NO781934L - ACYL DERIVATIVES. - Google Patents

ACYL DERIVATIVES.

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Publication number
NO781934L
NO781934L NO781934A NO781934A NO781934L NO 781934 L NO781934 L NO 781934L NO 781934 A NO781934 A NO 781934A NO 781934 A NO781934 A NO 781934A NO 781934 L NO781934 L NO 781934L
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salts
formula
methyl
compounds
hydrates
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NO781934A
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Norwegian (no)
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Marc Montavon
Roland Reiner
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Hoffmann La Roche
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Publication of NO781934L publication Critical patent/NO781934L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/36—Methylene radicals, substituted by sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Description

AcyIderivaterAcyI derivatives

Foreliggende oppfinnelse vedrører nye acylderivater med den generelle formel hvor R betyr furyl, thienyl eller eventuelt fenyl sub-stituert med hallogen, hydroksylavere alkoksy eller lavere alkyl, lavere alkyl eller aminokarbonylmetyl og X en gruppe med formelen The present invention relates to new acyl derivatives with the general formula where R means furyl, thienyl or optionally phenyl substituted with halogen, hydroxyl lower alkoxy or lower alkyl, lower alkyl or aminocarbonylmethyl and X a group with the formula

hvori en av de to restene R£og R^ henholdsvis R 4 og R5er hydrogen og den andre lavere alkyl, karboksyl-metyl eller sulfometyl, in which one of the two residues R£ and R^ respectively R 4 and R 5 is hydrogen and the other lower alkyl, carboxyl-methyl or sulfomethyl,

samt salter av disse forbindelser og hydrater av disse salter. as well as salts of these compounds and hydrates of these salts.

Eksempler på salter av forbindelsen med formel I er alkali-I^metallsalter som natrium-og kaliumsaltet, ammoniumsaltet, jordalkaliemetallsalter som kalsiumsaltet, salter med organiske baser som salter med. aminer, f.eks. salter med N-ety1-piperi-din , prokain, dibenzylamin, N.,N ' -dibenzyletyletylendiamin, alkylaminer eller dialkylaminer samt salter med aminosyrer som f.eks. salter med argenin eller lysin. Saltene kan være monosalter eller også disalter. Den andre saltdannelsen skjer på den tautomere enolformen av triazinresten b som har sur karakter. Examples of salts of the compound of formula I are alkali metal salts such as the sodium and potassium salts, the ammonium salt, alkaline earth metal salts such as the calcium salt, salts with organic bases such as salts with amines, e.g. salts with N-ethyl-piperidine, procaine, dibenzylamine, N.,N'-dibenzylethylethylenediamine, alkylamines or dialkylamines as well as salts with amino acids such as e.g. salts with arginine or lysine. The salts can be monosalts or disalts. The second salt formation occurs on the tautomeric enol form of the triazine residue b, which has an acidic character.

Forbindelsene med formel I danner likeledes addisjonssalter med organiske eller uorganiske syrer. Eksempler på slike salter er hydrohalogenider, f.eks. hydroklorider, hydrobromider, hydro-jodider samt andre mineralsyresalter som sulfater, nitrater, fosfater o.l., alkyl- og mono-arylsulfonater som etansulfonater, toluensulfonater, benzensulfonater o.l. og også andre organiske syresalter som acetater, tartrater, maleater, sitrater, benzoat-er, salisylater, askorbater o.l. The compounds of formula I likewise form addition salts with organic or inorganic acids. Examples of such salts are hydrohalides, e.g. hydrochlorides, hydrobromides, hydro-iodides as well as other mineral acid salts such as sulphates, nitrates, phosphates etc., alkyl and mono-aryl sulphonates such as ethane sulphonates, toluene sulphonates, benzene sulphonates etc. and also other organic acid salts such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates, etc.

Saltene av forbindelsene med formel I kan være hydratisert. Hy-dratiseringen kan skje under fremstillingen eller etter hvert som følge av de hygroskopiske egenskapene til et først vann-fritt salt av en forbindelse med formel I. The salts of the compounds of formula I may be hydrated. The hydration can take place during the preparation or gradually as a result of the hygroscopic properties of an initially anhydrous salt of a compound of formula I.

De foran nevnte lavere alkylgrupper er enten rettlinjede eller forgrenede og kan inneholde opptil 7 karbonatomer, f.eks. metyl, etyl, n-propyl, isopropyl, n-pentyl, n-heptyl. Lavere alkoksy-grupper har analog betydning. Halogen betyr alle fire halogener, d.v.s. fluor, klor, brom og jod, foretrukket er klor og brom. The aforementioned lower alkyl groups are either linear or branched and can contain up to 7 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-pentyl, n-heptyl. Lower alkoxy groups have an analogous meaning. Halogen means all four halogens, i.e. fluorine, chlorine, bromine and iodine, preferably chlorine and bromine.

Foretrukne R-grupper er furyl, thienyl og fenyl, spesielt furyl. Som R^foretrekkes metyl. Foretrukne X-grupper er gruppen (c) samt gruppene (a) og (b) hvor en av de to restene R2og R^ henholdsvis R^og R,- er hydrogen og den andre metyl. Spesielt foretrukne X-grupper er 1,2,5,6-tetrahydr6-2-metyl-5,6-dioxo-as-triazin-3-yl og 1,4,5,6-tetrahydro-4-metyl-5,6-dioxo-as-tri-azin-3-yl-gruppen. Preferred R groups are furyl, thienyl and phenyl, especially furyl. As R^, methyl is preferred. Preferred X groups are the group (c) and the groups (a) and (b) where one of the two residues R 2 and R 2 and R 2 and R 2 respectively is hydrogen and the other methyl. Particularly preferred X groups are 1,2,5,6-tetrahydr6-2-methyl-5,6-dioxo-as-triazin-3-yl and 1,4,5,6-tetrahydro-4-methyl-5, 6-dioxo-as-tri-azin-3-yl group.

i Foretrukne forbindelser er (7R)-7-[2-(2-fury.l)-2-(methoxyimino^)-•—acetamido] -3-/ [ (1,2,5 , 6-tetrahydro-2-metyl-5 , 6-dioxo-as-triazi'n- -3-yl)thio]metyl/-3-cephem-4-karbonsyre og dennes salter samt hydratene av disse saltene. i Preferred compounds are (7R)-7-[2-(2-furyl)-2-(methoxyimino^)-•-acetamido]-3-/[(1,2,5,6-tetrahydro-2- methyl-5,6-dioxo-as-triaziin-3-yl)thio]methyl/-3-cephem-4-carboxylic acid and its salts as well as the hydrates of these salts.

Forbindelsene med formel I samt deres salter henholdsvis hydrater av saltene kan foreligge i den syn-isomefe form. eller i den anti-isomere form The compounds of formula I as well as their salts or hydrates of the salts can exist in the syn-isomeric form. or in the anti-isomeric form

henholdsvis som blandinger av disse to formene. Foretrukket er den syn-isomere formen henholdsvis blandinger hvori den syn-isomere formen dominerer. respectively as mixtures of these two forms. Preferred are the syn-isomeric form or mixtures in which the syn-isomeric form predominates.

Acylderivatene med formel I samt disse saltene henholdsvis hydroater av disse saltene fremstilles ifølge oppfinnelsen ved én fremgangsmåte som erkarakterisert vedat man The acyl derivatives of formula I as well as these salts or hydrates of these salts are prepared according to the invention by one process which is characterized by

a) omsetter en forbindelse med den generelle formela) reacts a compound with the general formula

hvor X har den i formel I angitte betydning og karboksyl- . where X has the meaning given in formula I and carboxyl- .

gruppen kan foreligge i beskyttet form, j the group may be available in protected form, j

med en syre med den generelle formel with an acid of the general formula

hvor,R og R^har den i formel I gitte betydning, eller med et reaktivt funksjonelt derivat av denne syren og avspalter beskyttelsesgruppen, eller at man b) omsetter en forbindelse med den generelle formel where,R and R^ have the meaning given in formula I, or with a reactive functional derivative of this acid and cleaves off the protecting group, or that one b) reacts a compound with the general formula

hvor R og har den i formel I gitte betydning, Y er where R and has the meaning given in formula I, Y is

en avgangsgruppe og karboksylgruppen kan foreligge i beskyttet form, a leaving group and the carboxyl group can be present in protected form,

med en tiol med den generelle formelwith a thiol of the general formula

hvor X har den i formel I gitte betydning, where X has the meaning given in formula I,

og avspalter beskyttelsesgruppen, hvoretter reaksjonsproduktet eventuelt overføres i et salt henholdsvis et hydrat av dette saltet.. and cleaves off the protective group, after which the reaction product is optionally transferred into a salt or a hydrate of this salt.

Karbbksylgruppene som er til stede i utgangsforbindelsene med formelene II og IV kan om ønsket være beskyttet, f.eks. ved forestring til en lett spaltbar ester som en silylester, f.eks. L—trimetylsilylesteren. Karboksylgruppen kan også være beskyttet ved saltdannelser med en uorganisk eller tertiær organisk base som trietylamin. The carboxyl groups present in the starting compounds with the formulas II and IV can be protected if desired, e.g. by esterification to an easily cleavable ester such as a silyl ester, e.g. The L—trimethylsilyl ester. The carboxyl group can also be protected by salt formation with an inorganic or tertiary organic base such as triethylamine.

Som reaktive funksjonelle derivater av syrer med formel III kommer f.eks. halogenider, d.v.s. klorider, bromider og fluor-ider, azider, anhydrider, særlig blandede anhydride.r med sterke syrer, reaktive estere, f.eks. N-hydroksy-succinimidester, og amider, f.eks. imidazolider, i betraktning. As reactive functional derivatives of acids with formula III come e.g. halides, i.e. chlorides, bromides and fluorides, azides, anhydrides, especially mixed anhydrides with strong acids, reactive esters, e.g. N-hydroxy-succinimide esters, and amides, e.g. imidazolides, in consideration.

Som avgangsgruppe Y av en forbindelse med formel IV kommer eks-empelvis halogener, f.eks, klor, brom eller jod, acyloksyrester, f.eks. lavere alkanoylrester som acetoksy, lavere alkyl eller arylsulfonyloksyrester som mesyloksy eller tosyloksy eller syreresten i betraktning. As leaving group Y of a compound of formula IV are, for example, halogens, e.g. chlorine, bromine or iodine, acyloxy acid residues, e.g. lower alkanoyl residues such as acetoxy, lower alkyl or arylsulfonyloxy acid residues such as mesyloxy or tosyloxy or the acid residue under consideration.

Omsetningen av en forbindelse med formel II med en syre med formel III eller et reaktivt funksjonelt derivat derav kan ut-føres på i og for seg kjent måte. Således kan man f.eks. kon-densere én fri syre med formel III med en av de nevnte estere sVarende til formel II ved hjelp av et karbodiimid som disyklo-heksylkarbodiimid i et inert løsningsmiddel som eddikkester, acetonitril, dioxan, kloroform, metylenklorid, benzen eller dimetylformamid og deretter avspalte estergruppen. I stedet for karbodiimider kan også oxazoliumsalter, f.eks. N-etyl-5-fenyl-isoxazolium-3<1->sulfonat anvendes som kondensasjonsmiddel. The reaction of a compound of formula II with an acid of formula III or a reactive functional derivative thereof can be carried out in a manner known per se. Thus, one can e.g. condense one free acid of formula III with one of the mentioned esters corresponding to formula II by means of a carbodiimide such as dicyclohexylcarbodiimide in an inert solvent such as acetic ester, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide and then cleave off the ester group . Instead of carbodiimides, oxazolium salts, e.g. N-ethyl-5-phenyl-isoxazolium-3<1->sulfonate is used as condensation agent.

Ifølge en annen utførelsesform omsetter man et salt av en syre med formel II, f.eks. et trialkylammoniumsalt, med.et reaktivt funksjonelt derivat av en syre med formel III som ovenfor nevnt i et inert løsningsmiddel, f.eks. et av de ovenfor nevnte. According to another embodiment, a salt of an acid with formula II is reacted, e.g. a trialkylammonium salt, with a reactive functional derivative of an acid of formula III as mentioned above in an inert solvent, e.g. one of the above mentioned.

Ifølge en videre utførelsesform omsettes et syrehalogenid, fortrinnsvis kloridet av en syre med formel III med aminet med formel II. Omsetningen skjer fortrinnsvis i nærvær av et.syre-bindende middel, f.eks. i nærvær av vahndig alkalie fortrinnsvis natronlut eller også i nærvær av et alkalimetallkarbonat som kaliumkarbonat, eller i nærvær av et lavere alkylert amin som trietylamin. Som løsningsmiddel anvendes fortrinnsvis According to a further embodiment, an acid halide, preferably the chloride of an acid of formula III, is reacted with the amine of formula II. The reaction preferably takes place in the presence of an acid-binding agent, e.g. in the presence of aqueous alkali, preferably caustic soda or also in the presence of an alkali metal carbonate such as potassium carbonate, or in the presence of a lower alkylated amine such as triethylamine. It is preferably used as a solvent

vann, men man kan også arbeide i et aprotisk, organisk løsnings-middel som f.eks. dimetylformamid, dimetylsulfoksid eller water, but you can also work in an aprotic, organic solvent such as e.g. dimethylformamide, dimethylsulfoxide or

heksametylfosforsyretriamid. hexamethylphosphoric acid triamide.

Omsetningen av en forbindelse med formel II med en.forbindelse med formel III eller et reaktivt funksjonert derivat derav kan gjerne skje ved temperaturer mellom ca. -40°C og romtemperatur, f.eks. ved ca. 0 - 10°C. The reaction of a compound of formula II with a compound of formula III or a reactively functionalized derivative thereof can preferably take place at temperatures between approx. -40°C and room temperature, e.g. at approx. 0 - 10°C.

Omsetningen av en forbindelse med formel IV med et thiol med formel V kan skje på i og for seg kjent måte, f.eks. ved en temperatur mellom ca 40 og 80°C, fortrinnsvis ved ca. 60°C i et polart løsningsmiddel, f.eks. i en alkohol som f.eks. i en lavere alkanol som etanol, propanol o.l., i diraetylformamid eller dimetylsulfoksid, fortrinnsvis i vann eller i en puffer-løsning med en pH på ca. 6 til' 7, fortrinnsvis 6,5. The reaction of a compound of formula IV with a thiol of formula V can take place in a manner known per se, e.g. at a temperature between about 40 and 80°C, preferably at about 60°C in a polar solvent, e.g. in an alcohol such as in a lower alkanol such as ethanol, propanol etc., in diethylformamide or dimethylsulfoxide, preferably in water or in a buffer solution with a pH of approx. 6 to' 7, preferably 6.5.

Etter avsluttet omsetning av en forbindelse med formel II eller IV med en forbindelse med formel III henholdsvis V avspaltes den ennå tilstedeværende beskyttelsesgruppe. Når beskyttelsesgruppen er en silylgruppe (silylester) kan denne gruppen spesielt lett avspaltes ved behandling av omsetningsproduktet. med vann. Når karboksylgruppen til syren med formel IV er beskyttet ved saltdannelse (med trietylamin), kan avspaltningen av denne saltdannende beskyttelsesgruppen skje ved behandling med syre. Som syre kan herunder f.eks. saltsyre, svovelsyre, fosforsyre eller sitronsyre anvendes. After completion of the reaction of a compound of formula II or IV with a compound of formula III or V, the protective group still present is cleaved off. When the protecting group is a silyl group (silyl ester), this group can be cleaved off particularly easily during treatment of the reaction product. with water. When the carboxyl group of the acid of formula IV is protected by salt formation (with triethylamine), the cleavage of this salt-forming protecting group can take place by treatment with acid. As an acid, e.g. hydrochloric acid, sulfuric acid, phosphoric acid or citric acid are used.

De 7 aminoforbindelsene med formel II som anvendes som utgangs-produkter kan fremstilles ut fra en forbindelse med formel The 7 amino compounds of formula II which are used as starting products can be prepared from a compound of formula

hvor Y er en avgangsgruppe og karboksylgru<p>pen kan foreligge i beskyttet form, | where Y is a leaving group and the carboxyl group can be present in protected form, |

med et thiol med formel V. Omsetningen kan skje under de samme betingelser som for utgangsproduktene IV og V. with a thiol of formula V. The reaction can take place under the same conditions as for the starting products IV and V.

En eventuelt erholdt syn/anti-blanding av en forbindelse med formel I kan oppspaltes i de tilsvarende syn- og anti-former på vanlig måte, f.eks. ved omkrystallisasjon eller ved kromato-grafiske metoder under anvendelse av et egnet løsningsmiddel henholdsvis løsningsmiddelblanding. An optionally obtained syn/anti mixture of a compound of formula I can be split into the corresponding syn and anti forms in the usual way, e.g. by recrystallization or by chromatographic methods using a suitable solvent or solvent mixture.

Forbindelsene med formel I, deres salter og hydroatene- av disse saltene er antibiotisk, spesielt bakterieidvirksomme. • Det er et bredt virkningsspektrum mot gram-positive og gram-negative mikroorganismer inklusive &-laktamase-produserende stafylo-kokker og forskjellige 3-laktamase-produsernede gram-negative bakterier som f.eks. hemofilus influensa, escherichia coli, proteus- og klebsiella-arter. The compounds of formula I, their salts and hydroethenes of these salts are antibiotic, particularly bactericidal. • There is a broad spectrum of action against gram-positive and gram-negative microorganisms including &-lactamase-producing staphylococci and various 3-lactamase-producing gram-negative bacteria such as e.g. haemophilus influenzae, escherichia coli, proteus and klebsiella species.

Forbindelsene med formel I samt de farmasøytisk fordragelige salter og hydratiserte former derav kan anvendes for behandling og profylakse av infeksjonssykdommer. For voksne kan en dags-dose på ca. lg til ca. 4 g anvendes. Parenteral administrering av forbindelsen ifølge oppfinnelsen er spesielt foretrukket. The compounds of formula I as well as the pharmaceutically acceptable salts and hydrated forms thereof can be used for the treatment and prophylaxis of infectious diseases. For adults, a daily dose of approx. add to approx. 4 g is used. Parenteral administration of the compound according to the invention is particularly preferred.

For påvisning av antimikrobiell virkning av forbindelsen ifølge oppfinnelsen ble følgende representative representanter under-søkt: Produkt A: (7R)-7-[2-(2-furyl)-2-(metoksyimino)-actamido]-3- /[(1,2,5,6-tetrahydro-2-metyl-5,6-dioksd-as-tri-az,in-3-yl) thio]metyl/-3-cephem-4-karbonsyre To demonstrate the antimicrobial effect of the compound according to the invention, the following representatives were examined: Product A: (7R)-7-[2-(2-furyl)-2-(methoxyimino)-actamido]-3- /[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxd-az-tri-az,in-3-yl)thio]methyl/-3-cephem-4-carboxylic acid

Produkt B: (7R)-7-[2-(2-furyl)-2-(metoksyimino)acetamido]-3-/[1-amino-l, 2-dihydro-2-okso-4 -pyrimidinyl)-thio] Product B: (7R)-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-3-[1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio ]

-metyl/-3-cephem-4-carbonsyre-methyl/-3-cephem-4-carboxylic acid

Produkt C: (7R)-7-[2-(fenyl)-2-(metoksyimino) acetamido],-3-/- Product C: (7R)-7-[2-(phenyl)-2-(methoxyimino)acetamido],-3-/-

[(1,2,5,6-tetrahydro-2-metyl-5,6-diokso-as-tria-zin-3-yl) thio,]metyl/-3-cephem-4-karbonsyre Produkt D: (7R)-7-[2-(2-furyl)-2-(metoksyimino)acetamido]-3-/[(1,4,5,6-tetrahydro-4-mety1-5,6diokso-as-tri-azin-3-yl)thio]metyl/-3-cephem-4-karbonsyre [(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-az-tria-zin-3-yl)thio,]methyl/-3-cephem-4-carboxylic acid Product D: (7R )-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-3-/[(1,4,5,6-tetrahydro-4-methyl-5,6dioxo-az-tri-azine- 3-yl)thio]methyl/-3-cephem-4-carboxylic acid

Produkt E: (7R)-7-[ 2-(metoksyimino)-2-(2-thienyl)acetamido] Product E: (7R)-7-[ 2-(Methoxyimino)-2-(2-thienyl)acetamido]

-3-/ [ (1,2,5,6-tetrahydro-2-metyl-5,6-diokso-as-triazin-3-yl) thio ]metyl/-3-cephem-4-karbonsyre -3-/[ (1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl/-3-cephem-4-carboxylic acid

Produkt F: (7R)-3-/[(1-etyl-l,4,5,6-tetrahydro-5,6-diokso-as-tri'azin-3-yl)thio]metyl/-7-[2-(2-furyl)-2— Product F: (7R)-3-[(1-ethyl-1,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-yl)thio]methyl/-7-[ 2-(2-furyl)-2—

(metoksyimino)acetamido]-3-cephem-4-karbonsyre Produkt G: (7R)-7-/2-[(carbamoylmetoksy)imino]-2-(2-furyl)-acetamido/-3-/[(1,4,5,6-tetrahydro-4-metyl-5,6-diokso-as-triazin-3-yl)thio]metyl/-3-cephem-4-karbonsyre. (Methoxyimino)acetamido]-3-cephem-4-carboxylic acid Product G: (7R)-7-/2-[(carbamoylmethoxy)imino]-2-(2-furyl)-acetamido/-3-/[(1, 4,5,6-tetrahydro-4-methyl-5,6-dioxo-az-triazin-3-yl)thio]methyl/-3-cephem-4-carboxylic acid.

Aktivitet in vivo Grupper på 10 mus infiseres intraperitonealt med en vandig sus-pensjon av proteus mirabilis. En time etter infeksjonen appliseres forsøkssubstansen subkutant. Antallet av overlevende dyr bestemmes på 4. dag. Det appliseres forskjellige doseringer, og ved interpolering bestemmes den dose hvorved 50% av for-søksdyrene overlevet (CD^Q, mg/kg). Toksisitet (mus, 24-timers verdi) Activity in vivo Groups of 10 mice are infected intraperitoneally with an aqueous suspension of proteus mirabilis. One hour after the infection, the test substance is applied subcutaneously. The number of surviving animals is determined on the 4th day. Different dosages are applied, and by interpolation the dose at which 50% of the test animals survived is determined (CD^Q, mg/kg). Toxicity (mouse, 24-hour value)

Farmasøytiske preparater , fortrinnsvis tørre.ampuller, kan inneholde forbindelser med formel I, deres salter eller hydratiserte former av disse salter, eventuelt i blanding med et annet terapeutisk verdifullt stoff. Gjerne er de blandet med en spesielt egnet farmasøytisk, uorganisk eller organisk inert bærer for parenteral applikasjon som f.eks. med vann, gummi arabicum. De farmasøytiske preparater foreligger fortrinnsvis i flytende form, f.eks. som løsninger, suspensjoner eller emulsjoner. Eventuelt er de sterilisert og henholdsvis eller inneholder hjelpestoffer som konserverings-., stabiliserings-, fukte eller emul-geringsmidler, salter for endring av det osmotiske trykk eller puffer. Pharmaceutical preparations, preferably dry ampoules, may contain compounds of formula I, their salts or hydrated forms of these salts, possibly in admixture with another therapeutically valuable substance. They are preferably mixed with a particularly suitable pharmaceutical, inorganic or organic inert carrier for parenteral application such as e.g. with water, gum arabic. The pharmaceutical preparations are preferably in liquid form, e.g. as solutions, suspensions or emulsions. Optionally, they are sterilized and respectively or contain auxiliary substances such as preservatives, stabilisers, wetting or emulsifying agents, salts for changing the osmotic pressure or buffers.

Fremstilling av natriumsaltet av (7R)-7-t2-(2-furyl)-2-(metoksyimino) acetamido]-3-/[(1,2,5,6-tetrahydro-2-metyl-5,6-diokso-as-triazin-3-yl)thio]metyl/-3-cephem-4-karbonsyre: 5,06 g 2-metoksyimino-2-furyl-eddikksyre (syn/anti-blanding Preparation of the sodium salt of (7R)-7-t2-(2-furyl)-2-(methoxyimino)acetamido]-3-/[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo -as-triazin-3-yl)thio]methyl/-3-cephem-4-carboxylic acid: 5.06 g 2-methoxyimino-2-furyl-acetic acid (syn/anti mixture

00:20)oppløses i 150 ml benzen og blandes under nitrogengjennomblåsning ved 5 - 10°C med 4,2 ml trietylamin, 2,6 ml oksalylklorid og 6 dråper dimetylformamid. Blandingen røres 1 time ved 5 - 10°C og 1/2 time ved 25°C under nitrogengjennom-.blåsning og inndampes deretter i våkum ved 40°C. Resten suspenderes i 150 ml aceton og blandes ved 0°C med. en løsning av 11,2 g (7R)-7-amino-3-desacetoksy-3-[(1,2,5,6-tetrahydro-2-metyl-5,6-diokso-as-triazin-3-yl)-thio]-cephalosporansyre i 150 ml vann som forut var innstilt på pH 7,5 ved hjelp av 2-n vandig natronlut. Reaksjonsblandingen røres 2 1/2 time under nitrogen og ved 0 - 10°C, hvorved pH holdes mellom 7,5 og 8,0 ved hjelp av tilsetning av 2-n vandig natronlut. Så tilsettes 500 ml eddikkester og pH innstilles på 1,5 med 2-n vandig saltsyre. Etter adskillelsen av den organiske fasen ekstraheres de vandige fasene 1 gang med eddikkester. De forenede organiske fasene vaskes 2 ganger med mettet vandig koksaltløsning, tørkes over natriumsulfat og inndampes til et volum på ca. 100 ml. Resten filtreres fra uløst materiale og det erholdte 00:20) is dissolved in 150 ml of benzene and mixed under nitrogen blowing at 5 - 10°C with 4.2 ml of triethylamine, 2.6 ml of oxalyl chloride and 6 drops of dimethylformamide. The mixture is stirred for 1 hour at 5 - 10°C and 1/2 hour at 25°C under nitrogen blowing and then evaporated in a vacuum at 40°C. The residue is suspended in 150 ml of acetone and mixed at 0°C with. a solution of 11.2 g of (7R)-7-amino-3-desacetoxy-3-[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl )-thio]-cephalosporanic acid in 150 ml of water which had previously been adjusted to pH 7.5 using 2-N aqueous sodium hydroxide solution. The reaction mixture is stirred for 2 1/2 hours under nitrogen and at 0 - 10°C, whereby the pH is kept between 7.5 and 8.0 by means of the addition of 2-n aqueous caustic soda. Then 500 ml of acetic acid is added and the pH is adjusted to 1.5 with 2-n aqueous hydrochloric acid. After the separation of the organic phase, the aqueous phases are extracted once with acetic acid. The combined organic phases are washed twice with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated to a volume of approx. 100 ml. The remainder is filtered from undissolved material and that obtained

orangefargede filtratet fortynnes med 1000 ml eter. Den derved amorft utfelte (7R)-7-[2-(2-furyl)-2-(metoksyimino)acetamido ]-3-/[(1,2,5,6-tetrahydro-2-mety1-5,6-diokso-as-triazin-3-yl) thio]metyl/-"3-cephem-4-karbonsyre frafiltreres og vaskes med eter og lavtkokende petroleter. Det erholdte beige-farvede produktet løses i 250 ml eddikkester og filtreres fra uoppløst materiale. Det orange-fargede filtratet blandes med 10 ml av en 2-n løsning av 2-etylkapronsyre-natriumsalt i the orange colored filtrate is diluted with 1000 ml of ether. The thereby amorphously precipitated (7R)-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-3-/[(1,2,5,6-tetrahydro-2-methyl-5,6- dioxo-as-triazin-3-yl)thio]methyl/-"3-cephem-4-carboxylic acid is filtered off and washed with ether and low-boiling petroleum ether. The beige-coloured product obtained is dissolved in 250 ml of acetic acid and filtered from undissolved material. The the orange-coloured filtrate is mixed with 10 ml of a 2-n solution of 2-ethylcaproic acid sodium salt in

eddikkester, hvorved natriumsaltet av (7R)-7-[2-(2-furyl)-2-(metoksyimino)acetamido]-3-/[(1,2,5,6-tetrahydro-2-metyl-5,6-diokso-as-triazin-3-yl)thio]metyl/-3-cephem-4-karbonsyre ut-felles. Dette frafiltreres, vaskes med eddikkester og lavtkokende petroleter og tørkes 2 dager i våkum ved 2 5°C. Det erholdte produktet er et beige-farget pulver (syn/anti-bland- , (-ing 80:20). [ci]q<0>= -108,6° (c 0,5 i vann) . Rf-verdi=0, 10 acetic ester, whereby the sodium salt of (7R)-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-3-/[(1,2,5,6-tetrahydro-2-methyl-5,6 -dioxo-az-triazin-3-yl)thio]methyl/-3-cephem-4-carboxylic acid is precipitated. This is filtered off, washed with acetic acid and low-boiling petroleum ether and dried for 2 days in a vacuum at 25°C. The product obtained is a beige-colored powder (syn/anti-blend- , (-ing 80:20). [ci]q<0>= -108.6° (c 0.5 in water) . Rf value =0.10

(DC på kiselgel-F254-ferdigplater i systemet butanol/iseddikk/ (DC on silica gel F254 finished plates in the system butanol/glacial vinegar/

vann 4:1:1; synlig med UV-lys). water 4:1:1; visible with UV light).

Eksempel 2 Example 2

Fremstilling av natriumsaltet av (7.R)-7- [2- (2-furyl)-2-metoksyimino)acetamido]-3-/[1-amino-l,2-dihydro-2-okso-4-pyrimidinyl) thio]-metyl/-3-cephem-4-karbonsyre: Denne forbindelsen fremstilles analogt eksempel 1 fra 3,4 g 2-metoksyimino-2-furyl-eddikksyre og 7,11 g (7R)-7-amino-3-desacetoksy-3-[(1-amino-l,2-dihydro-2-okso-4-pyrimidinyl)-thio]-cephalosporansyre. Produktet er et beige pulver (syn/anti-blanding 70:30). Rf-verdi = 0,40 (DC på kiselgel-F254-ferdigplater i systemet butanol/iseddikk/vann 4:1:1; synlig med UV-lys). Preparation of the sodium salt of (7.R)-7-[2-(2-furyl)-2-methoxyimino)acetamido]-3-([1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl) thio]-methyl/-3-cephem-4-carboxylic acid: This compound is prepared analogously to example 1 from 3.4 g of 2-methoxyimino-2-furyl-acetic acid and 7.11 g of (7R)-7-amino-3-desacetoxy -3-[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]-cephalosporanic acid. The product is a beige powder (syn/anti mixture 70:30). Rf value = 0.40 (DC on silica gel F254 finished plates in the system butanol/glacial vinegar/water 4:1:1; visible with UV light).

Eksempel 3Example 3

Fremstilling av natriumsaltet av (7R)-7-[2-(fenyl)-2-(metoksyimino) acetamido] -3-/'[ 1,2,5 , 6-tetrahydro-2-metyl-5 , 6-diokso-as-triazin-3-yl)thio]metyl/-3-cephem-4-karbonsyre: Denne forbindelsen fremstilles analogt eksempel 1 av 1,8 g 2-metoksyimino-fenyl-eddikksyre (syn/anti-blanding 90:10) dg 3,7 3g (7R)-7-amino-3-desacetoksy-3-[(1,2,5,6-tetrahydro-2-metyl-5,6-diokso-as-triazin-3-yl)-thio]-cephalosporansyre. Produktet er et beige pulver (syn/anti-blanding 90:10). Preparation of the sodium salt of (7R)-7-[2-(phenyl)-2-(methoxyimino)acetamido]-3-/'[ 1,2,5 , 6-tetrahydro-2-methyl-5 , 6-dioxo- as-triazin-3-yl)thio]methyl/-3-cephem-4-carboxylic acid: This compound is prepared analogously to example 1 from 1.8 g of 2-methoxyimino-phenyl-acetic acid (syn/anti mixture 90:10) dg 3.7 3g (7R)-7-amino-3-desacetoxy-3-[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)-thio ]-cephalosporanic acid. The product is a beige powder (syn/anti mixture 90:10).

[a]p° = -135° (c = 0,5 i vann). Rf-verdi = 0,17 (DC på kiselgel-F2^^-ferdigplater i systemet butanol/iseddikk/vann 4:1:1, synlig med UV-lys). [a]p° = -135° (c = 0.5 in water). Rf value = 0.17 (DC on silica gel F2^^ finished plates in the system butanol/glacial vinegar/water 4:1:1, visible with UV light).

Eksempel 4Example 4

Fremstilling av natriumsaltet av (7R)-7-[2-(2-furyl)-2-(metoksyimino) acetamido]-3-/[(1,4,5,6-tetrahydro-4-metyl-5,6-diokso-as-triazin-3-yl)thio]metyl/-3-cephem-4-karbonsyre:<!>i Denne forbindelsen fremstilles analogt eksempel 1 av 3,4 g 2-metoksyimino-2-furyl-eddikksyre (syn/anti-blanding 80:20) og 7,46 g (7R)-7-amino-3-desacetoksy-3-[(1,4,5,6-tetrahydro-4-metyl-5,6-diokso-as-triazin-3-yl)-thio]-cephalosporansyre.Produktet er et beige pulver (syn/anti-blanding 80:20). [a]D 20= -44° (c - 0,5 i vann). Rf-verdi = 0,34 (DC på kiselgel-F254ferdigplater i systemet butanol/iseddikk/vann 4:1:1; synlig med UV-lys). Preparation of the sodium salt of (7R)-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-3-/[(1,4,5,6-tetrahydro-4-methyl-5,6- dioxo-as-triazin-3-yl)thio]methyl/-3-cephem-4-carboxylic acid:<!>i This compound is prepared analogously to example 1 from 3.4 g of 2-methoxyimino-2-furyl-acetic acid (syn/ anti-mixture 80:20) and 7.46 g of (7R)-7-amino-3-desacetoxy-3-[(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as- triazin-3-yl)-thio]-cephalosporanic acid. The product is a beige powder (syn/anti mixture 80:20). [a]D 20 = -44° (c - 0.5 in water). Rf value = 0.34 (DC on silica gel F254 finished plates in the system butanol/glacial vinegar/water 4:1:1; visible with UV light).

Eksempel 5 Example 5

Fremstilling av natriumsaltet av (7R)-7-[2-(metoksyimino)-2-(2-thienyl)acetamido]-3-/[(1,2,5,6-tetrahydro-2-metyl-5,6-diokso-as-triazin-3-yl)thio]metyl/-3-cephem-4-karbonsyre: Denne forbindelsen fremstilles analogt eksempel 1 av 1,85 g 2-metoksyimino-2-thienyl-eddikksyre (syn/anti-blanding ca. Preparation of the sodium salt of (7R)-7-[2-(methoxyimino)-2-(2-thienyl)acetamido]-3-/[(1,2,5,6-tetrahydro-2-methyl-5,6- dioxo-as-triazin-3-yl)thio]methyl/-3-cephem-4-carboxylic acid: This compound is prepared analogously to example 1 from 1.85 g of 2-methoxyimino-2-thienyl-acetic acid (syn/anti mixture approx. .

70:30) og 3,71 g (7R)-7-amino-3-desacetoksy-3-[(1,2,5,6-tetra-hydro-2-metyl-5,6-diokso-as-triazin-3-yl)thio]-cephalosporansyre . Produktet er et beige pulver (syn/anti-blanding ca. 70:30). [ct]^° = -128,2° (c = 0,5 i vann). Rf-verdi = 0,21 70:30) and 3.71 g (7R)-7-amino-3-desacetoxy-3-[(1,2,5,6-tetra-hydro-2-methyl-5,6-dioxo-as-triazine -3-yl)thio]-cephalosporanic acid. The product is a beige powder (syn/anti mixture approx. 70:30). [ct]^° = -128.2° (c = 0.5 in water). Rf value = 0.21

(DC på kiselgel-F2^4-ferdigplater i systemet butanol/iseddikk/- vann 4:1:1, synlig med UV-lys). (DC on silica gel F2^4 finished plates in the system butanol/glacial vinegar/water 4:1:1, visible with UV light).

Eksempel 6Example 6

Fremstilling av dinatriumsaltet av (7R)-7-[2-(2-furyl)-2-(metoksyimino)acetamido]-3-/[(2,5-dihydro-2-metyl-5-okso-6-hydroksy-as-triazin-3-yl)thio]metyl/-3-cephem-4-karbonsyre: Denne forbindelsen fremstilles analogt eksempel 1 av 10,12 g 2-metoksyimino-2-furyl-eddikksyre (syn-isomer) og 18,7 g (7R)-7-amino-3-desacetoksy-3-[(1,2,5,6-tetrahydro-2-metyl-5,6-diokso-as-triazin-3-yl)thio]-cephalosporansyre. Ved saltdannelsen anvendes 20 ml (2 ekvivalente) av en 2-n-løsning av 2-etylkapronsyre-natriumsalt i eddikkester. Produktet er et praktisk talt fargeløst pulver (syn-isomer). tQ]D = -141,6° (c = 0,5 i vann). I... Rf-verdi =0,14 (DC på kisel<gel-F>254-ferdigplater i systemet I butanol/iseddikk/vann 4:1:1, synlig med UV-lys). Preparation of the disodium salt of (7R)-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-3-/[(2,5-dihydro-2-methyl-5-oxo-6-hydroxy- as-triazin-3-yl)thio]methyl/-3-cephem-4-carboxylic acid: This compound is prepared analogously to example 1 from 10.12 g of 2-methoxyimino-2-furyl-acetic acid (syn isomer) and 18.7 g (7R)-7-amino-3-desacetoxy-3-[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio]-cephalosporanic acid. In the salt formation, 20 ml (2 equivalents) of a 2-n solution of 2-ethylcaproic acid sodium salt in acetic ester are used. The product is a practically colorless powder (syn isomer). tQ]D = -141.6° (c = 0.5 in water). I... Rf value =0.14 (DC on silicon<gel-F>254 finished plates in the system I butanol/glacial vinegar/water 4:1:1, visible with UV light).

Eksempel 7Example 7

Fremstilling av natriumsaltet av (7R)-3-/[(l-etyl-1,4,5,6-tetrahydro-5,6-diokso-as-triazin-3-yl)thio]metyl/-7-[2-(2-f ur,yl) -2- (metoksyimino) acetamido] -3-cephem-4-karbonsyre : Denne forbindelsen fremstilles analogt eksempel 1 av 1,69 g .2-metoksyimino-2-furyl-eddikksyre (syn-isomer) og 3.85 g (7R)-7-amino-3-desacetoksy-3-[(l-ety1-1,4,5,6-tetrahydro-5,6-diokso-as-triazin-3-yl)thio]-cephalosporansyre. Produktet er et beige pulver (syn/anti-blanding ca. 70:30). [a]p = -47,2° (c = 0,5 i vann). Rf-verdi = 0,47 (DC på kiselgel-F254-ferdigplater i systemet butanol/iséddikk/vann 4:1:1, synlig med UV-lys). Preparation of the sodium salt of (7R)-3-/[(1-ethyl-1,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-yl)thio]methyl/-7-[2 -(2-fur,yl)-2-(methoxyimino)acetamido]-3-cephem-4-carboxylic acid: This compound is prepared analogously to example 1 from 1.69 g of 2-methoxyimino-2-furyl-acetic acid (syn- isomer) and 3.85 g (7R)-7-amino-3-desacetoxy-3-[(1-ethyl-1,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-yl)thio ]-cephalosporanic acid. The product is a beige powder (syn/anti mixture approx. 70:30). [a]p = -47.2° (c = 0.5 in water). Rf value = 0.47 (DC on silica gel F254 finished plates in the system butanol/glacial acetic acid/water 4:1:1, visible with UV light).

Eksempel 8 Example 8

Fremstilling av natriumsaltet av (7R)-7-/2-[(karbamoyl-metoksy)-imino]-2-(2-furyl)acetamido/-3-/[(1,4,5,6-tetrahydro-4-metyl-5,6-diokso-as-triaziri-3-yl)thio]metyl/-3-cephem-4-karbonsyre: 9,76 g /o-{ (karbamoylmetoksy) imino] furfuryl/cephalosporin natriumsalt (syn/anti-blanding ca. 70:30) suspenderes sammen med 4,77 g 1,4,5,6-tetrahydro-4-metyl-5,6-diokso-3-merkapto-as-triazin i 200 ml fosfatpuffer med pH 6,4. Under nitrogengjennomblåsning stilles pH på 6,4, med l-n natronlut hvorved en mørk løsning oppstår. Denne løsningen røres 6 timer ved 55 - 60°C under nitrogengjennomblåsning ved pH 6,4 - 6,5, hvorved pH holdes konstant ved hjelp av en autotitrator under tilsetning av l-n natronlut. Réaksjonsløsningen avkjøles til 0 - 5°C og pH stilles på 2 med 2-n saltsyre, hvorved reaksjonsproduktet felles som syre. Dette filtreres, vaskes med isvann og tørkes i våkum ved 40°C natten over. Man får sluttproduktet i form av den rå syren. For rensning løses denne i 150 ml metanol Preparation of the sodium salt of (7R)-7-(2-[(carbamoyl-methoxy)-imino]-2-(2-furyl)acetamido/-3-/[(1,4,5,6-tetrahydro-4- methyl-5,6-dioxo-as-triaziri-3-yl)thio]methyl/-3-cephem-4-carboxylic acid: 9.76 g /o-{ (carbamoylmethoxy) imino] furfuryl/cephalosporin sodium salt (syn/anti -mixture approx. 70:30) is suspended together with 4.77 g of 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-3-mercapto-as-triazine in 200 ml of phosphate buffer with pH 6, 4. During nitrogen blowing, the pH is set to 6.4, with 1-1 caustic soda, which results in a dark solution. This solution is stirred for 6 hours at 55 - 60°C under nitrogen blowing at pH 6.4 - 6.5, whereby the pH is kept constant with the help of an autotitrator while adding 1-1 sodium hydroxide solution. The reaction solution is cooled to 0 - 5°C and the pH is adjusted to 2 with 2-n hydrochloric acid, whereby the reaction product is precipitated as acid. This is filtered, washed with ice water and dried in a vacuum at 40°C overnight. You get the final product in the form of the crude acid. For purification, this is dissolved in 150 ml of methanol

og løsningen kokes med aktivt kull i 2 min. Blandingen filtreres gjennom et foldefilter og det orangefargede filtrat-let inndampes i våkum. Den derved utskilte harpiks skildes and the solution is boiled with activated charcoal for 2 min. The mixture is filtered through a folding filter and the orange colored filtrate is evaporated in vacuo. The resulting resin is separated

fra og kastes. Den konsentrerte metanolløsningen helles i eter. Den derved utfelte syre frafiltreres, vaskes med eter og lavtkokende petroleter. Man får sluttproduktet i form av den rensede syre, som for overføring i natriumsaltet oppløses i 100 ml metanol og blandes med 5 ml av en 2-n løsning av 2-etylkapronsyre-natriumsalt i eddikkester. Litt uoppløst sub-stans frafiltreres og det orangefargede filtratet inndampes from and thrown away. The concentrated methanol solution is poured into ether. The thus precipitated acid is filtered off, washed with ether and low-boiling petroleum ether. The end product is obtained in the form of the purified acid, which for transfer into the sodium salt is dissolved in 100 ml of methanol and mixed with 5 ml of a 2-n solution of 2-ethylcaproic acid sodium salt in acetic acid. A little undissolved substance is filtered off and the orange-coloured filtrate is evaporated

i våkum ved 4 0°C. Denne konsentrerte løsningen tilsettes etanol, hvorved natriumsaltet faller ut. Dette frafiltreres, vaskes med etanol og lavtkokende petroleter og tørkes natten over i våkum ved 40°C. Man får natriumsaltet av (7R)-7-/2-[(karbamoylmetoksy)imino]-2-(2-furyl)acetamido/-3-/[(1,4,5,6-tetrahyd-ro-4-metyl-5,6-diokso-as-triazin-3-yl)thio]metyl/-3-cephem-4-karbonsyre som beige pulver (syn/anti-blanding ca. 70:30). in vacuum at 40°C. Ethanol is added to this concentrated solution, whereby the sodium salt is precipitated. This is filtered off, washed with ethanol and low-boiling petroleum ether and dried overnight in a vacuum at 40°C. The sodium salt of (7R)-7-/2-[(carbamoylmethoxy)imino]-2-(2-furyl)acetamido/-3-/[(1,4,5,6-tetrahydro-4-methyl) is obtained -5,6-dioxo-as-triazin-3-yl)thio]methyl/-3-cephem-4-carboxylic acid as beige powder (syn/anti mixture approx. 70:30).

[a]p° = -30,1° (c = 1 i vann), Rf = 0,29 (DC på kiselgel-F254~ferdigplater i systemet butanol/iseddikk/vann 4:1:1, synlig med UV-lys). ■ [a]p° = -30.1° (c = 1 in water), Rf = 0.29 (DC on silica gel-F254~finished plates in the system butanol/glacial vinegar/water 4:1:1, visible with UV light ). ■

Erstatter man utgangsmaterialene med ekvivalente mengder /a-[metoksy)imino]furfuryl/cephalosporin og 1,2,5,6-tetrahydro-2-metyl-5,6-dioxo-3-merkapto-as-triazin, får man under ellers like betingelser natriumsaltet av(7R)-7-[2-(2-furyl)-2-(metoksyimino) acetamido] - 3-/ [,(1, 2 ,5 , 6-tetrahydro-2-metyl-5 , 6-diokso-as-triazin-3-yl)thio]metyl/-3-cephem-4-karbonsyre. Produktet er identisk med den forbindelse man får ifølge eksempel 1. If one replaces the starting materials with equivalent amounts of /α-[methoxy)imino]furfuryl/cephalosporin and 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-3-mercapto-as-triazine, one obtains under otherwise similar conditions the sodium salt of (7R)-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-3-/[,(1,2,5,6-tetrahydro-2-methyl-5,6 -dioxo-az-triazin-3-yl)thio]methyl/-3-cephem-4-carboxylic acid. The product is identical to the compound obtained according to example 1.

Eksempel 9Example 9

Fremstilling av tørre ampuller for intramuskulær administrering: På vanlig måte fremstilles et lyofilisat av 1 g av natriumsatet av (7R) - 7- [ 2 - (2-furyl) -2 - (metoksyimino) acetamido] -3-/ [.(1, 2 , 5 , 6-tetrahydro-2-metyl-5,6-diokso-as-triazin-3-yl)thio]metyl/-3-cephem-karbonsyre og fylles i en ampulle. Før. administrering blandes sistnevnte med 2,5 ml av en 2%-ig vandig lidokainhydro-klorid-løsning. Preparation of dry ampoules for intramuscular administration: A lyophilisate of 1 g of the sodium satate of (7R) - 7- [ 2 - (2-furyl) -2 - (methoxyimino) acetamido] -3-/ [.(1 , 2 , 5 , 6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl/-3-cephem-carboxylic acid and fill into an ampoule. For. administration, the latter is mixed with 2.5 ml of a 2% aqueous lidocaine hydrochloride solution.

Claims (18)

1. Fremgangsmåte véd fremstilling av acylderivater med den generelle formel 1. Process for the preparation of acyl derivatives with the general formula hvor R betyr furyl, thienyl eller eventuelt med halogen, hydroksy, lavere alkoksy eller lavere alkylsubstituert fenyl, R^ lavere alkyl eller aminokarbonylmetyl og X en gruppe med formelene where R means furyl, thienyl or optionally with halogen, hydroxy, lower alkoxy or lower alkyl-substituted phenyl, R^ lower alkyl or aminocarbonylmethyl and X a group with the formulas hvor en av de to restene R2 og R^ henholdsvis R^ og R^ er hydrogen og den andre lavere alkyl, karboksymetyl eller sulfometyl, samt salter av disse forbindelsene og hydrater av disse saltene, karakterisert ved at mana) omsetter en forbindelse med den generelle formel where one of the two residues R2 and R^ respectively R^ and R^ is hydrogen and the other lower alkyl, carboxymethyl or sulfomethyl, as well as salts of these compounds and hydrates of these salts, characterized in that mana) reacts with a compound with the general formula hvor X har den i formel 1 gitte betydning og karboksy-gruppen kan foreligge i beskyttet form, med- en syre med den generelle formel where X has the meaning given in formula 1 and the carboxy group can be present in protected form, med- an acid with the general formula hvor R og R^ har den i formel I gitte betydning, eller med et reaktivt funksjonelt derivat av denne syren og som avspalter beskyttelsesgruppen, eller at manb) omsetter en forbindelse med den generelle formel where R and R^ have the meaning given in formula I, or with a reactive functional derivative of this acid and which cleaves the protecting group, or that manb) reacts with a compound of the general formula hvor R og R^ har den i formel I gitte betydning, Y er en avgangsgruppe <p> g karboksylgruppen kan foreligge i beskyttet form, méd en thiol med den generelle formel HS X V hvor X har den i formel I gitte betydning, <p> g avspalter beskyttelsesgruppen, hvoretter man overfører reaksjonsproduktet eventuelt, i et salt henholdsvis et hydrat av dette saltet.where R and R^ have the meaning given in formula I, Y is a leaving group <p> and the carboxyl group can be present in protected form, with a thiol of the general formula HS X V where X has the meaning given in formula I, <p> g cleaves off the protective group, after which the reaction product is optionally transferred into a salt or a hydrate of this salt. 2. Fremgangsmåte ifølge krav I, karakterisert ved at man går ut fra en utgangsforbindelse med formel II og en syre med formel III eller et reaktivt funksjonelt derivat av en slik syre.2. Method according to claim I, characterized in that one starts from a starting compound of formula II and an acid of formula III or a reactive functional derivative of such an acid. 3. Fremgangsmåte ifølge krav 2, karakterisert ved at man omsetter kloridet av en syre med formel III med en utgangsforbindelse med formel II i vandig alkalie.3. Method according to claim 2, characterized in that the chloride of an acid of formula III is reacted with a starting compound of formula II in aqueous alkali. 4. Fremgangsmåte ifølge ett av kravene 1 til 3 ved fremstilling av forbindelser med formel I, hvor R er furyl, samt av disses salter henholdsvis hydrater av disse salter, karakterisert ved at man anvender . tilsvarende substituerte utgangsforbindelser.4. Method according to one of claims 1 to 3 for the preparation of compounds of formula I, where R is furyl, as well as their salts or hydrates of these salts, characterized by using . correspondingly substituted starting compounds. 5. Fremgangsmåte ifølge ett av kravene 1 til 4 ved fremstilling av forbindelser med formel I, hvor R^ er metyl samt av disses salter henholdsvis av hydrater av disse.salter, karakterisert ved at man anvender tilsvarende substituerte utgangsforbindelser.5. Method according to one of claims 1 to 4 for the preparation of compounds of formula I, where R 1 is methyl and of their salts or hydrates of these salts, characterized in that correspondingly substituted starting compounds are used. 6. Fremgangsmåte ifølge ett av kravene 1 til 5 ved fremstilling av forbindelser med formel I, hvor X betyr gruppen (c) eller en av gruppene (a) og (b) hvori en av de to restene R2 og R^ henholdsvis R^ og R^ betyr hydrogen og den andre metyl, samt av disses salter henholdsvis hydrater av disse salter, karakterisert ved at man anvender tilsvarende substituerte utgangsforbindelser.6. Method according to one of claims 1 to 5 for the preparation of compounds of formula I, where X means the group (c) or one of the groups (a) and (b) in which one of the two residues R2 and R^ respectively R^ and R 1 means hydrogen and the other methyl, as well as their salts or hydrates of these salts, characterized by the use of correspondingly substituted starting compounds. 7. Fremgangsmåte ifølge krav 6 ved fremstilling av forbindelser med formel I, hvor X er en 1,2,5,6-tetrahydro-2-metyl-5,6-diokso-as-triazin-3-yl-gruppe, samt avdisses salter henholdsvis av hydrater av disse salter, karakterisert v e d at man anvender tilsvarende substituerte utgangsfor bindelser..7. Process according to claim 6 for the preparation of compounds of formula I, where X is a 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl group, as well as detd. salts respectively of hydrates of these salts, characterized by using correspondingly substituted starting materials bonds.. 8. Fremgangsmåte ifølge krav 6 ved fremstilling av forbindelser med formel I, hvor X er 1,4,5,6-tetrahydro-4-metyl-5,6-diokso-as-triazin-3-yl-gruppen, samt av disses salter henholdsvis av hydrater av disse salter, . karakterisert v e d at man anvender tilsvarende substituerte utgangsforbindelser.8. Process according to claim 6 for the preparation of compounds of formula I, where X is the 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl group, as well as of these salts respectively of hydrates of these salts, . characterized by using correspondingly substituted starting compounds. 9. Fremgangsmåte ifølge krav 7 ved fremstilling av (7R)-7-[2-(2-furyl)-2-(metoksyimino)acetamido]-3-/[(1,2,5,6-tetrahydro-2-met.yl-5 ,6-diokso-as-triazin-3-yl) thio] me tyl/-3-cephem-4-karbonsyre samt av disses salter henholdsvis hydrater av disse salter, karakterisert ved at man anvender tilsvarende substituerte utgangsforbindelser.9. Process according to claim 7 in the preparation of (7R)-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-3-/[(1,2,5,6-tetrahydro-2-met .yl-5,6-dioxo-as-triazin-3-yl)thio]methyl/-3-cephem-4-carboxylic acid as well as their salts or hydrates of these salts, characterized by using correspondingly substituted starting compounds. 10. Fremgangsmåte ved fremstilling av farmasøytiske preparater karakterisert ved at mån blander en forbindelse med den generelle formel 10. Procedure for the production of pharmaceutical preparations characterized by mixing a compound with the general formula hvor R betyr furyl, thienyl eller eventuelt ved halogen, hydroksyl, lavere alkoksy eller lavere alkylsubstituert f enyl, R-^ lavere alkyl eller aminokarbonylmetyl og X en gruppe med formelene where R means furyl, thienyl or optionally by halogen, hydroxyl, lower alkoxy or lower alkyl substituted phenyl, R-^ lower alkyl or aminocarbonylmethyl and X a group with the formulas hvori en av de to restene R2 og R^ henholdsvis R^ og R^ er hydrogen og den andre lavere alkyl, karboksymetyl eller sulfometyl, eller et farmasøytisk fordragelig salt derav henholdsvis et hydrat av et av disse saltene.som virksom bestanddel med en farmasøytisk fordragelig bærer.in which one of the two residues R2 and R^ respectively R^ and R^ is hydrogen and the other lower alkyl, carboxymethyl or sulfomethyl, or a pharmaceutically acceptable salt thereof, respectively a hydrate of one of these salts. as active ingredient with a pharmaceutically acceptable carrier. 11. Farmasøytiske preparater, karakterisert ved at de inneholder en forbindelse med den generelle formel 11. Pharmaceutical preparations, characterized in that they contain a compound with the general formula hvor R betyr furyl,thienyl eller eventuelt ved halogen, hydroksy, lavere alkoksy eller lavere alkylsubstituert fenyl, R^ lavere alkyl eller aminokarbonylmety1 og X en gruppe med formelene where R means furyl, thienyl or optionally by halogen, hydroxy, lower alkoxy or lower alkyl substituted phenyl, R^ lower alkyl or aminocarbonylmethyl and X a group with the formulas hvori en av de to restene R2 og henholdsvis R^ og R^ er hydrogen og den andre lavere alkyl, kårboksyrnetyl eller eller sulfometyl, eller et farmasøytisk fordragelig salt derav henholdsvis et hydrat av et sådant salt.in which one of the two residues R2 and R^ and R^ respectively is hydrogen and the other lower alkyl, carboxylmethyl or or sulfomethyl, or a pharmaceutically acceptable salt thereof or a hydrate of such a salt. 12. Acylderivater med den generelle formel 12. Acyl derivatives of the general formula hvor R betyr furyl, thienyl eller eventuelt ved halogen, hydrok.sy, lavere alkoksy eller lavere alkylsubstituert f enyl, R-^ lavere alkyl eller aminokarbonylmetyl og X en gruppe med formelene where R means furyl, thienyl or optionally by halogen, hydroxy, lower alkoxy or lower alkyl substituted phenyl, R-^ lower alkyl or aminocarbonylmethyl and X a group with the formulas hvor en av de to restene R.> og R-^ henholdsvis R^ og R^ er hydrogen og den andre lavere alkyl, karboksymety1 eller sulfometyl, samt salter av disse forbindelser og hydrater av disse salter.where one of the two residues R.> and R-^ respectively R^ and R^ is hydrogen and the other lower alkyl, carboxymethyl or sulfomethyl, as well as salts of these compounds and hydrates of these salts. 13. Acylderivater ifølge krav 12, karakterisert ved at R er furyl, samt salter av disse forbindelser og hydrater av disse salter.13. Acyl derivatives according to claim 12, characterized in that R is furyl, as well as salts of these compounds and hydrates of these salts. 14. Acylderivater ifølge krav 12 eller 13, k a r a k t e r-j i- sert v e d at R-^ er metyl samt salter av disse for- bindelsér og hydrater av disse salter.14. Acyl derivatives according to claim 12 or 13, characterized in that R-^ is methyl as well as salts of these compounds and hydrates of these salts. 15. Acylderivater ifølge ett av kravene 12 til 14, karakterisert ved at X betyr gruppen (c) eller en av gruppene (a) og (b) hvor en av de to restene R2 og R3 henholdsvis R^ og R5 betyr hydrogen og den andre metyl, samt salter av disse forbindelser og hydrater av disse salter.15. Acyl derivatives according to one of claims 12 to 14, characterized in that X means the group (c) or one of the groups (a) and (b) where one of the two residues R2 and R3 respectively R1 and R5 means hydrogen and the other methyl, as well as salts of these compounds and hydrates of these salts. 16. Acylderivater ifølge krav 15, karakterisert ved at X er en 1,2,5,6-tertrahydro-2-raetyl-5,6-diokso-as triazin-3-yl-gruppe samt salter av disse forbindelser og. hydrater av disse salter.16. Acyl derivatives according to claim 15, characterized in that X is a 1,2,5,6-tertrahydro-2-raethyl-5,6-dioxo-as triazin-3-yl group and salts of these compounds and. hydrates of these salts. 17. Acylderivater ifølge krav 15, karakterisert ved at X er 1, 4 , 5 , 6-tetrahydrio-4-metyl-5 , 6-diokso-as-tri-azin-3-yl-gruppen samt salter av disse forbindelser og hydrater av disse salter.17. Acyl derivatives according to claim 15, characterized in that X is 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-tri-azin-3-yl and salts of these compounds and hydrates of these salts. 18. (7R)-7-[2-(2-furyl)-2-(metoksyimino)acetamido]-3-/[(1,2,-5,6-tetrahydro-2-metyl-5,6-diokso-as-triazin-3-yl)thio]-metyl/- 3-cephem-4-karbonsyre samt salter av denne forbindelse og hydrater av disse salter.18. (7R)-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-3-/[(1,2,-5,6-tetrahydro-2-methyl-5,6-dioxo -as-triazin-3-yl)thio]-methyl/- 3-cephem-4-carboxylic acid as well as salts of this compound and hydrates of these salts.
NO781934A 1977-06-03 1978-06-02 ACYL DERIVATIVES. NO781934L (en)

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US4200745A (en) * 1977-12-20 1980-04-29 Eli Lilly And Company 7[2-(2-Aminothiazol-4-yl)-2-alkoxyimino]acetamido 3[4-alkyl-5-oxo-6-hydroxy-3,4 dihydro 1,2,4-triazin 3-yl]thio methyl cephalosporins
FR2432521A1 (en) * 1978-03-31 1980-02-29 Roussel Uclaf NOVEL O-SUBSTITUTED OXIMES DERIVED FROM 7-AMINO THIAZOLYL ACETAMIDO CEPHALOSPORANIC ACID, THEIR PREPARATION PROCESS AND THEIR USE AS MEDICAMENTS
MC1259A1 (en) * 1978-05-30 1980-01-14 Hoffmann La Roche ACYL DERIVATIVES
FI782683A (en) * 1978-07-19 1980-01-20 Hoffmann La Roche KEFALOSPORINESTRAR OCH -ESTRAR
US4472574A (en) * 1981-05-22 1984-09-18 Hoffman-La Roche Inc. Process for the manufacture of a cephem carboxylic acid derivative
US4698338A (en) * 1986-02-19 1987-10-06 Eli Lilly And Company 7[2-(2-aminothiazol-4-yl)-2-benzyloximino]acetamido-3[4-alkyl-5-oxo-6-hydroxy-3,4-dihydro-1,2,4-triazin-3-yl]thiomethyl cephalosporins

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CA1100129A (en) * 1974-08-02 1981-04-28 William H.W. Lunn Cephalosporin compounds
GB1555471A (en) * 1975-06-19 1979-11-14 Glaxo Lab Ltd 7 carbamoylalkoxyimino acetamido 3 em 4 carboxylic acidsand derivatives thereof
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