeltepunkt: 166-168°C. Yield: 8.6 g 7-chloro-1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester Melting point: 166-168°C.

I 50 ml absolutt dioksan anbringes 1,6 ml (0,015 mol) cyanoeddiksyreetylester og det tilsettes deretter ved 20°C 0,58 g natriumhydrid (80$). Etter 30 minutter tilsettes 3,45 g (0,01 mol) stoff fra a). Deretter kokes i 6 timer under tilbakeløp. Etter avkjøling til 20°C fortynnes med vann og det surgjøres med saltsyre. Det faste stoffet isoleres, tørkes og omkrystalliseres fra isopropanol. 1.6 ml (0.015 mol) of cyanoacetic acid ethyl ester is placed in 50 ml of absolute dioxane and 0.58 g of sodium hydride (80$) is then added at 20°C. After 30 minutes, 3.45 g (0.01 mol) of substance from a) are added. Then boil for 6 hours under reflux. After cooling to 20°C, dilute with water and acidify with hydrochloric acid. The solid is isolated, dried and recrystallized from isopropanol.

Utbytte: 2,3 g 7-klor-5-(cyano-etoksykarbonylmetyl)-l-cyklopropyl-6,8-difluor-1,4-dihydro-4-okso-3-kinolinkarboksylsyreetylester Yield: 2.3 g of 7-chloro-5-(cyano-ethoxycarbonylmethyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester

Smeltepunkt: 156-57°C. Melting point: 156-57°C.

2,3 g stoff fra b) oppvarmes sammen med 6 ml eddiksyre, 5 ml vann og 0,5 ml svovelsyre i 4 timer til 140°C. Det avkjøles til 20°C og fortynnes med vann. Det faste stoffet isoleres, vaskes med vann og tørkes. 2.3 g of substance from b) is heated together with 6 ml of acetic acid, 5 ml of water and 0.5 ml of sulfuric acid for 4 hours at 140°C. It is cooled to 20°C and diluted with water. The solid is isolated, washed with water and dried.

Utbytte: 1,6 g 5-karboksymetyl-7-klor-l-cyklopropyl-6,8-difluor-1 , 4 -dihydro -4 -okso-3-kinol inkarboksyl-syre Yield: 1.6 g of 5-carboxymethyl-7-chloro-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinol incarboxylic acid

Smeltepunkt: 236-8°C (D). Melting point: 236-8°C (D).

Analyse: Analysis:

1,0 g (2,8 mmol) stoff fra c) og 0,9 g (8,4 mmol ) 1,4-diazabicyklo[2,2,2]oktan oppvarmes i 3 timer i 20 ml dimetylsulfoksyd til 140°C. Deretter fjernes oppløsningsmid-let i høyvakuum og resten kromatograferes på kiselgel (elueringsmiddel: metylenklorid/metanol 99/1). 1.0 g (2.8 mmol) of substance from c) and 0.9 g (8.4 mmol) of 1,4-diazabicyclo[2,2,2]octane are heated for 3 hours in 20 ml of dimethylsulfoxide to 140°C . The solvent is then removed under high vacuum and the residue is chromatographed on silica gel (eluent: methylene chloride/methanol 99/1).

Utbytte: 0,2 g 7-klor-l-cyklopropyl-6,8-difluor-1,4-dihydro-5-metyl-4-okso-3-kinolinkarboksylsyre Smeltepunkt: 195-7°C. Yield: 0.2 g of 7-chloro-1-cyclopropyl-6,8-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid Melting point: 195-7°C.

Eksempel 1 Example 1

0,56 g (2 mmol) l-cyklopropyl-6,7-difluor-1,4-dihydro-5-metyl-4-okso-3-kinolinkarboksylsyre oppvarmes med 0,384 g (3 mmol) 2,8-diazabicyklo[4,3,0]nonan og 0,672 g (6 mmol) 1,4-diazabicyklo[2,2,2]oktan i 3,5 ml dimetylsulfoksyd i 2 timer til 140°C. Etter avkjøling fjernes DMS0 i høyvakuum. Resten opptas med acetonitril. Det faste stoffet fraskilles, vaskes med acetonitril og tørkes ved 60-80°C. 0.56 g (2 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid is heated with 0.384 g (3 mmol) of 2,8-diazabicyclo[4 ,3,0]nonane and 0.672 g (6 mmol) of 1,4-diazabicyclo[2,2,2]octane in 3.5 ml of dimethylsulfoxide for 2 hours at 140°C. After cooling, the DMS0 is removed under high vacuum. The residue is taken up with acetonitrile. The solid is separated, washed with acetonitrile and dried at 60-80°C.

Utbytte: 0,7 g l-cyklopropyl-7-(2,8-diazabicyklo-[4,3, 0]non-8-yl )-6-fluor-1,4-dihydro-5-metyl-4-okso-3-klnolinkarboksylsyre Yield: 0.7 g of 1-cyclopropyl-7-(2,8-diazabicyclo[4,3,0]non-8-yl)-6-fluoro-1,4-dihydro-5-methyl-4-oxo -3-Chlorolinecarboxylic acid

Smeltepunkt: 174-6°C under dekomponering. Melting point: 174-6°C during decomposition.

Eksempel 2 Example 2

0,28 g (1 mmol) l-cyklopropyl-6,7-difluor-1,4-dihydro-5-metyl-4-okso-3-kinolinkarboksylsyre oppvarmes i 3,5 ml dimetylsulfoksyd med 0,19 g (1,5 mmol) 2-oksa-5,8-diazabicyklo[4,3,0]nonan og 0,34 g (3 mmol) 1,4-diazabicyklo-[2,2,2]oktan i 2 timer til 140°C. Dimetylsulfoksydet avdestilleres i høyvakuum. Resten utrøres med acetonitril og faststoffet isoleres. 0.28 g (1 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid is heated in 3.5 ml of dimethyl sulfoxide with 0.19 g (1, 5 mmol) 2-oxa-5,8-diazabicyclo[4,3,0]nonane and 0.34 g (3 mmol) 1,4-diazabicyclo-[2,2,2]octane for 2 hours at 140°C . The dimethyl sulphoxide is distilled off under high vacuum. The residue is stirred with acetonitrile and the solid is isolated.

Utbytte: 0,27 g l-cyklopropyl-6-fluor-1,4-dihydro-5-metyl-7-(2-oksa-5,8-diazabicyklo[4,3 ,0]non-8-yl)-4-okso-3-kinolinkarboksylsyre Yield: 0.27 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7-(2-oxa-5,8-diazabicyclo[4,3,0]non-8-yl)- 4-oxo-3-quinolinecarboxylic acid

Smeltepunkt: 273-5°C. Melting point: 273-5°C.

Eksempel 3 Example 3

0,14 g (0,5 mmol) 1-cyklopropyl-6,7-difluor-1,4-dihydro-5-metyl-4-okso-3-klnolinkarboksylsyre oppvarmes i 3,5 ml dimetylsulfoksyd med 0,084 g (0,75 mmol) 2,7-diazabicyklo-[3,3,0]oktan og 0,17 g (1,5 mmol) 1,4-diazabicyklo[2,2,2]-oktan i 2 timer til 140°C. Deretter avdestilleres dimetylsulfoksyd i høyvakuum. Resten tilsettes acetonitril hvorved det dannes et faststoff. 0.14 g (0.5 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-chlorolinecarboxylic acid is heated in 3.5 ml of dimethylsulfoxide with 0.084 g (0, 75 mmol) 2,7-diazabicyclo-[3,3,0]octane and 0.17 g (1.5 mmol) 1,4-diazabicyclo[2,2,2]-octane for 2 hours at 140°C. Dimethyl sulfoxide is then distilled off in high vacuum. Acetonitrile is added to the residue, whereby a solid is formed.

Utbytte: 0,15 g l-cyklopropyl-7-(2,7-diazabicyklo-[3,3,0] okt-7-yl)-6-fluor-1,4-dihydro-5-metyl-4-okso-3-kinolinkarboksylsyre Yield: 0.15 g of 1-cyclopropyl-7-(2,7-diazabicyclo-[3,3,0]oct-7-yl)-6-fluoro-1,4-dihydro-5-methyl-4-oxo -3-quinoline carboxylic acid

Smeltepunkt: 232-4°C under dekomponering. Melting point: 232-4°C during decomposition.

Eksempel 4 Example 4

0,28 g (1 mmol) l-cyklopropyl-6,7-difluor-1,4-dihydro-5-metyl-4-okso-3-kinolinkarboksylsyre oppvarmes i 3,5 ml dimetylsulfoksyd med 0,17 g (1,5 mmol) 1,4-diazabicyklo-[3,2,l]oktan og 0,34 g (3 mmol) 1,4-diazabicyklo[2,2,2]oktan i 2 timer til 140°C. Etter fjernelse av oppløsningsmidlet i høyvakuum utrøres resten med acetonitril og faststoffet isoleres. 0.28 g (1 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid is heated in 3.5 ml of dimethyl sulfoxide with 0.17 g (1, 5 mmol) 1,4-diazabicyclo[3,2,1]octane and 0.34 g (3 mmol) 1,4-diazabicyclo[2,2,2]octane for 2 hours at 140°C. After removing the solvent under high vacuum, the residue is stirred with acetonitrile and the solid is isolated.

Utbytte: 0,24 g l-cyklopropyl-7-(1,4-diazabicyklo-[3,2,1] okt-4-yl)-6-fluor-l,4-dihydro-5-metyl-4-okso-3-kinolinkarboksylsyre Yield: 0.24 g of 1-cyclopropyl-7-(1,4-diazabicyclo-[3,2,1]oct-4-yl)-6-fluoro-1,4-dihydro-5-methyl-4-oxo -3-quinoline carboxylic acid

Smeltepunkt: 274-76°C under dekomponering. Melting point: 274-76°C during decomposition.

Eksempel B Example B

6 ,7-difluor-l-(2,4-difluor-fenyl)-l,4-dihydro-5-metyl-4-okso-3-kinolon-karboksylsyre 21 g 3-etoksy-2-(2,4,5-trifluor-6-metyl-benzoyl)-akryl-syreetylester anbringes i 55 ml etanol. Under avkjøling tilsettes dråpevis 9,4 g 2,4-difluoranilin. Deretter omrøres 1 time ved 25°C. Det tilsettes deretter 55 ml vann og det utfelte faste stoffet isoleres. 6,7-difluoro-1-(2,4-difluoro-phenyl)-1,4-dihydro-5-methyl-4-oxo-3-quinolone-carboxylic acid 21 g 3-ethoxy-2-(2,4, 5-trifluoro-6-methyl-benzoyl)-acrylic acid ethyl ester is placed in 55 ml of ethanol. During cooling, 9.4 g of 2,4-difluoroaniline are added dropwise. Then stir for 1 hour at 25°C. 55 ml of water is then added and the precipitated solid is isolated.

Utbytte: 25 g 3-(2,4-difluorfenylamino)-2-(2,4,5-trifluor-6-metyl-benzoyl)-akrylsyreetylester Smeltepunkt: 109-10°C. Yield: 25 g 3-(2,4-difluorophenylamino)-2-(2,4,5-trifluoro-6-methyl-benzoyl)-acrylic acid ethyl ester Melting point: 109-10°C.

12,5 g stoff fra a) og 5,1 g kaliumkarbonat oppvarmes i 60 ml dimetylformamid i 4 timer til 140"C. Etter avkjøling til romtemperatur fortynnes med vann. Det utfelte faste stoffet isoleres og tørkes. 12.5 g of substance from a) and 5.1 g of potassium carbonate are heated in 60 ml of dimethylformamide for 4 hours to 140°C. After cooling to room temperature, dilute with water. The precipitated solid is isolated and dried.

Utbytte: 11,3 g 6,7-difluor-l-(2,4-difluorfenyl)-l,4-dihydro-5-metyl-4-okso-3-kinolinkarboksylsyreetylester Yield: 11.3 g 6,7-difluoro-1-(2,4-difluorophenyl)-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid ethyl ester

Smeltepunkt: 157-9"C. Melting point: 157-9"C.

11,2 g stoff fra b), 70 ml eddiksyre, 70 ml vann og 3,5 ml svovelsyre oppvarmes i 4 timer til 140°C. Etter avkjøling til romtemperatur fortynnes med vann. Det faste stoffet isoleres og tørkes. Det oppnås 10,3 g av forbindelsen i overskriften. 11.2 g of substance from b), 70 ml of acetic acid, 70 ml of water and 3.5 ml of sulfuric acid are heated for 4 hours to 140°C. After cooling to room temperature, dilute with water. The solid is isolated and dried. 10.3 g of the title compound are obtained.

Smeltepunkt: 277-8°C. Melting point: 277-8°C.

Eksempel 5 Example 5

0,6 g stoff fra eksempel B, 0,57 g 1,4-diazabicyklo[2,2,2]-oktan og 0,25 g 2,8-diazabicyklo[4,3, Ojnonan i 6 ml DMSO omrøres ved romtemperatur inntil det i tynnsjiktkromatogram-met ikke lenger kan påvises utgangsmaterlale. Deretter inndampes i vakuum. Resten blandes med vann og det faste stoffet isoleres. 0.6 g of substance from example B, 0.57 g of 1,4-diazabicyclo[2,2,2]-octane and 0.25 g of 2,8-diazabicyclo[4,3,Ojnonane in 6 ml of DMSO are stirred at room temperature until starting material can no longer be detected in the thin-layer chromatogram. It is then evaporated in a vacuum. The residue is mixed with water and the solid is isolated.

Utbytte: 0,6 g 7-(2,8-diazabicyklo[4,3,0]non-8-yl )-l-( 2 , 4-dif luorfenyl )-6-f luor-1,4-dihydro-5-metyl-4-okso-3-kinolinkarboksylsyre Yield: 0.6 g of 7-(2,8-diazabicyclo[4,3,0]non-8-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro- 5-methyl-4-oxo-3-quinolinecarboxylic acid

Smeltepunkt: 147-8°C. Melting point: 147-8°C.

Claims (5)

1. Analogifremgangsmåte for fremstilling av terapeutisk aktive kinolonkarboksylsyrederivater med formelen (I) hvori R<*> står for cyklopropyl eller 2 ,4-difluorfenyl, A betyr hydrogen eller fluor, og R<4> står for eller samt farmasøytisk anvendbare salter derav, karakterisert ved at at man omsetter forbindelser med formelen (II) hvori R<1> og A har betydningen angitt ovenfor, og X<4> står for halogen, spesielt fluor eller klor, med forbindelser med formel (III) hvori R<4> har den ovenfor angitte betydningen, eventuelt i nærvær av syreoppfangende midler og eventuelt avspalter beskyttelsesgrupper som inneholder R<4>, og eventuelt omdanner oppnådde forbindelser til farmasøytisk akseptable salter ved i og for seg kjente fremgangsmåter.1. Analogous process for the preparation of therapeutically active quinolone carboxylic acid derivatives of the formula (I) in which R<*> stands for cyclopropyl or 2,4-difluorophenyl, A means hydrogen or fluorine, and R<4> stands for or as well as pharmaceutically usable salts thereof, characterized in that compounds of the formula (II) are reacted in which R<1> and A have the meanings given above, and X<4> stands for halogen, especially fluorine or chlorine, with compounds of formula (III) in which R<4> has the meaning given above, optionally in the presence of acid scavengers and optionally cleaves off protective groups containing R<4>, and optionally converts obtained compounds into pharmaceutically acceptable salts by methods known per se. 2. Analogifremgangsmåte ifølge krav 1 for fremstilling av 1-cyklopropyl-7-(2,8-diazabicyklo[4,3,0]non-8-yl)-6-fluor-1,4-dihydro-5-metyl-4-okso-3-kinolinkarboksylsyre, karakterisert ved at tilsvarende utgangs-materialer anvendes.2. Analogous process according to claim 1 for the preparation of 1-cyclopropyl-7-(2,8-diazabicyclo[4,3,0]non-8-yl)-6-fluoro-1,4-dihydro-5-methyl-4-oxo -3-quinoline carboxylic acid, characterized in that corresponding starting materials are used. 3. Analogifremgangsmåte ifølge krav 1 for fremstilling av 1-cyklopropyl-6-fluor-l , 4-dihydro-5-metyl-7-(2-oksa-5 ,8-diazabicyklo[4,3,0]non-8-yl)-4-okso-3-kinolinkarboksylsyre, karakterisert ved at tilsvarende utgangs-materialer anvendes.3. Analogous process according to claim 1 for the production of 1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7-(2-oxa-5,8-diazabicyclo[4,3,0]non-8-yl) -4-oxo-3-quinoline carboxylic acid, characterized in that corresponding starting materials are used. 4. Analogifremgangsmåte ifølge krav 1 for fremstilling av 1-cyklopropyl-7-(2,7-diazabicyklo[3,3,0]okt-7-yl)-6-fluor-1,4-dihydro-5-metyl-4-okso-3-kinolinkarboksylsyre, karakterisert ved at tilsvarende utgangs-materialer anvendes.4. Analogous process according to claim 1 for the preparation of 1-cyclopropyl-7-(2,7-diazabicyclo[3,3,0]oct-7-yl)-6-fluoro-1,4-dihydro-5-methyl-4-oxo -3-quinoline carboxylic acid, characterized in that corresponding starting materials are used. 5. Analogifremgangsmåte ifølge krav 1 for fremstilling av 1-cyklopropyl-7-(l,4-diazabicyklo[3,2,l]okt-4-yl )-6-fluor-1,4-dihydro-5-metyl-4-okso-3-kino1inkarboksylsyre, karakterisert ved at tilsvarende utgangs-materialer anvendes.5. Analogous process according to claim 1 for the preparation of 1-cyclopropyl-7-(1,4-diazabicyclo[3,2,1]oct-4-yl)-6-fluoro-1,4-dihydro-5-methyl-4-oxo -3-quinone carboxylic acid, characterized in that corresponding starting materials are used.
NO901274A 1989-04-03 1990-03-20 Analogous Procedures for the Preparation of Therapeutically Active Quinolone Carboxylic Acid Derivatives NO173547C (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE3910663A DE3910663A1 (en) 1989-04-03 1989-04-03 5-ALKYLCHINOLON CARBONIC ACIDS

Publications (4)

Publication Number Publication Date
NO901274D0 NO901274D0 (en) 1990-03-20
NO901274L NO901274L (en) 1990-10-04
NO173547B true NO173547B (en) 1993-09-20
NO173547C NO173547C (en) 1993-12-29

Family

ID=6377683

Family Applications (1)

Application Number Title Priority Date Filing Date
NO901274A NO173547C (en) 1989-04-03 1990-03-20 Analogous Procedures for the Preparation of Therapeutically Active Quinolone Carboxylic Acid Derivatives

Country Status (16)

Country Link
EP (1) EP0391132A1 (en)
JP (1) JP3046035B2 (en)
KR (1) KR0156245B1 (en)
CN (1) CN1035945C (en)
AU (1) AU638005B2 (en)
CA (1) CA2013449C (en)
DD (1) DD298400A5 (en)
DE (1) DE3910663A1 (en)
FI (1) FI901615A0 (en)
HU (2) HUT58056A (en)
IL (1) IL93954A0 (en)
NO (1) NO173547C (en)
NZ (1) NZ233142A (en)
PH (1) PH27364A (en)
PT (1) PT93639A (en)
ZA (1) ZA902510B (en)

Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4920120A (en) * 1988-01-25 1990-04-24 Warner-Lambert Company Antibacterial agents
MY105136A (en) * 1988-04-27 1994-08-30 Daiichi Seiyaku Co Optically active pyridonecarboxylic acid derivatives.
DD285601A5 (en) * 1988-07-15 1990-12-19 Bayer Ag,De PROCESS FOR PREPARING 7- (1-PYRROLIDINYL) -3-CHINOLONE AND NAPHTHYRIDONE CARBOXYLIC ACID DERIVATIVES
US5241076A (en) * 1989-04-17 1993-08-31 Bayer Aktiengesellschaft 1,4-diazatricyclo [6.3.0.0]undecanes
US5177210A (en) * 1989-04-17 1993-01-05 Bayer Aktiengesellschaft Preparation of 2,7-diazabicyclo(3.3.0)octanes
EP0393424B1 (en) * 1989-04-17 1995-09-27 Bayer Ag Process for the preparation of 2,7-Diazabicyclo(3.3.O)octanes
WO1992021659A1 (en) * 1991-05-28 1992-12-10 Daiichi Pharmaceutical Co., Ltd. Pyridonecarboxylic acid derivative
DE4120646A1 (en) * 1991-06-22 1992-12-24 Bayer Ag 7-ISOINDOLINYL-CHINOLONE AND NAPHTHYRIDONE CARBONIC ACID DERIVATIVES
TW209865B (en) * 1992-01-10 1993-07-21 Bayer Ag
KR960003611B1 (en) * 1992-07-23 1996-03-20 재단법인 한국화학연구소 New diazabicyclo alkene derivatives and the preparation process thereof
DE4234078A1 (en) * 1992-10-09 1994-04-14 Bayer Ag Quinolonecarboxylic acids
DE4234330A1 (en) * 1992-10-12 1994-04-14 Bayer Ag Quinolonecarboxylic acids
JP3268098B2 (en) * 1992-12-25 2002-03-25 第一製薬株式会社 Bicyclic cyclic amine derivative
AU4272793A (en) * 1993-04-24 1994-11-21 Korea Research Institute Of Chemical Technology Novel quinolone carboxylic acid derivatives and process for preparing the same
DE4329600A1 (en) * 1993-09-02 1995-03-09 Bayer Ag Pyrido [1,2,3-d, e] [1,3,4] benzoxadiazine derivatives
DE4339134A1 (en) * 1993-11-16 1995-05-18 Bayer Ag 1- (2-fluorocyclopropyl) quinolone and naphthyridonecarboxylic acid derivatives
DE4408212A1 (en) * 1994-03-11 1995-09-14 Bayer Ag 5-vinyl and 5-ethynyl quinolone and naphthyridone carboxylic acids
DE19546249A1 (en) * 1995-12-12 1997-06-19 Bayer Ag New crystal modification of 1-cyclopropyl-7 - ([S, S] -2,8-diazabicyclo [4,3,0] non-8-yl) -6-fluoro-1,4-dihydro-8-methoxy-4 -oxo-3-quinoline carboxylic acid hydrochloride (CDCH), process for its preparation and pharmaceutical preparations containing it
CZ291251B6 (en) * 1996-02-23 2003-01-15 Bayer Aktiengesellschaft Optionally substituted 8-cyan-1-cyclopropyl-7-(2,8-diazabicyclo-[4,3,0]-nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acids and their derivatives, process of their preparation, medicaments containing these compounds and their use
DE19633805A1 (en) * 1996-02-23 1997-08-28 Bayer Ag Optionally substituted 8-cyano-l-cyclopropyl-7- (2,8-diazabicyclo- [4.3.0] -nonan-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids and their derivatives
DE19652239A1 (en) 1996-12-16 1998-06-18 Bayer Ag Use of 7- (2-oxa-5,8-diazabicyclo [4.3.0] non-8-yl) -quinolone and naphthyridonecarboxylic acid derivatives for the therapy of Helicobacter pylori infections and the associated gastroduodenal diseases
DE19854356A1 (en) * 1998-11-25 2000-05-31 Bayer Ag Crystal modification A of 8-cyan-1-cyclopropyl-7- (1S, 6S-2,8-diazabicyclo- / 4.3.0 / nonan-8-yl) -6-fluoro-1,4-dihydro-4-oxo 3-quinoline carboxylic acid
DE19854357A1 (en) * 1998-11-25 2000-05-31 Bayer Ag Semi-hydrochloride of 8-cyano-1-cyclopropyl-7- (1S, 6S-2,8-diazabicyclo / 4.3.0 / -nonan-8-yl) -6-fluoro-1,4-dihydro-4-oxo -3-quinoline carboxylic acid
DE19854355A1 (en) * 1998-11-25 2000-05-31 Bayer Ag Crystal modification B of 8-cyan-1-cyclopropyl-7- (1S, 6S-2,8-diazabicyclo- / 4.3.O / nonan-8-yl) -6-fluoro-1,4-dihydro-4-oxo 3-quinoline carboxylic acid
EP1551843A1 (en) * 2002-09-10 2005-07-13 Pfizer Products Inc. Diazabicyclic compounds useful in the treatment of cns and other disorders
WO2005026147A1 (en) 2003-09-10 2005-03-24 Kyorin Pharmaceutical Co., Ltd. 7-(4-substituted 3- cyclopropylaminomethyl-1­ pyrrolidinyl) quinolonecarboxylic acid derivative
US8222407B2 (en) 2007-05-24 2012-07-17 Kyorin Pharmaceutical Co., Ltd. Mutilin derivative having heterocyclic aromatic ring carboxylic acid structure in substituent at 14-position
CN101718743B (en) * 2009-11-30 2013-03-20 宁波大学 Method for preparing mixed conductor dense diffusion barrier-type oxygen sensor

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3522405A1 (en) * 1985-06-22 1987-01-02 Bayer Ag 1,8-BRIDGED 4-CHINOLON-3-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE MEDICINAL PRODUCTS CONTAINING THE SAME AND THE USE THEREOF FOR THE PRODUCTION OF MEDICINAL PRODUCTS
DE3543513A1 (en) * 1985-12-10 1987-06-11 Bayer Ag ENANTIOMER-PURE 1,8-BRIDGED 4-CHINOLON-3-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE MEDICINAL PRODUCTS CONTAINING THEM AND THEIR USE FOR THE PRODUCTION OF MEDICINAL PRODUCTS
DE3601567A1 (en) * 1986-01-21 1987-07-23 Bayer Ag 7- (AZABICYCLOALKYL) -CHINOLONCARBONIC ACID AND -NAPHTHYRIDON-CARBONIC ACID DERIVATIVES
DE3702393A1 (en) * 1987-01-28 1988-08-11 Bayer Ag 8-CYANO-1-CYCLOPROPYL-1,4-DIHYDRO-4-OXO- 3-CHINOLINE CARBONIC ACIDS, METHOD FOR THEIR PRODUCTION AND ANTIBACTERIAL AGENTS CONTAINING THEM
US5563138A (en) * 1987-04-16 1996-10-08 Otsuka Pharmaceutical Company, Limited Benzoheterocyclic compounds
US4920120A (en) * 1988-01-25 1990-04-24 Warner-Lambert Company Antibacterial agents

Also Published As

Publication number Publication date
CA2013449C (en) 2001-01-02
CN1046162A (en) 1990-10-17
PH27364A (en) 1993-06-21
NO901274D0 (en) 1990-03-20
NO173547C (en) 1993-12-29
PT93639A (en) 1990-11-20
CA2013449A1 (en) 1990-10-03
NO901274L (en) 1990-10-04
HUT56563A (en) 1991-09-30
ZA902510B (en) 1991-01-30
KR900016186A (en) 1990-11-12
EP0391132A1 (en) 1990-10-10
DE3910663A1 (en) 1990-10-04
AU5231790A (en) 1990-10-04
JPH02289583A (en) 1990-11-29
HUT58056A (en) 1992-01-28
HU902055D0 (en) 1990-08-28
CN1035945C (en) 1997-09-24
HU204811B (en) 1992-02-28
DD298400A5 (en) 1992-02-20
NZ233142A (en) 1992-09-25
AU638005B2 (en) 1993-06-17
IL93954A0 (en) 1990-12-23
FI901615A0 (en) 1990-03-30
JP3046035B2 (en) 2000-05-29
KR0156245B1 (en) 1998-11-16
HU912263D0 (en) 1991-12-30

Similar Documents

Publication Publication Date Title
NO173547B (en) ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE QUINOLONCARBOXYLIC ACID DERIVATIVES
CA1314544C (en) 8-cyano-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinoline- carboxylic acids, processes for their preparation and antibacterial agents containing these compounds
AU650316B2 (en) Intermediates for preparing 7-(1-pyrrolidinyl) -3-quinolone- and -naphthyridone- carboxylic acid derivatives
AU647627B2 (en) 7-Azaisoindolinyl-quinolone- and-naphthyridonecarboxylic acid derivatives
US4958045A (en) Intermediates for preparing 1,8-bridged 4-quinolone-3-carboxylic acids
HU201050B (en) Process for production of derivatives of 5-substituated quinolone carbonic acid and medical compositions containing them as active substance
US5173484A (en) Quinolone- and naphthyridone carboxylic acid derivatives, process for their production, antibacterial compositions and feed additives containing them
JPS62169789A (en) 7-(azabicycloalkyl)-quinolone carboxylic acid and-naphthylidone carboxylic acid derivative
JP2788043B2 (en) Quinolone- or naphthyridonecarboxylic acids
DK169334B1 (en) 7- (1-Pyrrolidinyl) -3-quinolone carboxylic acid derivatives, processes for their preparation and their use in pharmaceuticals and animal feed additives
JPH02290870A (en) Enantiomerically pure 7-(3-amino-1- pyrrolidinyl)-quinolone- and naphthyridonecarboxylic acid
AU720322B2 (en) 7-(3-Vinyl-1,4-piperazin-1-yl)-substituted quinolonecarboxylic acids
US5153204A (en) 7-(1-Pyrrolidinyl)-quinolonecarboxylic acid derivatives
AU668286B2 (en) Diazabicyclo(4.3.0)nonane and (3.3.0)octane heterocycles
JPH0348682A (en) Pyridonecarboxylic acid compound
NZ239485A (en) Diazabicyclo(3.3.0)octane and (4.3.0)nonane compounds and trans-3-(ethyl or methyl) amino-4-methylthio-pyrrolidine
HU209300B (en) Method for producing quinolone-carboxylic acid derivatives and pharmaceutical preparatives containing these compounds

Legal Events

Date Code Title Description
MM1K Lapsed by not paying the annual fees

Free format text: LAPSED IN SEPTEMBER 2002