NO862042L - ANTIBACTERYLY EFFECTIVE CHINOLONCARBOXYLIC ACID ESTERS. - Google Patents

ANTIBACTERYLY EFFECTIVE CHINOLONCARBOXYLIC ACID ESTERS.

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Publication number
NO862042L
NO862042L NO862042A NO862042A NO862042L NO 862042 L NO862042 L NO 862042L NO 862042 A NO862042 A NO 862042A NO 862042 A NO862042 A NO 862042A NO 862042 L NO862042 L NO 862042L
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Norway
Prior art keywords
dihydro
oxo
cyclopropyl
fluoro
carboxylic acid
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NO862042A
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Norwegian (no)
Inventor
Klaus Grohe
Uwe Petersen
Hans-Joachim Zeiler
Karl Georg Metzger
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Bayer Ag
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Publication of NO862042L publication Critical patent/NO862042L/en

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    • 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
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • 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
    • 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
    • C07D471/06—Peri-condensed systems

Description

Oppfinnelsen vedrører chinolonkarboksylsyreestere, fremgangsmåte til deres fremstilling, samt antibakterielle midler som inneholder disse forbindelser for den parenterale anvendelse. The invention relates to quinolone carboxylic acid esters, methods for their preparation, and antibacterial agents containing these compounds for parenteral use.

Det ble funnet chinolonkarboksylsyreestrene med formlene I eller II hvori A betyr nitrogen eller C-R 4, idet R 4 betyr hydrogen, fluor, klor eller metyl, når R"*" ikke betyr cyklopropyl, hvori R 5 betyr hydrogen, en forgrenet eller uforgrenet alkylgruppe med 1 til 4 karbonatomer som eventuelt kan være substituert med en hydroksy- eller metoksygruppe, R betyr hydrogen, metyl eller fenyl, R 7 betyr hydrogen eller metyl, og R° g betyr hydrogen, hydroksy, amino, alkyl- eller dialkylamino med 1 eller 2 karbonatomer i alkylgruppen, hydroksy-metyl, aminometyl, alkyl- eller dialkylaminometyl med 1 eller 2 karbonatomer i alkylgruppen, R"1" betyr en alkylrest med 1 til 3 karbonatomer, cyklopropyl, 2-fluoretyl, metoksy, 4-fluorfenyl eller metylamino, R 2betyr eventuelt med metoksy eller 2-metoksyetoksy substituert alkyl med 1 til 6 karbonatomer, samt cykloheksyl, benzyl, 2-oksopropyl, fenacyl, etoksykarbonylmetyl, piva-loyloksymetyl, samt R 3 betyr hydrogen, metyl eller etyl, og Z betyr oksygen, med metyl eller fenyl substituert nitrogen, samt ,og deres farmasøytiske anvendbare hydrater og syreaddisjonssalter har en høy antibakteriell virkning og egner seg spesielt godt for den parenterale anvendelse. De er i motsetning til de tilsvarende karboksylsyrer meget godt tålbare, og kan derfor spesielt fordelaktig anvendes for parenterale formuleringer i human- og veterinærmedisinen. The quinolone carboxylic acid esters of formulas I or II were found in which A means nitrogen or C-R 4, in that R 4 means hydrogen, fluorine, chlorine or methyl, when R"*" does not mean cyclopropyl, in which R 5 means hydrogen, a branched or unbranched alkyl group with 1 to 4 carbon atoms which may optionally be substituted with a hydroxy or methoxy group, R means hydrogen, methyl or phenyl, R 7 means hydrogen or methyl, and R° g means hydrogen, hydroxy, amino, alkyl- or dialkylamino with 1 or 2 carbon atoms in the alkyl group, hydroxy-methyl, aminomethyl, alkyl- or dialkylaminomethyl with 1 or 2 carbon atoms in the alkyl group, R"1" means an alkyl radical with 1 to 3 carbon atoms, cyclopropyl, 2-fluoroethyl, methoxy, 4-fluorophenyl or methylamino, R 2 optionally means alkyl substituted with methoxy or 2-methoxyethoxy with 1 to 6 carbon atoms, as well as cyclohexyl, benzyl, 2-oxopropyl, phenacyl, ethoxycarbonylmethyl, piva-loyloxymethyl, and R 3 means hydrogen, methyl or ethyl, and Z means oxygen, with methyl or phenyl substituted nitrogen, as well as , and their pharmaceutically usable hydrates and acid addition salts have a high antibacterial effect and are particularly well suited for the parenteral application. In contrast to the corresponding carboxylic acids, they are very well tolerated, and can therefore be particularly advantageously used for parenteral formulations in human and veterinary medicine.

Oppfinnelsen vedrører fortrinnsvis nye chinolonkarboksylsyrer 2 5 6 7 A, R , R , R og R har overnevnte betydning, samt deres farma-søytiske anvendbare hydrater og syreaddisjonssalter. The invention preferably relates to new quinolone carboxylic acids 2 5 6 7 A, R , R , R and R have the above meaning, as well as their pharmaceutically usable hydrates and acid addition salts.

Oppfinnelsen vedrører spesielt nye chinolonkarboksylsyreestere hvori R 2 betyr eventuelt med metoksy substituert alkyl med 1 til 4 karbonatomer, samt benzyl, 2-oksopropyl, fenacyl, samt The invention relates in particular to new quinolone carboxylic acid esters in which R 2 optionally means alkyl substituted with methoxy with 1 to 4 carbon atoms, as well as benzyl, 2-oxopropyl, phenacyl, and

R g betyr hydrogen eller metyl, 7 R betyr hydrogen eller metyl, og A har overnevnte betydning, samt deres farmasøytisk anvendbare hydrater og syreaddisjonssalter.R g means hydrogen or methyl, 7 R means hydrogen or methyl, and A has the above meaning, as well as their pharmaceutically usable hydrates and acid addition salts.

Videre ble det funnet at forbindelsene med formel I og II fåes når de tilsvarende chinolonkarboksylsyre III resp. IV Furthermore, it was found that the compounds of formula I and II are obtained when the corresponding quinolone carboxylic acid III resp. IV

hvori in which

A, B, R 1 , R 3 og Z har overnevnte betydning, omsettes i -nærvær av sterke syrer med alkoholer med formel V hvori R 2 har overnevnte betydning (metode a). A, B, R 1 , R 3 and Z have the above meaning, are reacted in the presence of strong acids with alcohols of formula V in which R 2 has the above meaning (method a).

Forbindelsen ifølge oppfinnelsen med formel I resp. II kan også fåes med chinolonkarboksylsyreestere med formel VI resp. VII : hvori 12 3 A, R , R , R og Z har overnevnte betydning, og X betyr halogen, fortrinnsvis fluor eller klor, omsettes eventuelt i nærvær av syrebindere med aminer med formel (VIII) The compound according to the invention with formula I resp. II can also be obtained with quinolone carboxylic acid esters of formula VI or VII : in which 12 3 A, R , R , R and Z have the above meaning, and X means halogen, preferably fluorine or chlorine, optionally reacted in the presence of acid binders with amines of formula (VIII)

hvori B har overnevnte betydning, (metode b). in which B has the above meaning, (method b).

Forbindelsen ifølge oppfinnelsen med formel I resp. II kan også fåes idet et salt av en karboksylsyre med formlene IX rep. X hvori 1 3 A, B, R , R og Z har overnevnte betydning, og The compound according to the invention with formula I resp. II can also be obtained as a salt of a carboxylic acid with the formulas IX rep. X in which 1 3 A, B, R , R and Z have the above meaning, and

M ø betyr Na ø, K Ø , \ Ca 2 © eller Ag ©omsettes med forbindelser med formel (XI) M ø means Na ø, K ø , \ Ca 2 © or Ag © are reacted with compounds of formula (XI)

hvori R 2 har overnevnte betydning, og Y betyr halogen, fortrinnsvis klor, brom eller jod, (metode c). in which R 2 has the above meaning, and Y means halogen, preferably chlorine, bromine or iodine, (method c).

Anvendes ifølge metode a l-cyklopropyl-7-(4-etyl-l-piperazinyl)-6-fluor-1,4-dihydro-4-okso-chinolin-3-karboksylsyre og etylalkohol som utgangsstoffer så kan reaksjonsforløpet gjengis If, according to method a, l-cyclopropyl-7-(4-ethyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and ethyl alcohol are used as starting materials, the course of the reaction can be reproduced

Anvendes eksempelvis ved omsetningen ifølge metode b 7-klor-1-cyklopropyl -6-fluor-1,4-dihydro-4-okso-chinolin-3-karboksylsyre og 1-etylpiperazin som utgangsstoffer, så kan reak- sjonsforløpet gjengis med følgende formelskjerna: Anvendes eksempelvis ved omsetningen ifølge metode c 1-cyklopropyl-6-fluor-1,4-dihydro-7-(3,5-dimetylmorfolino)-4-okso-3-chinolinkarboksylsyre-natriumsalt og kloraceton som ut-gangsforbindelser, så kan reaksjonsforløpet gjengis ved føl- If, for example, 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and 1-ethylpiperazine are used as starting materials in the reaction according to method b, then the course of the reaction can be reproduced with the following formula core : If used, for example, in the reaction according to method c 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(3,5-dimethylmorpholino)-4-oxo-3-quinolinecarboxylic acid sodium salt and chloroacetone as starting compounds, then the course of the reaction is reproduced by following

De som utgangsstoffer ifølge metode a anvendte chinolonkarboksylsyre med formel III og IV samt de ifølge metode b som utgangsstoffer anvendte chinolonkarboksylsyreestere (VI) og (VII) er kjent eller kan fremstilles etter kjente fremgangs-måter. The quinolone carboxylic acid of formula III and IV used as starting materials according to method a and the quinolone carboxylic acid esters (VI) and (VII) used as starting materials according to method b are known or can be prepared according to known methods.

Som eksempler skal nevnes: l-etyl-6-fluor-1,4-dihydro-4-okso-7-(1-piperazinyl)-chinolin-3-karboksylsyre, l-ety1-6-fluor-1,4-dihydro-7-(4-metyl-l-piperazinyl)-4-okso-chinolin-3-karboksylsyre, l-etyl-6-fluor-1/4-dihydro-4-okso-7-(1-piperazinyl)-1,8-haftyridin-3-karboksylsyre, 9-fluor-3-metyl-10-(4-metyl-l-piperazinyl)-7-okso-2,3-dihydro-7,4-pyrido/~l,2,3-de/-l,4-benzoksazin-6-karboksylsyre, 9-fluor-5-metyl-8-(4-metyl-l-piperazinyl)-6,7-dihydro-l- okso-IH,5H-benzo/ i,j/chinolin-2-karboksylsyre, 6-fluor-1-(4-fluorfenyl)-1,4-dihydro-4-okso-7-(1-piperazinyl)-chinolin-3-karboksylsyre, 6-fluor-1-(2-fluoretyl)-1,4-dihydro-4-okso-7-(1-piperazinyl)-chinolin-3-karboksylsyre, l-etyl-6,8-difluor-1,4-dihydro-4-okso-7-(4-metyl-l-piperazinyl)-chinolin-3-karboksylsyre, l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-(1-piperazinyl) -chinolin-3-karboksylsyre, l-cyklopropyl-6-fluor-1,4-di-hydro-4-okso-7-(4-etyl-l-piperazinyl)-chinolin-3-karboksylsyre, l-cyklopropyl-6,8-difluor-1,4-dihydro-4-okso-7-(1-piperazinyl)-chinolin-3-karboksylsyre, l-cyklopropyl-6,8-difluor-1,4-di-hydro-4-okso-7-(4-metyl-l-piperazinyl)-chinolin-3-karboksylsyre, l-cyklopropyl-8-klor-6-fluor-1,4-dihydro-4-okso-7-(4-metyl-l-piperazinyl) -chinolin-3-karboksylsyre, l-cyklopropyl-8-klor-6-fluor-1,4-dihydro-4-okso-7-(4-metyl-l-piperazinyl)-chinolin-3- karboksylsyre, l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-(3,5-dimetylmorfonyl-chinolin-3-karboksylsyre, 7-klor-l-etyl-6-fluor-1,4-dihydro-4-okso-chinolin-3-karboksylsyreetylester, l-etyl-6,7-dihydro-4-okso-chinolin-3-karboksylsyreetylester, 7-klor-l-etyl-6-fluor-1,4-dihydro-4-okso-l,8-naftyridin-3-kar-boksylsyreetylester, 9,10-difluor-3-metyl-7-okso-2,3-dihydro-7,4-pyrido/ 2,3-d§7-l,4-benzoksacin-6-karboksylsyreetylester, 8,9-difluor-5-metyl-6,7-dihydro-l-okso-lH,5H-benzo/~i,j7chino-licin-2-karboksylsyreetylester, 7-klor-6-fluor-1-(4-fluorfenyl)-l,4-dihydro-4-okso-chinolin-3-karboksylsyreetylester, 6,7,8-trifluor-1-(4-fluorfenyl)-1,4-dihydro-4-okso-chinolin-3-karbok-syl syree tyle ster , 7-klor-l-cyklopropyl-6-fluor-1,4-dihydro-4- okso-chinolin-3-karboksylsyreetylester, 7-klor-l-cyklopropyl-6- fluor-1,4-dihydro-4-okso-chinolin-3-karboksylsyrernetylester, 7- klor-l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-chinolin-3-karboksylsyre-n-butylester, l-cyklopropyl-6,7-difluor-1,4-dihydro-4-okso-chinolin-3-karboksylsyreetylester, l-cyklopropyl-6,7,8-trifluor-1,4-dihydro-4-okso-chinolin-3-karboksylsyreetylester, 8- klor-l-cyklopropyl-6,7-difluor-1,4-dihydro-4-okso-chinolin-3-karboksylsyreetylester, l-cyklopropyl-7-klor-6-fluor-1,4-dihydro-4-okso-l,8-naftyridin-3-karboksylsyreetylester. Examples include: l-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid, l-ethyl-6-fluoro-1,4-dihydro -7-(4-methyl-1-piperazinyl)-4-oxo-quinoline-3-carboxylic acid, l-ethyl-6-fluoro-1/4-dihydro-4-oxo-7-(1-piperazinyl)-1 . 3-de/-1,4-benzoxazine-6-carboxylic acid, 9-fluoro-5-methyl-8-(4-methyl-1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo /i,j/quinoline-2-carboxylic acid, 6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid, 6-fluoro -1-(2-fluoroethyl)-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid, l-ethyl-6,8-difluoro-1,4-dihydro-4 -oxo-7-(4-methyl-1-piperazinyl)-quinoline-3-carboxylic acid, l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3 -carboxylic acid, l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-ethyl-1-piperazinyl)-quinoline-3-carboxylic acid, l-cyclopropyl-6,8-difluoro -1,4-dihydro-4-oxo-7-(1-piperazine). yl)-quinoline-3-carboxylic acid, l-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)-quinoline-3-carboxylic acid, l -cyclopropyl-8-chloro-6-fluoro-1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)-quinoline-3-carboxylic acid, l-cyclopropyl-8-chloro-6-fluoro -1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)-quinoline-3-carboxylic acid, l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-( 3,5-dimethylmorphonyl-quinoline-3-carboxylic acid, 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester, l-ethyl-6,7-dihydro- 4-oxo-quinoline-3-carboxylic acid ethyl ester, 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 9,10-difluoro- 3-Methyl-7-oxo-2,3-dihydro-7,4-pyrido/2,3-d§7-1,4-benzoxazine-6-carboxylic acid ethyl ester, 8,9-difluoro-5-methyl-6, 7-dihydro-1-oxo-1H,5H-benzo[i,j7quino-lycine-2-carboxylic acid ethyl ester, 7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo -quinoline-3-carboxylic acid ethyl ester, 6,7,8-trifluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid tyle ester, 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester, 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4 -oxo-quinoline-3-carboxylic acid n-butyl ester, 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid n-butyl ester, l-cyclopropyl-6,7-difluoro -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester, l-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester, 8-chloro-l -cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester, 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8 -naphthyridine-3-carboxylic acid ethyl ester.

Likeledes kjent er de som utgangsstoffer anvendte aminer med formel (VIII) (US-patent 4 166 180, J. Med. Chem. 26, 1116 (1983) ) . Also known are the amines of formula (VIII) used as starting materials (US patent 4,166,180, J. Med. Chem. 26, 1116 (1983)).

Som eksempler skal nevnes:Examples include:

Piperazin, N-metylpiperazin, N-etylpiperazin, N-(2-hydroksy-etyl)-piperazin, N-(2-metoksyetyl)-piperazin, N-propylpipera-zin, N-isopropylpiperazin, N-butylpiperazin, N-(sek.-butyl)-piperazin, 2-metyl-piperazin, cis- og trans-2,6-dimetylpipera-zin, 2-fenylpiperazin, 2-(4-fluorfenyl)-piperazin, 2-(4-klorfenyl)-piperazin, 2-(4-metylfenyl)-piperazin, 2-(4-metoksyfenyl)-piperazin, 2-(4-hydroksyfenyl)-piperazin, 2-(2-tienyl)-piperazin, pyrrolidin, 3-aminopyrrolidin, 3-metylamino-pyrrolidin, 3-aminometyl-pyrrolidin, 3-metylamino-metyl-pyrrolidin, 3-dimetylaminometyl-pyrrolidin, 3-etylamino-metyl-pyrrolidin, 3-hydroksy-pyrrolidin. Piperazine, N-methylpiperazine, N-ethylpiperazine, N-(2-hydroxyethyl)piperazine, N-(2-methoxyethyl)piperazine, N-propylpiperazine, N-isopropylpiperazine, N-butylpiperazine, N-(sec .-butyl)-piperazine, 2-methyl-piperazine, cis- and trans-2,6-dimethylpiperazine, 2-phenylpiperazine, 2-(4-fluorophenyl)-piperazine, 2-(4-chlorophenyl)-piperazine, 2-(4-methylphenyl)-piperazine, 2-(4-methoxyphenyl)-piperazine, 2-(4-hydroxyphenyl)-piperazine, 2-(2-thienyl)-piperazine, pyrrolidine, 3-aminopyrrolidine, 3-methylamino- pyrrolidine, 3-aminomethyl-pyrrolidine, 3-methylamino-methyl-pyrrolidine, 3-dimethylaminomethyl-pyrrolidine, 3-ethylamino-methyl-pyrrolidine, 3-hydroxy-pyrrolidine.

Omsetningen av (III) resp. (IV) med (V) ifølge metode a foretas fortrinnsvis i overskytende alkohol (V) som fortynningsmiddel. The turnover of (III) resp. (IV) with (V) according to method a is preferably carried out in excess alcohol (V) as diluent.

De billige alkoholer arbeides her med 5- til 100-ganger over-skudd. The cheap alcohols are worked here with a 5- to 100-fold excess.

Med sterke syrer forstås svovelsyre, vannfri klorhydrogen-syre, sulfonsyrer som f. eks. metansulfonsyre eller p-toluen-sulfonsyre og sure ioneutvekslere. Strong acids are understood to mean sulfuric acid, anhydrous hydrochloric acid, sulphonic acids such as e.g. methanesulfonic acid or p-toluenesulfonic acid and acidic ion exchangers.

Reaksjonstemperaturene ligger mellom 20 og 200°C, fortrinnsvis 60 - 160°C. The reaction temperatures are between 20 and 200°C, preferably 60 - 160°C.

Omsetningen kan gjennomføres ved normaltrykk, men også ved forhøyet trykk. Vanligvis arbeides under trykk mellom ca. 1 og ca. 100 bar, fortrinnsvis mellom 1 og 15 bar. The turnover can be carried out at normal pressure, but also at elevated pressure. Usually work is done under pressure between approx. 1 and approx. 100 bar, preferably between 1 and 15 bar.

Reaksjons-vannet kan også fjernes ved aseotrop destillasjon med kloroform, karbontetraklorid eller benzen som sleper. Omsetningen av (VI) resp. (VII) ifølge metode b med (VIII) foretas fortrinnsvis i et fortynningsmiddel som dimetyl-sulfoksyd, sulfolan, N-metylpyrrolidon, N,N-dimetylformamid, heksametyl-fosforsyretrisamid, pyridin, dioksan eller tetrahydrofuran. The water of reaction can also be removed by azeotropic distillation with chloroform, carbon tetrachloride or benzene as a trailing agent. The turnover of (VI) resp. (VII) according to method b with (VIII) is preferably carried out in a diluent such as dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, N,N-dimethylformamide, hexamethylphosphoric acid trisamide, pyridine, dioxane or tetrahydrofuran.

Som syrebindere kan det anvendes alle vanlige tertiære organiske aminer og amidiner. Som spesielt egnet skal det i detalj nevnes: All common tertiary organic amines and amidines can be used as acid binders. The following should be mentioned in detail as particularly suitable:

Trietylamin, 1,4-diaza-bicyklo/~2,2,27~oktan (DABCO) 1,8-diaza-bicyklo/ 5,4,0/-undec-7-en (DBU) eller overskytende amin (VIII) . Triethylamine, 1,4-diaza-bicyclo/~2,2,27~octane (DABCO) 1,8-diaza-bicyclo/ 5,4,0/-undec-7-ene (DBU) or excess amine (VIII) .

Reaksjonstemperaturene kan varieres innen et stort område. Vanligvis arbeider man mellom ca. 20 og 200°C, fortrinnsvis mellom 80 og 180°C. The reaction temperatures can be varied within a large range. Usually you work between approx. 20 and 200°C, preferably between 80 and 180°C.

Omsetningen kan gjennomføres ved normaltrykk, men også ved for-høyet trykk. Vanligvis arbeider man under trykk mellom ca. 1 og ca. 100 bar, fortrinnsvis mellom 1 og 10 bar. The turnover can be carried out at normal pressure, but also at elevated pressure. Usually, you work under pressure between approx. 1 and approx. 100 bar, preferably between 1 and 10 bar.

Ved gjennomføring av fremgangsmåten ifølge oppfinnelsen, an-vender man på 1 mol av esteren (VI); resp. (VII) 1 tii 6 mol, fortrinnsvis 1 til 2mol av aminet (VIII). When carrying out the method according to the invention, 1 mol of the ester (VI) is used; respectively (VII) 1 tii 6 mol, preferably 1 to 2 mol of the amine (VIII).

De som utgangsstoffer etter metode c anvendte salter med formel (IX) resp. (X) er kjent eller de kan fåes etter kjente metoder fra de tilgrunnliggende karboksylsyrer med alkali-, jord-alkali- eller sølvhydroksyder. Those used as starting materials according to method c salts with formula (IX) resp. (X) are known or they can be obtained by known methods from the basic carboxylic acids with alkali, alkaline earth or silver hydroxides.

De som utgangsstoffer anvendte halogenforbindelser med formel (XI) er kjent. Som eksempler kan det nevnes: Kloraceton, bromaceton, fenacylbromid, benzylklorid, bromeddiksyreetylester, pivaloyloksymetylklorid, 3-klormetyl-2(3H)-benzenoksazolon. The halogen compounds of formula (XI) used as starting materials are known. Examples include: Chloroacetone, bromoacetone, phenacyl bromide, benzyl chloride, bromoacetic acid ethyl ester, pivaloyloxymethyl chloride, 3-chloromethyl-2(3H)-benzeneoxazolone.

Omsetningen av (IX) resp. (X) med (XI) ifølge metode c foretas fortrinnsvis i dimetyformamid, dimetylacetamid eller di-metylsulfoksyd som fortynningsmiddel. The turnover of (IX) resp. (X) with (XI) according to method c is preferably carried out in dimethylformamide, dimethylacetamide or dimethylsulfoxide as diluent.

Reaksjonstemperaturene ligger mellom ca. 0°C og ca. 150°C, fortrinnsvis mellom 10°C og 50°C. The reaction temperatures are between approx. 0°C and approx. 150°C, preferably between 10°C and 50°C.

Omsetningen kan gjennomføres ved normaltrykk men også ved for-høyet trykk. Vanligvis arbeider man ved normaltrykk. The turnover can be carried out at normal pressure but also at elevated pressure. Usually you work at normal pressure.

Ved gjennomføring av fremgangsmåten ifølge oppfinnelsen anvendes på 1 mol av saltet (IX) resp. (X), 1 til 5 mol, fortrinnsvis 1 til 2 mol av halogenforbindelse (XI). When carrying out the method according to the invention, 1 mol of the salt (IX) or (X), 1 to 5 mol, preferably 1 to 2 mol of halogen compound (XI).

Ved fremstillingen av syreaddisjonssaltene av forbindelsen i-følge oppfinnelsen foregår på vanlig måte, eksempelvis ved opp-løsning eller suspendering av esteren (I) resp. (II) i den tilsvarende alkohol, metylklorid, kloroform, dietyleter, dimetylformamid, dioksan, acetonitril eller tetrahydrofuran og utfelling med minst den støkiometriske megde av den tilsvarende syre, eventuelt under tilsetning av eter. Man kan også oppløse eteren (i) resp. (II) i overskytende vandig syre, og utfelle saltet med et med vann blandbart organisk oppløsningsmiddel (metanol, etanol, aceton, acetonitril). Som farmasøytiske anvendbare salter er det eksempelvis å forstå saltene av saltsyre, svovelsyre, eddiksyre, glykolsyre, melkesyre, sitronsyre, vinsyre, metansulfonsyre, galacturonsyre, gluconsyre, glutamin-syre, asparaginsyre eller embonsyre. The production of the acid addition salts of the compound according to the invention takes place in the usual way, for example by dissolving or suspending the ester (I) or (II) in the corresponding alcohol, methyl chloride, chloroform, diethyl ether, dimethylformamide, dioxane, acetonitrile or tetrahydrofuran and precipitation with at least the stoichiometric amount of the corresponding acid, possibly with the addition of ether. You can also dissolve the ether (i) or (II) in excess aqueous acid, and precipitate the salt with a water-miscible organic solvent (methanol, ethanol, acetone, acetonitrile). Pharmaceutically applicable salts include, for example, the salts of hydrochloric acid, sulfuric acid, acetic acid, glycolic acid, lactic acid, citric acid, tartaric acid, methanesulfonic acid, galacturonic acid, gluconic acid, glutamic acid, aspartic acid or embonic acid.

For uten de i eksemplene oppførte forbindelser skal det som virksomme stoffer i detalj nevnes: l-etyl-6-fluor-1,4-dihydro-4-okso-7-(1-piperazinyl)-chinolin-3-karboksylsyreetylester, l-etyl-6-fluor-1,4-dihydro-4-okso-7-(1-piperazinyl)-chinolin-3-karboksylsyrernetylester, l-etyl-6-fluor-1,4-dihydro-4-okso-7-(1-piperazinyl)-chinolin-3- karboksylsyre-n-butylester, l-etyl-6-fluor-1,4-dihydro-7-(4-metyl-l-piperazinyl)-4- okso-chinolin-3-karboksylsyreetylester, l-etyl-6-fluor-1,4-dihydro-4-okso-7-(1-piperazinyl)-1,8-naftyridin-3-karboksyisyreetylester, 9-f luor^-3-metyl-lO- (4-metyl-l-piperazinyl) -7-okso-2 , 3-dihydro-7,4-pyrido/~l,2,3-de/l,4-benzoksazin-6-karboksylsyreetylester, 9-fluor-5-metyl-8-(4-metyl-l-piperazinyl)-6,7-dihydro-l-okso-1H,5H-benzo/ i,^7chinolin-2-karboksylsyreetylester, 6-fluor-1-(4-fluorfenyl)-1,4-dihydro-4-okso-7-(1-piperazinyl)-chinolin-3-karboksylsyreetylester, 6-fluor-1-(2-fluoretyl)-1,4-dihydro-4-okso-7-(1-piperazinyl)-chinolin-3-karboksylsyreetylester, l-etyl-6,8-difluor-1,4-dihydro-4-okso-7-(1-piperazinyl)-chinolin-3-karboksylsyreetylester, l-etyl-6,8-difluor-1,4-dihydro-4-okso-7-(4-metyl-l-piperazinyl)-chinolin-3-karboksylsyre-n-propylester, l-cyklopropyl-6,8-difluor-1,4-dihydro-4-okso-7-(1-piperazinyl)-chinolin-3-karboksylsyreetylester, l-cyklopropyl-6,8-difluor-1,4-dihydro-4-okso-7-(4-metyl-l-piperazinyl) -chinolin-3-karboksylsyreetylester, l-cyklopropyl-6,8-difluor-1,4-dihydro-4-okso-7-(3-metyl-l-piperazinyl)-chino1in-3-karboksylsyre-n-butylester, l-cyklopropyl-8-klor-6-fluor-1,4-dihydro-4-okso-7-(4-etyl-1-piperazinyl)-chinolin-3-karboksylsyreetylester, l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-8-metyl-7-(4-metyl-l-piperazinyl) -chinolin-3-karboksylsyremetylester og l-etyl-6-fluor-1,4-dihydro-4-okso-7-(3-amino-l-pyrrolidinyl)-chinolin-3-karboksylsyreetylester. Because without the compounds listed in the examples, the active substances must be mentioned in detail: l-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid ethyl ester, l- ethyl 6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid ethyl ester, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl)-quinoline-3- carboxylic acid n-butyl ester, l-ethyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-quinoline-3- carboxylic acid ethyl ester, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester, 9-fluoro^-3-methyl-1O- (4-Methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7,4-pyrido[1,2,3-de/1,4-benzoxazine-6-carboxylic acid ethyl ester, 9-fluoro-5 -methyl-8-(4-methyl-1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo/ i,^7quinoline-2-carboxylic acid ethyl ester, 6-fluoro-1-(4-fluorophenyl )-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid ethyl ester, 6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-7- (1-piperazinyl)-quinoline-3-carboxylic acid ethyl ester, l-ethyl-6,8- difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid ethyl ester, l-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4 -methyl-1-piperazinyl)-quinoline-3-carboxylic acid-n-propyl ester, l-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3- carboxylic acid ethyl ester, l-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)-quinoline-3-carboxylic acid ethyl ester, l-cyclopropyl-6,8-difluoro- 1,4-Dihydro-4-oxo-7-(3-methyl-1-piperazinyl)-quinolin-3-carboxylic acid-n-butyl ester, 1-cyclopropyl-8-chloro-6-fluoro-1,4-dihydro- 4-oxo-7-(4-ethyl-1-piperazinyl)-quinoline-3-carboxylic acid ethyl ester, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8-methyl-7-(4-methyl -1-piperazinyl)-quinoline-3-carboxylic acid methyl ester and 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-amino-1-pyrrolidinyl)-quinoline-3-carboxylic acid ethyl ester.

Forbindelsene ifølge oppfinnelsen viser liten toksisitet,The compounds according to the invention show little toxicity,

et bredt antibakterielt spektrum mot grampositive og gramnegative kimer, spesielt mot Enterobakteriaceen, fremfor alt også mot slike som er resistente mot forskjellige antibiotika, som f. eks. penicilliner, eefalosporiner, aminoglykosider, sulfonamider, tetracykliner. a broad antibacterial spectrum against gram-positive and gram-negative germs, especially against Enterobacteriaceae, above all also against those that are resistant to various antibiotics, such as e.g. penicillins, cephalosporins, aminoglycosides, sulfonamides, tetracyclines.

Disse verdifulle egenskaper muliggjør deres anvendelse som chemoterapeutiske virksomme stoffer i medisinen, såvel som stoffer til konservering av uorganiske eller organiske materialer ,. spesielt av organiske materialer av enhver type, f. eks. polymere, smøremidler, farver, fibre, lær, papir og tre, av næringsmidler og av vann. These valuable properties enable their use as chemotherapeutic active substances in medicine, as well as substances for the preservation of inorganic or organic materials,. especially of organic materials of any type, e.g. polymers, lubricants, paints, fibres, leather, paper and wood, of foodstuffs and of water.

Forbindelsene ifølge oppfinnelsen er virksomme mot et meget bredt spektrum av mikroorganismer. Ved deres hjelp kan gramnegative og grampositive bakterier og bakterielignende mikroorganismer bekjempes, samt de ved disse frembringere frembrakte sykdommer nedsettes, bedres og/eller helbredes. The compounds 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 organisms can be reduced, improved and/or cured.

Spesielt virksomme er forbindelsene ifølge oppfinnelsen mot bakterier og bakterielignende mikroorganismer. Det er derfor spesielt gode til profylaks og chemoterapi av lokale og systemiske infeksjoner, i human- og dyremedisinen som frem-bringes ved disse frembringere. The compounds according to the invention are particularly effective against bacteria and bacteria-like microorganisms. They are therefore particularly good for prophylaxis and chemotherapy of local and systemic infections, in the human and animal medicine produced by these producers.

Eksempelvis kan lokale og/eller systemiske sykdommer behandles og/eller endres som forårsakes ved følgende frembringere eller ved blandinger av følgende frembringere: Gram-positive kommer, f. eks. stafylokokker, Staph. aureus, Staph. epidermidis) og streptokokker .(Strept. agalactiae, Strept. faecalis, Strept. pneumoniae, Strept. pyogenes), gramnegative kokker (Neisseria gonorrheae) samt gramnegative staver, som Enterobakteriaceen, f. eks. Escherichia coli, Hemophilus influenzae, Citrobakter, (Citrob. Freundii, Citrob. diversus), Salmonella, Shigella, videre klebsieller, (kleb-siella pneumoniae, Klebs. oxytoca)..Enterobakter (Ent. aeregenes, Ent. agglomerans), Hafnia, Serratia.(Serr. masc-escens), Proteus (Pr. mirabilis, Pr. rettgeri, Per. vulgaris), Providencia, Yersinia samt slekten av Acinetobakter. Dessuten omfatter antibakterielle spektrum slekten Pseudomonas (Ps. aeruginosa, Ps. maltophilia), samt strekt anaerobe bakterier som f. eks. Bacteroides fragilis, representanter av slekten Peptococcus, Peptostreptococcus, samt slekten Clostridium, videre Mykoplasmer (M. pneumoniae, M. hominis, M. urealyticum), samt Mykobakterier, f. eks. Mycobacterium tuberculosis. For example, local and/or systemic diseases can be treated and/or changed which are caused by the following agents or by mixtures of the following agents: Gram-positive come, e.g. staphylococci, Staph. aureus, Staph. epidermidis) and streptococci. Escherichia coli, Hemophilus influenzae, Citrobacter, (Citrob. Freundii, Citrob. diversus), Salmonella, Shigella, further Klebsiella, (kleb-siella pneumoniae, Klebs. oxytoca). Serratia. (Serr. masc-escens), Proteus (Pr. mirabilis, Pr. rettgeri, Per. vulgaris), Providencia, Yersinia and the genus Acinetobacter. In addition, 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 genus Peptococcus, Peptostreptococcus, as well as the genus Clostridium, further Mycoplasmas (M. pneumoniae, M. hominis, M. urealyticum), as well as Mycobacteria, e.g. Mycobacterium tuberculosis.

Den overnevnte oppramsning av frembringere er bare å oppfatte eksempelvis, og på ingen måte begrensende. Som sykdommer som kan hindre, bedres, og/eller heles ved forbindelsen ifølge oppfinnelsen, skal det eksempelvis nevnes: Otitis, Pharyngitis, Pneumonie, Peritonitis, Pyelonephritis, Cystitis, Endocarditis, systeminfeksjoner, Bronchitis, Arth-ritis, lokale infeksjoner, septiske sykdommer. The above-mentioned list of producers is only to be taken as an example, and in no way limiting. As diseases that can be prevented, improved and/or cured by the compound according to the invention, the following should be mentioned, for example: Otitis, Pharyngitis, Pneumonia, Peritonitis, Pyelonephritis, Cystitis, Endocarditis, systemic infections, Bronchitis, Arthritis, local infections, septic diseases.

Oppfinnelsen omfatter og farmasøytiske tilberedninger til parenteral anvendelse,som ved siden av ikke toksiske inerte farmasøytiske egnede bærestoffer inneholder en eller flere forbindelser ifølge oppfinnelsen, eller som består av en eller flere virksomme stoffer ifølge oppfinnelsen, som fremgangsmåte til fremstilling av disse tilberedninger. The invention also includes pharmaceutical preparations for parenteral use, which, in addition to non-toxic inert pharmaceutical suitable carriers, contain one or more compounds according to the invention, or which consist of one or more active substances according to the invention, as a method for producing these preparations.

Oppfinnelsen omfatter også farmasøytiske tilberedninger i dos-eringsenheter. Dette betyr at tilberedningene foreligger i form av enkelte deler, f. eks. ampuller, hvis virksomme stoff-innhold tilsvarer en brøkdel eller ét multiplum av en enkelt dose. Doseringsenhetene kan inneholde f. eks. 1,2,3 eller 4 enkeltdoser eller 1/2, 1/3 eller 1/4 av en enkeltdose. En enkeltdose inneholder fortrinnsvis den mengde virksomt stoff som administreres ved en applikasjon, og som vanligvis tilsvarer en hel, 1/2 eller 1/3 eller 1/4 av en dagsdose. The invention also covers pharmaceutical preparations in dosage units. This means that the preparations are in the form of individual parts, e.g. ampoules, whose active substance content corresponds to a fraction or a multiple of a single dose. The dosage units can contain e.g. 1,2,3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose. A single dose preferably contains the amount of active substance that is administered in one application, and which usually corresponds to a whole, 1/2 or 1/3 or 1/4 of a daily dose.

Med ikke toksiske inerte, farmasøytiske egnede bærestoffer, er det å forstå flytende fortynningsmidler, fyllstoffer og formuleringshjelpemidler av enhver type. By non-toxic inert, pharmaceutically suitable carriers, is meant liquid diluents, fillers and formulation aids of any type.

Som foretrukkede farmasøytiske tilberedninger skal det nevnes oppløsninger, suspensjoner og emulsjoner. Preferred pharmaceutical preparations are solutions, suspensions and emulsions.

Oppløsninger og emulsjoner kan ved siden av det eller de virksomme stoffer, inneholde de vanlige bærestoffer som opp-løsningsmidler, oppløsningsformidlere, og emulgatorer, f. eks. vann, metylalkohol, isopropylalkohol, etylkarbonater, etyl-acetat, benzylalkohol, benzylbenzoat, propylenglykol, 1,3-butylenglykol, dimetylformamid, oljer, spesielt bomullsfrø-olje, jordnøttolje, maiskimolje, olivenolje, risinusolje og sesamolje, glycerol, glycerolformal, tetrahydrofurylalkohol, polyetylenglykoler og fettsyreestere av sorbitan eller blandinger av disse stoffer. Solutions and emulsions can, in addition to the active substance(s), contain the usual carriers such as solvents, dissolution mediators and emulsifiers, e.g. water, methyl alcohol, isopropyl alcohol, ethyl carbonates, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, glycerol formal, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

Til parenteral applikasjon kan oppløsningene og emulsjonene og-så forligge i steril og blodisotonisk form. For parenteral application, the solutions and emulsions can also be available in sterile and blood isotonic form.

Suspensjonene kan ved siden av det eller de virksomme stoffer inneholde de vanlige bærestoffer som flytende fortynningsmidler, f. eks. vann, etylalkohol, propylenglykol, suspenderingsmidler, f. eks. etoksylerte isostearylalkohol, polyoksyetylensorbit-og sorbitanestere, mikrokrystallinsk cellulose, aluminium-metahydroksyd, bentonit, agar-agar og tragant eller blandinger av disse stoffer. In addition to the active substance(s), the suspensions may contain the usual carriers such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, suspending agents, e.g. ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances.

Terapeutisk virksomme forbindelser skal være tilstede i de ovenfor oppførte farmasøytiske tilberedninger, fortrinnsvis i en konsentrasjon fra ca. 0,1 til 99,5, fortrinnsvis fra ca. 0,5 til 95 vekt-% av den samlede blanding. Therapeutically active compounds must be present in the pharmaceutical preparations listed above, preferably in a concentration from approx. 0.1 to 99.5, preferably from approx. 0.5 to 95% by weight of the overall mixture.

De ovenfor anførte farmasøytiske tilberedninger, kan foruten forbindelsene ifølge oppfinnelsen, også inneholde ytterligere farmasøytiske virksomme stoffer. The pharmaceutical preparations listed above, in addition to the compounds according to the invention, may also contain further pharmaceutical active substances.

Fremstillingen av de ovenfor oppførte farmasøytiske tilberedninger foregår på vanlig måte etter kjente metoder, f. eks. ved blanding av det eller de virksomme stoffer med bærestoffer eller stoffene. The production of the pharmaceutical preparations listed above takes place in the usual way according to known methods, e.g. by mixing the active substance(s) with carrier substances or substances.

De virksomme stoffer eller de farmasøytiske tilberedninger kan fortrinnsvis appliseres parenteralt, som intravenøst eller intramuskulært. The active substances or the pharmaceutical preparations can preferably be applied parenterally, such as intravenously or intramuscularly.

Vanligvis har det såvel i human- og også i veterinærmedisinen vist seg fordelaktig å administrere det eller de virksomme stoffer ifølge oppfinnelsen i samlede mengder fra ca. 0,5 til ca. 500, fortrinnsvis 5 til 100 mg/kg legemsvekt pr. 24 timer, eventuelt i form av flere enkeltinngivninger for oppnåelse av de ønskede resultater. En enkeltdose inneholder det eller de virksomme stoffer ifølge oppfinnelsen, fortrinnsvis i mengder på ca. 1 til ca. 250, spesielt 3 til 60 mg/kg legemsvekt. Det kan imidlertid være nødvendig å avvike fra de nevnte dosering-er, nemlig i avhengighet av type og legemsvekt av objektet som skal behandles, type og tyngde av sykdommen, type og tilbered-ningen av applikasjonen av legemidlet samt tidsrommet resp. intervallet, i hvilke administreringen foregår. Generally, both in human and also in veterinary medicine, it has proven advantageous to administer the active substance(s) according to the invention in total amounts from approx. 0.5 to approx. 500, preferably 5 to 100 mg/kg body weight per 24 hours, possibly in the form of several individual submissions to achieve the desired results. A single dose contains the active substance(s) according to the invention, preferably in amounts of approx. 1 to approx. 250, especially 3 to 60 mg/kg body weight. However, it may be necessary to deviate from the aforementioned dosages, namely depending on the type and body weight of the object to be treated, the type and severity of the disease, the type and preparation of the application of the medicine as well as the time period or the interval in which the administration takes place.

Således kan det i noen tilfelle være tilstrekkelig å komme ut med mindre enn overnevnte mengde virksomt stoff, mens i andre tilfeller den ovenfor anførte virksomme stoffmengde må over-skrides. Fastleggelse av den resp. nødvendige optimale doser-ing og applikasjonstype av det virksomme stoffet, kan lett fore-gå av enhver fagmann på grunn av hans fagkunnskaper. Thus, in some cases it may be sufficient to come out with less than the above-mentioned amount of active substance, while in other cases the above-mentioned amount of active substance must be exceeded. Determination of the resp. necessary optimal dosing and type of application of the active substance can easily be carried out by any expert due to his professional knowledge.

Fortrinnsvis kan forbindelsen ifølge oppfinnelsen anvendes parenteralt også .til kvalitativt og kvantitativt forbedring av dyriske produkter. Preferably, the compound according to the invention can be used parenterally also for qualitative and quantitative improvement of animal products.

Forbindelsen ifølge oppfinnelsen viser en utmerket lokal tålbarhet, f. eks. etter subkutan applikasjon i motsetning til de fri karboksylsyrer. Hertil ble mus over 5 dager behandlet subkutant 2 x pr. dag med 1 til 10 % oppløsninger av de virksomme stoffer, tilsvarende en dose fra 100 mg/kg til 300 mg/kg. Under behandlingsperioden samt etter avslutning av behandlingen ble dyrene iakttatt. Det viste seg at musene som var blitt behandlet med forbindelsen ifølge oppfinnelsen, f. eks. fra eksempel 1 i området av injeksjonsstedet, ikke har trekk av en lokal vevbeskadigelse, mens de tilsvarende fri karboksylsyrer førte til de tyngste nekrotiske endringer og hårdheter av huden, The compound according to the invention shows an excellent local tolerability, e.g. after subcutaneous application in contrast to the free carboxylic acids. In addition, mice were treated subcutaneously twice per day over 5 days. day with 1 to 10% solutions of the active substances, corresponding to a dose from 100 mg/kg to 300 mg/kg. During the treatment period and after the end of the treatment, the animals were observed. It turned out that the mice that had been treated with the compound according to the invention, e.g. from example 1 in the area of the injection site, does not have features of a local tissue damage, while the corresponding free carboxylic acids led to the heaviest necrotic changes and hardness of the skin,

og de derunder liggende bindevevssjikt. Således er forbindelsen ifølge oppfinnelsen lokalt tydelig bedre tålbare enn de tilsvarende fri karboksylsyrer, og kan flere ganger anvendes opp-løsninger til det overnevnte konsentrasjonsområdet ved god lokal tålbarhet. I et museproteksjonsforsøk (infeksjon intra-peritonealt, terapi 30 minutter etter infeksjon ved subkutan inngivning) kunne det vises at stoffene etter parenteral applikasjon har en god protektiv virkning ved forhøyet lokal tålbarhet av esteren. Forbindelsen ifølge oppfinnelsen er dermed samme dosis virksom protektive, som de tydelige dårligere tålbare fri karboksylsyrer. and the underlying connective tissue layers. Thus, the compound according to the invention is locally clearly better tolerated than the corresponding free carboxylic acids, and solutions to the above-mentioned concentration range can be used several times with good local tolerability. In a mouse protection experiment (infection intraperitoneally, therapy 30 minutes after infection by subcutaneous administration) it could be shown that the substances after parenteral application have a good protective effect due to increased local tolerability of the ester. The compound according to the invention is thus the same effective protective dose as the clearly less tolerable free carboxylic acids.

Oppfinnelsen skal forklares nærmere ved hjelp av følgende eksempler: The invention shall be explained in more detail by means of the following examples:

a) Klorhydrogenfremgangsmåte: a) Chlorine hydrogen method:

I en suspensjon av 184 g l-cyklopropyl-7-(4-etyl-l-piperazinyl)-6-fluor-1,4-dihydro-4-okso-chinolin-3-karboksylsyre i 2750 ml etanol innføres ved være1sestemperatur tørr klorhydrogen. Deretter ble det under videre innføring av klorhydrogen i tilbakeløp kokt ca. 14 timer, den klare oppløsning inndampes i vakuum residuet oppløst i 2200 ml isvann og oppløs-ningen med 800 ml 6-n natronlut innstillet på pH til 12-14. Utfellingen avsuges hurtig, vaskes med isvann og tørkes i vakuum ved lOOoC. Omkrystallisasjonen fra 750 mg toluen ga etter tilsetning av 750 ml lettbenzin 140,1 g(70,6 % av det teoretiske) l-cyklopropyl-6-fluor-7-(4-etyl-l-piperazinyl)-1,4-dihydro-4-okso-chinolin-3-karboksylsyreetylester av sm.p. 186-187°C. In a suspension of 184 g of 1-cyclopropyl-7-(4-ethyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid in 2750 ml of ethanol, dry hydrogen chloride is introduced at room temperature . Then, during the further introduction of hydrogen chloride under reflux, approx. 14 hours, the clear solution is evaporated in a vacuum, the residue dissolved in 2200 ml of ice water and the solution with 800 ml of 6-n caustic soda adjusted to pH 12-14. The precipitate is quickly suctioned off, washed with ice water and dried in a vacuum at lOOoC. The recrystallization from 750 mg of toluene gave, after the addition of 750 ml of light gasoline, 140.1 g (70.6% of the theoretical) 1-cyclopropyl-6-fluoro-7-(4-ethyl-1-piperazinyl)-1,4-dihydro -4-oxo-quinoline-3-carboxylic acid ethyl ester of m.p. 186-187°C.

b) Svovelsyre-fremgangsmåten:b) The sulfuric acid method:

En suspensjon av 18 g l-cyklopropyl-7-(4-etyl-l-piperazinyl)-6-fluor-1,4-dihydro-4-okso-chinolin-3-karboksylsyre i 120 ml etanol blandes dråpvis med 24 g 96 % svovelsyre. Man tilbake-løpskoker 12 timer, fjerner overskytende alkohol i vakuum, og oppløser residuet i 200 ml isvann. Under isavkjøling inn-stilles en kald oppløsning av 19,2 g natriumhdyroksyd i 100 ml vann på pH = 12-14, den vandige utfelling frasuges, vaskes med vann og tørkes i vakuum ved 100°C. Etter omkrystallisering fra toluen/lettbenzin fåes 10 g (52,5 % av det teoretiske) l-cyklopropyl-7-(4-etyl-l-piperazinyl)-6-fluor-1,4-dihydro-4-okso-chinolin-3-karboksylsyreetylester av sm.p. 187 til 189°C. A suspension of 18 g of 1-cyclopropyl-7-(4-ethyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid in 120 ml of ethanol is mixed dropwise with 24 g 96 % sulfuric acid. Boil under reflux for 12 hours, remove excess alcohol in a vacuum, and dissolve the residue in 200 ml of ice water. Under ice cooling, a cold solution of 19.2 g of sodium hydroxide in 100 ml of water is adjusted to pH = 12-14, the aqueous precipitate is suctioned off, washed with water and dried in a vacuum at 100°C. After recrystallization from toluene/light gasoline, 10 g (52.5% of the theoretical) of 1-cyclopropyl-7-(4-ethyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-quinoline- 3-carboxylic acid ethyl ester of m.p. 187 to 189°C.

c) Omsetning av 7-klor-l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-chinolin-3-karboksylsyreetylester med 1-etylpiperazin.c) Reaction of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester with 1-ethylpiperazine.

En oppløsning av 15,5 g 7-klor-l-cyklopropyl-6-fluor-1,4-di-hydro-4-okso-chinolin-3-karboksylsyreetylester i 60 ml dimetyl-sulfoksyd, blandes med 11,8 g 1-etylpiperazin og oppvarmes deretter i 5 timer ved 15 0°C. Den varme oppløsning heller man på is, frasuger utfellingen, vasker godt med vann og tørker i vakuum ved 100°C. Etter omkrystallisering fra toluen/lettben-sin i nærvær av tonsil fåes 12,2 g l-cyklopropyl-7-(4-etyl-l-piperazinyl ) -6-fluor-1,4-dihydro-4-okso-chinolin-3-karboksyl-syreetylester av sm.p. 185 - 187°C. A solution of 15.5 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester in 60 ml of dimethyl sulfoxide is mixed with 11.8 g of 1 -ethylpiperazine and then heated for 5 hours at 150°C. The hot solution is poured onto ice, the precipitate is sucked off, washed well with water and dried in a vacuum at 100°C. After recrystallization from toluene/light benzine in the presence of tonsil, 12.2 g of 1-cyclopropyl-7-(4-ethyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-quinoline-3 are obtained -carboxylic acid ethyl ester of m.p. 185 - 187°C.

Analogt eksempel 1 (b) gjennomføres forestringen i metanol Analogous to example 1 (b), the esterification is carried out in methanol

idet det i 78 %-ig utbytte fåes l-cyklopropyl-7-(4-etyl-l-piperazinyl) -6-fluor-1,4-dihydro-4-okso-chinolin-3-karboksylsyre-metylester av sm.p. 218 - 220°C. whereby 1-cyclopropyl-7-(4-ethyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid methyl ester of m.p. . 218 - 220°C.

Analogt eksempel 1(b) gjennomføres forestringen i n-propanol idet etter 5 timers tilbakeløp i 58 %-ig utbytte fåes 1-cyklopropyl-7-(4-etyl-l-piperazinyl)-6-fluor-1,4-dihydro-4-okso-chinolin-3-karboksylsyre-n-propyl-ester av sm.p. 168-169°C. Analogt eksempel 1 (b) gjennomføres forestringen i n-butanol idet etter 3 timers tilbakeløp i 56 %-ig utbytte fåes l-cyklopropyl-7- (4-etyl-l-piperazinyl)-6-fluor-1,4-dihydro-4-okso-chinolin-3-karboksylsyre-n-butylester av sm.p. 159-161°C. - Analogous to example 1(b), the esterification is carried out in n-propanol, whereby after 5 hours of reflux in 58% yield, 1-cyclopropyl-7-(4-ethyl-1-piperazinyl)-6-fluoro-1,4-dihydro- 4-oxo-quinoline-3-carboxylic acid n-propyl ester of m.p. 168-169°C. Analogous to example 1 (b), the esterification is carried out in n-butanol, whereby after 3 hours reflux in 56% yield, 1-cyclopropyl-7-(4-ethyl-1-piperazinyl)-6-fluoro-1,4-dihydro- 4-oxo-quinoline-3-carboxylic acid n-butyl ester of m.p. 159-161°C. -

6,6 g (20 mmol) l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-(1-piperazinyl)-3-chinolinkarboksylsyre suspenderes i 150 ml abs. metanol og ved tilbakeløpstemperatur innføres i 4 timer tørr HCl-strøm, idet det danner seg en gul oppløsning. Inndamper, oppløser det oljeaktige residuet (gjennomkrystalli-seres ved henstand) med en gang i vann, og innstiller med kald, fortynnet natronlut ved isavkjøling forsiktig på pH 8-9. Den dannede utfelling frasuges hurtig, vaskes med isvann og tørkes. Man får 3,7 g (54 % av det teoretiske) l-cyklopropyl-6 -f luor-1 , 4-dihydro-4-okso-7-(1-piperazinyl)-3-chinolinkarboksylsyre-metylester av sm.p. 247-249°C (etter omkrystallisering av metanol: Sm.p. 249-251°C). 6.6 g (20 mmol) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid are suspended in 150 ml of abs. methanol and at reflux temperature a dry stream of HCl is introduced for 4 hours, a yellow solution forming. Evaporate, dissolve the oily residue (recrystallises on standing) immediately in water, and adjust with cold, diluted caustic soda by ice-cooling carefully to pH 8-9. The formed precipitate is rapidly suctioned off, washed with ice water and dried. 3.7 g (54% of the theoretical) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid methyl ester of m.p. 247-249°C (after recrystallization from methanol: mp 249-251°C).

Analogt eksempel 5 gjennomføres forestringen i etanol, idet det fåes l-cyklopr.opyl-6-f luor-1, 4-dihydro-4-okso-7-(1-piperazinyl)-3-chinolinkarboksylsyreetylester av sm.p. 228 - 230°C. Analogous to example 5, the esterification is carried out in ethanol, obtaining 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid ethyl ester of m.p. 228 - 230°C.

Man arbeider analogt i eksempel 5 i 2-metoksyetanol og får l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-(1-piperazinyl)-3-chinolinkarboksylsyre-(2-metoksyetylester) av sm.p. 140 - 142°C. Man arbeider analogt eksempel 5 i 2-(2-metoksyetoksy)-etanol (dietylenglykolmonometyleter) og får 1-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-(1-piperazinyl)-3-chinolinkarboksylsyre-/ 2-(2-metoksyetoksy)-etylester7 av sm.p. 182-190°C. One works analogously to example 5 in 2-methoxyethanol and obtains 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid (2-methoxyethyl ester) of sm. p. 140 - 142°C. One works analogously to example 5 in 2-(2-methoxyethoxy)-ethanol (diethylene glycol monomethyl ether) and obtains 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid / 2-(2-methoxyethoxy)-ethyl ester7 of m.p. 182-190°C.

Analogt eksempel 5, forestres l-cyklopropyl-6-fluor-1,4-di-hydro-7-(4-isopropyl-l-piperazinyl)-4-okso-3-chinolinkarboksylsyre med etanol. Man får l-cyklopropyl-6-fluor-1,4-dihydro-7-(4-isopropyl-l-piperazinyl)-4-okso-3-chinolinkarboksylsyre-etylester av sm.p. 186-187°C. Analogous to example 5, 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-isopropyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid is esterified with ethanol. One obtains 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-isopropyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid ethyl ester of m.p. 186-187°C.

Den hertil nødvendige 1-cyklopropyl -6-fluor-1,4-dihydro-7-(4-isopropyl-l-piperazinyl)-4-okso-3-chinolinkarboksylsyre fåes på følgende måte: 6,6 g (20 mmol) l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-(1-piperazinyl)-3-chinolinkarboksylsyre oppvarmes i 100 ml dimetylformamid med 6,8 g (40 mmol) isopropyljodid og 4,2 g trietylamin i 2 1/2 time under 70 - 80°C. Oppløsningen inndampes i vakuum, residuet utrøres med 6 0 ml vann og ved pH rundt 5, isoleres 7,7 g l-cyklopropyl-6-fluor-1,4-dihydro-7-(4-isopropyl-l-piperazinyl)-4-okso-3-chinolinkarboksylsyrejodid av sm.p.: 288 - 291°C under spaltning. The necessary 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-isopropyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid is obtained in the following way: 6.6 g (20 mmol) l -cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid is heated in 100 ml of dimethylformamide with 6.8 g (40 mmol) of isopropyl iodide and 4.2 g of triethylamine in 2 1/2 hours below 70 - 80°C. The solution is evaporated in vacuo, the residue is stirred with 60 ml of water and at pH around 5, 7.7 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-isopropyl-1-piperazinyl)-4 is isolated -oxo-3-quinolinecarboxylic acid iodide of m.p.: 288 - 291°C with decomposition.

For overføring i betainet blandes 7,7 g av hydrojodidet i 80 ml vann med en oppløsning av 1,7 g natriumhydrogenkarbonat i 20 ml vann og omrøres 3 timer ved 20°C. Utfellingen frasuges, vaskes med vann og tørkes. 4,2 g l-cyklopropyl-6-fluor-1,4-dihydro-7-(4-isopropyl-l-piperazinyl)-4-okso-3-chinolinkarboksylsyre av sm.p. 224-227°C (under spaltning). For transfer into the betaine, 7.7 g of the hydroiodide in 80 ml of water are mixed with a solution of 1.7 g of sodium bicarbonate in 20 ml of water and stirred for 3 hours at 20°C. The precipitate is suctioned off, washed with water and dried. 4.2 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-isopropyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid of m.p. 224-227°C (under decomposition).

Til overføring til hydrokloridet suspenderes 10,4 g av betainet i 50 ml vann, blandes med 25 ml kons. saltsyre, og oppvarmes 15 minutter ved 90°C. Oppløsningen filtreres, blandes med 200 ml etanol og det utfelte salt frasuges etter avkjøling, vaskes med etanol og tørkes. Man får 8,8 g l-cyklopropyl-6-fluor-1,4-dihydro-7-(4-isopropyl-l-piperazinyl)-4-okso-3-chinolinkarboksylsyre-hydroklorid av sm.p. > 330°C under spaltning. To transfer to the hydrochloride, suspend 10.4 g of the betaine in 50 ml of water, mix with 25 ml of conc. hydrochloric acid, and heated for 15 minutes at 90°C. The solution is filtered, mixed with 200 ml of ethanol and the precipitated salt is sucked off after cooling, washed with ethanol and dried. 8.8 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-isopropyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid hydrochloride of m.p. > 330°C during decomposition.

a) 5,6 g (20 mmol) l-cyklopropyl-7-klor-8-fluor-1,4-dihydro-4-okso-3-chinolinkarboksylsyre oppvarmes i 70 ml dimetylsul-foksyd med 2,53 (22 mmol) 2,6-dimetylmorfolin og 4,4 g 1,4-diazabicyklo/~2 , 2 , 2_7oktan i 6 timer ved 120°C.Blandingen inndampes i høyvakuum,utrystes med 30 ml vann, og utfellingen frasuges, vaskes med vann, og omkrystalliseres fra glykol-monometyleter. Man får 2,4 g (33 % av det teoretiske) l-cyklopropyl-6 -f luor-1 ,4-dihydro-4-okso-7-(3,5-dimetylmorfolino)-3-chinolinkarboksylsyre av sm.p. 253-257°C under spaltning. a) 5.6 g (20 mmol) of 1-cyclopropyl-7-chloro-8-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated in 70 ml of dimethyl sulfoxide with 2.53 (22 mmol) 2,6-dimethylmorpholine and 4.4 g of 1,4-diazabicyclo/~2 , 2 , 2_7octane for 6 hours at 120°C. The mixture is evaporated under high vacuum, shaken with 30 ml of water, and the precipitate is filtered off with suction, washed with water, and recrystallized from glycol monomethyl ether. 2.4 g (33% of the theoretical) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3,5-dimethylmorpholino)-3-quinolinecarboxylic acid of m.p. 253-257°C during decomposition.

b) 1,8 g (5 mmol) l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-(3,5-dimetylmorfolino)-3-chinolinkarboksylsyre bringes i en oppløsning av 0,2 g (5 mmol) NaOH i 5 ml vann, filtreres, og filtratet inndampes til tørrhet. For fullstendig fjerning av vann, blandes ennå tre ganger med resp. 5 ml diklormetan og inndampes. b) 1.8 g (5 mmol) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3,5-dimethylmorpholino)-3-quinolinecarboxylic acid is brought into a solution of 0.2 g (5 mmol) of NaOH in 5 ml of water, filtered, and the filtrate evaporated to dryness. For complete removal of water, mix three more times with resp. 5 ml of dichloromethane and evaporate.

Man får 1- cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-(3,5-dimetylmorfolino)-3-chinolinkarboksylsyre-natriumsalt i prak-tisk talt kvantitativt utbytte. One obtains 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3,5-dimethylmorpholino)-3-quinolinecarboxylic acid sodium salt in practically quantitative yield.

c) 3,8 g (10 mmol) l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-(3,5-dimetylmorfolino)-3-chinolinkarboksylsyre-natriumsalt suspenderes i 100 ml abs. dimetylformamid, og omrøres med 2,7 g kloraceton 24 timer ved 25°C. Man inndamper i høyvakuum, utrører residuet med 100 ml vann, frasuger utfellingen, vasker med vann og metanol, tørker i vakuum og får 2,8 g (67 % av det teoretiske) l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-(3,5-dimetylmorfolino)-3-chinolinkarboksylsyre-(2-oksopropyl-ester) av sm.p. 206 - 210°C under spaltning. c) 3.8 g (10 mmol) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3,5-dimethylmorpholino)-3-quinolinecarboxylic acid sodium salt are suspended in 100 ml abs. dimethylformamide, and stirred with 2.7 g of chloroacetone for 24 hours at 25°C. Evaporate in high vacuum, stir the residue with 100 ml of water, filter off the precipitate, wash with water and methanol, dry in vacuum and obtain 2.8 g (67% of the theoretical) of 1-cyclopropyl-6-fluoro-1,4-dihydro -4-oxo-7-(3,5-dimethylmorpholino)-3-quinolinecarboxylic acid-(2-oxopropyl ester) of m.p. 206 - 210°C during decomposition.

Analogt eksempel 10 c) vil man med bromeddiksyreetylester få l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-(3,5-dimetyl-morfolino)-3-chinolinkarboksylsyre-(etoksykarbonylmetylester) av sm.p. 181 - 183°C. Analogously to example 10 c), with bromoacetic acid ethyl ester, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3,5-dimethyl-morpholino)-3-quinolinecarboxylic acid (ethoxycarbonylmethyl ester) of sm. p. 181 - 183°C.

Analogt eksempel 10 c) vil man med benzylklorid få l-cyklopropyl-6 -f luor-1 ,4-dihydro-4-okso-7-(3,5-dimetylmorfolino)-3-chinolinkarboksylsyrebenzylester av sm.p. 195 - 198°C under spaltning. Analogously to example 10 c), with benzyl chloride, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3,5-dimethylmorpholino)-3-quinolinecarboxylic acid benzyl ester of m.p. 195 - 198°C during decomposition.

Analogt eksempel 10 c) vil man med 3-klormetyl-2(3H)-benz-oksazolon få l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-(3,5-dimetylmorfolino-3-chinolinkarboksylsyre-/~2(3H)-benz-oksazolon-3-ylmetylester/ av sm.p. 192 til 195°C under spaltning . Analogous to example 10 c) with 3-chloromethyl-2(3H)-benz-oxasolone you get 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3,5-dimethylmorpholino-3- quinoline carboxylic acid-/~2(3H)-benz-oxazolon-3-ylmethyl ester/ of m.p. 192 to 195°C with cleavage.

Eksempel 14Example 14

Analogt eksempel 1 b) ble det også fremstilt de følgende for- Forbindelsen 14e) ble dessuten også fremstillet ved fremgangsmåten ifølge eksempel lc). Analogously to example 1 b), the following compounds were also prepared - Compound 14e) was also prepared by the method according to example lc).

Claims (2)

1. Fremgangsmåte til fremstilling av chinolonkarboksylsyreestere med formel I eller II 1. Process for the preparation of quinolone carboxylic acid esters of formula I or II hvori A betyr nitrogen eller C-R 4, idet R 4betyr hydrogen, fluor, klor eller metyl, in which A means nitrogen or C-R 4, where R 4 means hydrogen, fluorine, chlorine or methyl, når R ikke betyr cyklopropyl, og hvori R^ betyr hydrogen, en forgrenet eller uforgrenet alkylgruppe med 1 til 4 karbonatomer som eventuelt kan være substituert med en hydroksy- eller metoksygruppe, R c betyr hydrogen, metyl eller fenyl, R 7 betyr hydrogen eller metyl, og R betyr hydrogen, hydroksy, amino, alkyl- eller dialkylamino med 1 eller 2 karbonatomer i alkylgruppen, hydroksyrnety1, aminometyl, alkyl- eller dialkylaminometyl med 1 eller 2 karbonatomer i alkylgruppen, R <1> betyr en alkylrest med 1 til 3 karbonatomer, cyklopropyl, 2-fluoretyl, metoksy, 4-fluorfenyl eller metylamino, R 2betyr eventuelt med metoksy eller 2-metoksyetoksy substituert alkyl med 1 til 6 karbonatomer, samt cykloheksyl, benzyl, 2-oksopropyl, fenacyl, etoksykarbonylmetyl, piva-loyloksymetyl, samt 3 R betyr hydrogen, metyl eller etyl, og Z betyr oksygen, med metyl eller fenyl substituert nitrogen samt CH2, og deres farmasøytisk anvendbare hydrater og syreaddisjonssalter , karakterisert ved ata) de tilsvarende chinolonkarboksylsyrer ( LIT) resp. (IV) hvori A, B, R 1 , R 2 og Z har overnevnte betydning, omsettes i nærvær av sterke syrer med alkoholer med formel (V) when R does not mean cyclopropyl, and wherein R^ means hydrogen, a branched or unbranched alkyl group with 1 to 4 carbon atoms which may optionally be substituted with a hydroxy or methoxy group, R c means hydrogen, methyl or phenyl, R 7 means hydrogen or methyl, and R means hydrogen, hydroxy, amino, alkyl- or dialkylamino with 1 or 2 carbon atoms in the alkyl group, hydroxynethy1, aminomethyl, alkyl- or dialkylaminomethyl with 1 or 2 carbon atoms in the alkyl group, R <1> means an alkyl radical with 1 to 3 carbon atoms, cyclopropyl, 2-fluoroethyl, methoxy, 4-fluorophenyl or methylamino, R 2 optionally means alkyl substituted with methoxy or 2-methoxyethoxy with 1 to 6 carbon atoms, as well as cyclohexyl, benzyl, 2-oxopropyl, phenacyl, ethoxycarbonylmethyl, piva-loyloxymethyl, and 3 R means hydrogen, methyl or ethyl, and Z means oxygen, with methyl or phenyl substituted nitrogen as well as CH2, and their pharmaceutically usable hydrates and acid addition salts, characterized by ata) the corresponding quinolone carboxylic acids (LIT) resp. (IV) in which A, B, R 1 , R 2 and Z have the above meaning, are reacted in the presence of strong acids with alcohols of formula (V) hvori R 2 har overnevnte betydning, eller b) chinolonkarboksylsyreestere med formel (VI) resp. (VII) hvori 12 3 A, R , R r R og Z har overnevnte betydning, og X betyr halogen, fortrinnsvis fluor eller klor, omsettes eventuelt i nærvær av syrebindere med aminer med formel (VIII) in which R 2 has the above meaning, or b) quinolone carboxylic acid esters of formula (VI) or (VII) in which 12 3 A, R , R r R and Z have the above meaning, and X means halogen, preferably fluorine or chlorine, optionally reacted in the presence of acid binders with amines of formula (VIII) hvori B har overnevnte betydning eller C) et salt av en karboksylsyre med formlene (IX) resp. (X) hvori 1 3 A, B, R , R og Z har overnevnte betydning, og M <®> betyr Na <®> ,. K <®> , 1/2 Ca <2®> eller Ag <®> , omsettes med forbindelser med formel (XI) in which B has the above meaning or C) a salt of a carboxylic acid with the formulas (IX) or (X) in which 1 3 A, B, R , R and Z have the above meaning, and M <®> means Na <®> ,. K <®> , 1/2 Ca <2®> or Ag <®> , react with compounds of formula (XI) hvori R 2 har overnevnte betydning, og Y betyr halogen, fortrinnsvis klor, brom eller jod. in which R 2 has the above meaning, and Y means halogen, preferably chlorine, bromine or iodine. 2. Fremgangsmåte til fremstilling av 1-cyklopropyl -6-fluor-1,4-dihydro-7-(4-isopropyl-l-piperazinyl)-4-okso-3-chinolinkarboksylsyre, karakterisert ved at l-cyklopropyl-6-fluor-1,4-dihydro-4-okso-7-(1-piperazinyl)-3-chinolinkarboksylsyre, omsettes i et oppløsningsmiddel med isopropylhalogenid i nærvær av et amin, og eventuelt isoleres den fri syre fra det dannede hydrohalogenid.2. Process for the production of 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-isopropyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, characterized in that 1-cyclopropyl-6-fluoro -1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid, is reacted in a solvent with isopropyl halide in the presence of an amine, and optionally the free acid is isolated from the hydrohalide formed.
NO862042A 1985-06-07 1986-05-22 ANTIBACTERYLY EFFECTIVE CHINOLONCARBOXYLIC ACID ESTERS. NO862042L (en)

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