EP0000005B1 - New cephalosporin derivatives, their preparations and their pharmaceutical compositions - Google Patents

New cephalosporin derivatives, their preparations and their pharmaceutical compositions Download PDF

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Publication number
EP0000005B1
EP0000005B1 EP78100078A EP78100078A EP0000005B1 EP 0000005 B1 EP0000005 B1 EP 0000005B1 EP 78100078 A EP78100078 A EP 78100078A EP 78100078 A EP78100078 A EP 78100078A EP 0000005 B1 EP0000005 B1 EP 0000005B1
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salts
formula
compounds
methyl
hydrates
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EP0000005A1 (en
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Marc Dr. Montavon
Roland Dr. Reiner
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F Hoffmann La Roche AG
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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

Definitions

  • the present invention relates to new acyl derivatives of the general formula in which R is furyl, thienyl or phenyl which is optionally substituted by halogen, hydroxy, lower alkoxy or lower alkyl, R 1 is lower alkyl or aminocarbonylmethyl and X is a group of the formulas in which one of the two radicals R 2 and R 3 or R 4 and R 5 is hydrogen and the other is lower alkyl, carboxymethyl or sulfomethyl, and salts of these compounds and hydrates of these salts.
  • salts of the compounds of formula 1 are alkali metal salts such as the sodium and potassium salt; 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'-dibenzyl-ethyl-ethylenediamine, alkylamines or dialkylamines, and salts with amino acids, such as e.g. Salts with arginine or lysine.
  • the salts can be mono-salts or also disalts.
  • the second salt formation takes place on the tautomeric enol form of the triazine residue b, which has an acid character.
  • the compounds of formula I also form addition salts with organic or inorganic acids.
  • such salts are hydrohalides, for example hydrochlorides, hydrobromides; Hydroiodides, as well as other minor acid salts, such as sulfates, nitrates, phosphates and the like, alkyl and mono-aryl sulfonates, such as ethanesulfonates, toluenesulfonates, benzenesulfonates and the like, and also other organic acid salts, such as acetates, tartrates, maleates, citrates, benzoates, salic , Abscorbate and the like
  • the salts of the compounds of formula I can be hydrated.
  • the hydration can take place in the course of the production process or can occur gradually as a result of hygroscopic properties of an initially anhydrous salt of a compound of the formula I.
  • lower alkyl groups are either straight chain 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 represents all four halogens, i.e. Fluorine, chlorine, bromine and iodine; chlorine and bromine are preferred.
  • Preferred R groups are furyl, thienyl and phenyl, especially furyl. Methyl is preferred as R 1 .
  • Preferred X groups are group (c) and groups (a) and (b), in which one of the two radicals R 2 and R 3 or R 4 and R 5 is hydrogen and the other is methyl. Particularly preferred X groups are the 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl and the 1,4,5,6-tetrahydro-4-methyl - 5,6-dioxo-as-triazin-3-yl group.
  • Preferred compounds are (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 and its salts and the hydrates of these salts.
  • the compounds of the formula I and their salts or hydrates of the salts can be in the synisomeric form or in the anti-isomeric form or as mixtures of these two forms.
  • the syn-isomeric form or mixtures in which the syn-isomeric form predominates is preferred.
  • the carboxy groups present in the starting compounds of formulas II and IV can optionally be protected, e.g. by esterification to an easily cleavable ester such as a silyl ester, e.g. the trimethylsilyl ester.
  • the carboxy group can also be protected by salt formation with an inorganic or tertiary organic base such as triethylamine.
  • Suitable reactive functional derivatives of acids of the formula III are e.g. Halides, i.e. Chlorides, bromides and fluorides; Azides; Anhydrides, especially mixed anhydrides with stronger acids; reactive esters, e.g. N-hydroxy succinimide esters, and amides, e.g. Imidazolides.
  • Halogens e.g. Chlorine, bromine or iodine
  • acyloxy residues e.g. lower alkanoyl radicals, such as acetoxy, lower alkyl or arylsulfonyloxy radicals, such as mesyloxy or tosyloxy, or the azidorest in question.
  • a free acid of formula III can be condensed with one of the esters corresponding to formula II by means of a carbodiimide, such as dicyclohexylcarbodiimide, in an inert solvent, such as ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide, and then the ester group is split off .
  • carbodiimides can be as Condensing agents also use oxazolium salts, for example N-ethyl-5-phenyl-isoxazolium-3'-sulfonate.
  • an acid halide preferably the chloride of an acid of the formula III
  • the reaction is preferably carried out in the presence of an acid binding agent, e.g. in the presence of aqueous alkali, preferably sodium hydroxide solution, 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.
  • an acid binding agent e.g. in the presence of aqueous alkali, preferably sodium hydroxide solution, 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.
  • Water is preferably used as the solvent; but it can also be in an aprotic organic solvent such as e.g. Dimethylformamide, dimethyl sulfoxide, or hexamethylphosphoric triamide can be worked.
  • reaction of a compound of formula II with a compound of formula III or a reactive functional derivative thereof can be advantageously carried out at temperatures between about -40 ° C and room temperature, for example at about 0-10 o C, take place.
  • reaction of a compound of formula IV with a thiol of formula V can be carried out in a manner known per se, e.g. at a temperature between about 40 and 80 ° C, suitably at about 60 ° C, in a polar solvent, for example in an alcohol, e.g. in a lower alkanol such as ethanol, propanol and the like, in dimethylformamide or dimethyl sulfoxide, preferably in water or in a buffer solution with a pH of about 6 to 7, preferably 6.5.
  • a polar solvent for example in an alcohol, e.g. in a lower alkanol such as ethanol, propanol and the like, in dimethylformamide or dimethyl sulfoxide, preferably in water or in a buffer solution with a pH of about 6 to 7, preferably 6.5.
  • the protective group is a silyl group (silyl ester), this group can be split off particularly easily by treating the reaction product with water. If the carboxyl group of an acid of formula IV is protected by salt formation (e.g. with triethylamine), this salt-forming protective group can be split off by treatment with acid.
  • the acid can be e.g. Hydrochloric acid, sulfuric acid, phosphoric acid or citric acid can be used.
  • the 7-amino compounds of the formula 11 used as starting products can be started from a compound of the formula in which Y represents a leaving group and the carboxy group can be in protected form, are prepared with a thiol of the formula V.
  • the reaction can be carried out under the same conditions as those of the starting compounds IV and V.
  • syn / anti mixture of a compound of the formula I obtained can be separated into the corresponding syn and anti forms in the customary manner, for example by recrystallization or by chromatographic methods using a suitable solvent or solvent mixture.
  • 2,275,215 and 2,280,381 cephalosporin derivatives which can carry a substituted thiomethyl radical of the present type ⁇ CH 2 ⁇ S ⁇ X in the 3-position. It has now been found that the new cephalosporin derivatives of the formula I and their salts and the hydrates of these salts, in which the substituents mentioned in positions 7 and 3 are present simultaneously for the first time, have valuable antibiotic, in particular bactericidal activity.
  • ß-lactamase-forming staphylococci and various ß-lactamase-forming gram-negative bacteria, such as, for example, Haemophilus influenzae, Escherichia coli, Proteus and Klebsiella species.
  • the compounds of formula I can be used for the treatment and prophylaxis of infectious diseases.
  • a daily dose of approximately 1 g to approximately 4 g is suitable for the adult.
  • the parenteral administration of the compounds according to the invention is particularly preferred.
  • mice are infected intraperitoneally with an aqueous suspension of Proteus mirabilis.
  • the test substance is applied subcutaneously one hour after the infection.
  • the number of surviving animals is determined on the 4th day.
  • Different doses are applied and the dose at which 50% of the test animals survived (CD sa , mg / kg) is determined by interpolation.
  • compositions can contain the compounds of formula I, their salts or hydrated forms of these salts, possibly in a mixture with another therapeutically valuable substance. They are expediently mixed with a pharmaceutical, inorganic or organic inert carrier material which is particularly suitable for parenteral administration, such as e.g. with water, gum arabic.
  • the pharmaceutical preparations are preferably in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers.

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Description

Die vorliegende Erfindung betrifft neue Acylderivate der allgemeinen Formel

Figure imgb0001
in der R Furyl, Thienyl oder ggf. durch Halogen, Hydroxy, niederes Alkoxy oder niederes Alkyl substituiertes Phenyl, R1 niederes Alkyl oder Aminocarbonylmethyl und X eine Gruppe der Formeln
Figure imgb0002
in denen einer der beiden Reste R2 und R3 bzw. R4 und R5 Wasserstoff und der andere niederes Alkyl, Carboxymethyl oder Sulfomethyl darstellt, bedeutet,
sowie Salze dieser Verbindungen und Hydrate dieser Salze.The present invention relates to new acyl derivatives of the general formula
Figure imgb0001
 in which R is furyl, thienyl or phenyl which is optionally substituted by halogen, hydroxy, lower alkoxy or lower alkyl, R 1 is lower alkyl or aminocarbonylmethyl and X is a group of the formulas
Figure imgb0002
 in which one of the two radicals R 2 and R 3 or R 4 and R 5 is hydrogen and the other is lower alkyl, carboxymethyl or sulfomethyl,
and salts of these compounds and hydrates of these salts.

Beispiele von Salzen der Verbindungen der Formel 1 sind Alkalimetallsalze, wie das Natrium- und Kaliumsalz; das Ammoniumsalz; Erdalkalimetallsalze, wie das Calciumsalz; Salze mit organischen Basen, wie Salze mit Aminen, z.B. Salze mit N-Aethyl-piperidin, Procain, Dibenzylamin, N,N'-Dibenzyl- äthyl-äthylendiamin, Alkylaminen oder Dialkylaminen, sowie Salze mit Aminosäuren, wie z.B. Salze mit Arginin oder Lysin. Die Salze können Monosalze oder auch Disalze sein. Die zweite Salzbildung erfolgt an der tautomeren Enolform des Triazinrestes b, welche sauren Charakter hat.Examples of salts of the compounds of formula 1 are alkali metal salts such as the sodium and potassium salt; 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'-dibenzyl-ethyl-ethylenediamine, alkylamines or dialkylamines, and salts with amino acids, such as e.g. Salts with arginine or lysine. The salts can be mono-salts or also disalts. The second salt formation takes place on the tautomeric enol form of the triazine residue b, which has an acid character.

Die Verbindungen der Formel I bilden ebenfalls Additionssalze mit organischen oder anorganischen Säuren. Beispiele solcher Salze sind Hydrohalogenide, beispielsweise Hydrochloride, Hydrobromide; Hydrojodide, sowie andere Minderalsäuresalze, wie Sulfate, Nitrate, Phosphate und dgl., Alkyl- und Mono-arylsulfonate, wie Aethansulfonate, Toluolsulfonate, Benzolsulfonate und dgl. und auch andere organische Säuresalze, wie Acetate, Tartrate, Maleate, Citrate, Benzoate, Salicylate, Abscorbate und dgl.The compounds of formula I also form addition salts with organic or inorganic acids. Examples of such salts are hydrohalides, for example hydrochlorides, hydrobromides; Hydroiodides, as well as other minor acid salts, such as sulfates, nitrates, phosphates and the like, alkyl and mono-aryl sulfonates, such as ethanesulfonates, toluenesulfonates, benzenesulfonates and the like, and also other organic acid salts, such as acetates, tartrates, maleates, citrates, benzoates, salic , Abscorbate and the like

Die Salze der Verbindungen der Formel I können hydratisiert sein. Die Hydratisierung kann im Zuge des Herstellungsverfahrens erfolgen oder allmählich als Folge hygroskopischer Eigenschaften eines zunächst wasserfreien Salzes einer Verbindung der Formel I auftreten.The salts of the compounds of formula I can be hydrated. The hydration can take place in the course of the production process or can occur gradually as a result of hygroscopic properties of an initially anhydrous salt of a compound of the formula I.

Die vorstehend genannten niederen Alkylgruppen sind entweder geradkettig oder verzweigt und können bis zu 7 Kohlenstoffatome enthalten, z.B. Methyl, Aethyl, n-Propyl, Isopropyl, n-Pentyl, n-Heptyl, Niedere Alkoxygruppen haben analoge Bedeutung. Halogen stellt alle vier Halogene dar, d.h. Fluor, Chlor, Brom und Jod; bevorzugt sind Chlor und Brom.The above lower alkyl groups are either straight chain 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 represents all four halogens, i.e. Fluorine, chlorine, bromine and iodine; chlorine and bromine are preferred.

Bevorzugte R-Gruppen sind Furyl, Thienyl und Phenyl, insbesondere Furyl. Als R1 ist Methyl bevorzugt. Bevorzugte X-Gruppen sind die Gruppe (c) sowie die Gruppen (a) und (b), worin einer der beiden Reste R2 und R3 bzw. R4 und R5 Wasserstoff und der andere Methyl darstellt. Besonders bevorzugte X-Gruppen sind die 1,2,5,6-Tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl- und die 1,4,5,6 - Tetrahydro - 4 - methyl - 5,6 - dioxo - as - triazin - 3 - yl - gruppe.Preferred R groups are furyl, thienyl and phenyl, especially furyl. Methyl is preferred as R 1 . Preferred X groups are group (c) and groups (a) and (b), in which one of the two radicals R 2 and R 3 or R 4 and R 5 is hydrogen and the other is methyl. Particularly preferred X groups are the 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl and the 1,4,5,6-tetrahydro-4-methyl - 5,6-dioxo-as-triazin-3-yl group.

Bevorzugte Verbindungen sind (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 - carbonsäure und deren Salze sowie die Hydrate dieser Salze.Preferred compounds are (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 and its salts and the hydrates of these salts.

Die Verbindungen der Formel I sowie deren Salze bzw. Hydrate der Salze können in der synisomeren Form

Figure imgb0003
oder in der anti-isomeren Form
Figure imgb0004
bzw. als Gemische dieser beiden Formen vorliegen. Bevorzugt ist die syn-isomere Form bzw. Gemische, in denen die syn-isomere Form überwiegt.The compounds of the formula I and their salts or hydrates of the salts can be in the synisomeric form
Figure imgb0003
 or in the anti-isomeric form
Figure imgb0004
 or as mixtures of these two forms. The syn-isomeric form or mixtures in which the syn-isomeric form predominates is preferred.

Die Acylderivate der Formel I sowie deren Salze bzw. Hydrate dieser Salze werden erfindungsgemäss durch ein Verfahren hergestellt, welches dadurch gekennzeichnet ist, dass man

  • a) eine Verbindung der allgemeinen Formel
    Figure imgb0005
    in der X die in Formel I gegebene Bedeutung hat und die Carboxygruppe in geschützter Form vorliegen kann, mit einer Säure der allgemeinen Formel
    Figure imgb0006
    in der R und R, die in Formel I gegebene Bedeutung haben, oder mit einem reaktionsfähigen funktionellen Derivat dieser Säure umsetzt und die Schutzgruppe abspaltet, oder dass man
  • b) eine Verbindung der allgemeinen Formel
    Figure imgb0007
    in der R und R, die in Formel I gegebene Bedeutung haben, Y eine austretende Gruppe darstellt und die Carboxygruppe in geschützter Form vorliegen kann, mit einem Thiol der allgemeinen Formel
    Figure imgb0008
    in der X die in Formel 1 gegebene Bedeutung hat, umsetzt und die Schutzgruppe abspaltet, wonach man das Reaktionsprodukt ggfs. in ein Salz bzw. ein Hydrat dieses Salzes überführt.
According to the invention, the acyl derivatives of the formula I and their salts or hydrates of these salts are prepared by a process which is characterized in that
  • a) a compound of the general formula
    Figure imgb0005
     in which X has the meaning given in formula I and the carboxy group can be in protected form, with an acid of the general formula
    Figure imgb0006
     in which R and R, which have the meaning given in formula I, or react with a reactive functional derivative of this acid and split off the protective group, or in that
  • b) a compound of the general formula
    Figure imgb0007
     in which R and R, which have the meaning given in formula I, Y represents a leaving group and the carboxy group can be in protected form, with a thiol of the general formula
    Figure imgb0008
     in which X has the meaning given in formula 1, and the protective group is split off, after which the reaction product is converted, if appropriate, into a salt or a hydrate of this salt.

Die in den Ausgangsverbindungen der Formeln II and IV vorhandenen Carboxygruppen können wahlweise geschützt sein, z.B. durch Veresterung zu einem leicht spaltbaren Ester, wie einem Silylester, z.B. dem Trimethylsilylester. Die Carboxygruppe kann auch durch Salzbildung mit einer anorganischen oder tertiären organischen Base, wie Triäthylamin, geschützt werden.The carboxy groups present in the starting compounds of formulas II and IV can optionally be protected, e.g. by esterification to an easily cleavable ester such as a silyl ester, e.g. the trimethylsilyl ester. The carboxy group can also be protected by salt formation with an inorganic or tertiary organic base such as triethylamine.

Als reaktionsfähige funktionelle Derivate von Säuren der Formel III kommen z.B. Halogenide, d.h. Chloride, Bromide und Fluoride; Azide; Anhydride, insbesondere gemischte Anhydride mit stärkeren Säuren; reaktionsfähige Ester, z.B. N-Hydroxy-succinimidester, und Amide, z.B. Imidazolide, in Betracht.Suitable reactive functional derivatives of acids of the formula III are e.g. Halides, i.e. Chlorides, bromides and fluorides; Azides; Anhydrides, especially mixed anhydrides with stronger acids; reactive esters, e.g. N-hydroxy succinimide esters, and amides, e.g. Imidazolides.

Als austretende Gruppe Y einer Verbindung der Formel IV kommen beispielsweise Halogene, z.B. Chlor, Brom oder Jod, Acyloxyreste, z.B. niedere Alkanoylreste, wie Acetoxy, niedere Alkyl- oder Arylsulfonyloxyreste, wie Mesyloxy oder Tosyloxy, oder der Azidorest in Frage.Halogens, e.g. Chlorine, bromine or iodine, acyloxy residues, e.g. lower alkanoyl radicals, such as acetoxy, lower alkyl or arylsulfonyloxy radicals, such as mesyloxy or tosyloxy, or the azidorest in question.

Die Umsetzung einer Verbindung der Formel II mit einer Säure der Formel III oder einem reaktionsfähigen funktionellen Derivat davon kann in an sich bekannter Weise durchgeführt werden. So kann man z.B. eine freie Saüre der Formel III mit einem der erwähnten Ester entsprechend Formel II mittels eines Carbodiimids, wie Dicyclohexylcarbodiimid, in einem inerten Lösungsmittel, wie Essigester, Acetonitril, Dioxan, Chloroform, Methylenchlorid, Benzol oder Dimethylformamid kondensieren und anschliessend die Estergruppe abspalten. Anstelle von Carbodiimiden lassen sich als Kondensationsmittel auch Oxazoliumsalze, z.B. N-Aethyl-5-phenyl-isoxazolium-3'-sulfonat, verwenden.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. For example, a free acid of formula III can be condensed with one of the esters corresponding to formula II by means of a carbodiimide, such as dicyclohexylcarbodiimide, in an inert solvent, such as ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide, and then the ester group is split off . Instead of carbodiimides can be as Condensing agents also use oxazolium salts, for example N-ethyl-5-phenyl-isoxazolium-3'-sulfonate.

Nach einer anderen Ausführungsform setzt man ein Salz einer Säure der Formel 11, z.B. ein Trialkylammoniumsalz, mit einem reaktionsfähigen funktionellen Derivat einer Säure der Formel III wie oben erwähnt in einem inerten Lösungsmittel, z.B. einem der oben genannten, um.In another embodiment, a salt of an acid of formula 11, 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 to.

Nach einer weiteren Ausführungsform wird ein Säurehalogenid, vorzugsweise das Chlorid einer Säure der Formel 111 mit dem Amin der Formel II umgesetzt. Die Umsetzung erfolgt vorzugsweise in Gegenwart eines säurebindenden Mittels, z.B. in Gegenwart von wässrigem Alkali, vorzugsweise Natronlauge, oder auch in Gegenwart eines Alkalimetallcarbonats, wie Kaliumcarbonat, oder in Gegenwart eines nieder-alkylierten Amins, wie Triäthylamin. Als Lösungsmittel wird vorzugsweise Wasser verwendet; es kann aber auch in einem aprotischen organischen Lösungsmittel, wie z.B. Dimethylformamid, Dimethylsulfoxid, oder Hexamethylphosphorsäuretriamid, gearbeitet werden.According to a further embodiment, an acid halide, preferably the chloride of an acid of the formula III, is reacted with the amine of the formula II. The reaction is preferably carried out in the presence of an acid binding agent, e.g. in the presence of aqueous alkali, preferably sodium hydroxide solution, 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. Water is preferably used as the solvent; but it can also be in an aprotic organic solvent such as e.g. Dimethylformamide, dimethyl sulfoxide, or hexamethylphosphoric triamide can be worked.

Die Umsetzung einer Verbindung der Formel II mit einer Verbindung der Formel III oder einem reaktionsfähigen funktionellen Derivat davon kann zweckmässig bei Temperaturen zwischen etwa -40°C und Zimmertemperatur, beispielsweise bei etwa 0-10oC, erfolgen.The reaction of a compound of formula II with a compound of formula III or a reactive functional derivative thereof can be advantageously carried out at temperatures between about -40 ° C and room temperature, for example at about 0-10 o C, take place.

Die Umsetzung einer Verbindung der Formel IV mit einem Thiol der Formel V kann in an sich bekannter Weise, z.B. bei einer Temperatur zwischen etwa 40 und 80°C, zweckmässig bei etwa 60°C, in einem polaren Lösungsmittel, beispielsweise in einem Alkohol, wie z.B. in einem niederen Alkanol, wie Aethanol, Propanol und dgl., in Dimethylformamid oder Dimethylsulfoxid, vorzugsweise in Wasser oder in einer Pufferlösung mit einem pH von etwa 6 bis 7, vorzugsweise 6,5, durchgeführt werden.The reaction of a compound of formula IV with a thiol of formula V can be carried out in a manner known per se, e.g. at a temperature between about 40 and 80 ° C, suitably at about 60 ° C, in a polar solvent, for example in an alcohol, e.g. in a lower alkanol such as ethanol, propanol and the like, in dimethylformamide or dimethyl sulfoxide, preferably in water or in a buffer solution with a pH of about 6 to 7, preferably 6.5.

Nach erfolgter Umsetzung einer Verbindung der Formel 11 oder IV mit einer Verbindung der Formel II bzw. V wird die allenfalls vorhandene Schutzgruppe abgespalten.After the reaction of a compound of formula 11 or IV with a compound of formula II or V, the protective group which may be present is split off.

Wenn die Schutzgruppe eine Silylgruppe darstellt (Silylester), kann diese Gruppe besonders leicht durch Behandlung des Umsetzungsproduktes mit Wasser abgespalten werden. Wenn die Carboxylgruppe einer Säure der Formel IV durch Salzbildung (z.B. mit Triäthylamin) geschützt ist, so kann die Abspaltung dieser salzbildenen Schutzgruppe durch Behandlung mit Säure erfolgen. Als Säure kann hierbei z.B. Salzsäure, Schwefelsäure, Phosphorsäure oder Citronensäure verwendet werden.If the protective group is a silyl group (silyl ester), this group can be split off particularly easily by treating the reaction product with water. If the carboxyl group of an acid of formula IV is protected by salt formation (e.g. with triethylamine), this salt-forming protective group can be split off by treatment with acid. The acid can be e.g. Hydrochloric acid, sulfuric acid, phosphoric acid or citric acid can be used.

Die als Ausgangsprodukte verwendeten 7-Aminoverbindungen der Formel 11 können ausgehend von einer Verbindung der Formel

Figure imgb0009
in der Y eine austretende Gruppe darstellt und die Carboxygruppe in geschützter Form vorliegen kann, mit einem Thiol der Formel V hergestellt werden. Die Umsetzung kann unter den gleichen Bedingungen wie diejenige der Ausgangsverbindungen IV und V erfolgen.The 7-amino compounds of the formula 11 used as starting products can be started from a compound of the formula
Figure imgb0009
 in which Y represents a leaving group and the carboxy group can be in protected form, are prepared with a thiol of the formula V. The reaction can be carried out under the same conditions as those of the starting compounds IV and V.

Ein allenfalls erhaltenes syn/anti-Gemisch einer Verbindung der Formel I kann in die entsprechenden syn- und anti-Formen in üblicher Weise getrennt werden, beispielsweise durch Umkristallisation oder durch chromatographische Methoden unter Verwendung eines geeigneten Lösungsmittels bzw. Lösungsmittelgemisches.Any syn / anti mixture of a compound of the formula I obtained can be separated into the corresponding syn and anti forms in the customary manner, for example by recrystallization or by chromatographic methods using a suitable solvent or solvent mixture.

Aus der französischen Patentpublikation No. 2.137.899 sind Cephalosporinderivate bekannt, welche in 7-Stellung u.a. einen Substituenten des vorliegenden Typs R,ON=CR-CONH- tragen können. Andererseits sind aus den französischen Patentpublikationen Nos. 2.275.215 und 2.280.381 Cephalosporinderivate bekannt, welche in 3-Stellung einen substituierten Thiomethylrest des vorliegenden Typs ―CH2―S―X tragen können. Es wurde nun gefunden, daß die neuen Cephalosporinderivate der Formel I sowie deren Salze und die Hydrate dieser Salze, in welchen erstmals die erwähnten Substituenten in den Stellungen 7 und 3 gleichzeitig vorliegen, wertvolle antibiotische, insbesondere bakterizide Wirksamkeit besitzen. Sie besitzen ein breites Wirkungsspektrum gegen Grampositive und Gram-negative Mikroorganismen, einschließlich ß-Lactamase bildende Staphylokokken und verschiedene ß-Lactamase bildende Gram-negative Bakterien, wie z.B. Haemophilus influenzae, Escherichia coli, Proteus- und Klebsiella-Spezies.From French patent publication No. 2,137,899 cephalosporin derivatives are known which, in the 7-position, can include a substituent of the type R, ON = CR-CONH- present. On the other hand, there are Nos from the French patent publications. 2,275,215 and 2,280,381 cephalosporin derivatives are known which can carry a substituted thiomethyl radical of the present type ―CH 2 ―S ― X in the 3-position. It has now been found that the new cephalosporin derivatives of the formula I and their salts and the hydrates of these salts, in which the substituents mentioned in positions 7 and 3 are present simultaneously for the first time, have valuable antibiotic, in particular bactericidal activity. They have a broad spectrum of activity against gram-positive and gram-negative microorganisms, including ß-lactamase-forming staphylococci and various ß-lactamase-forming gram-negative bacteria, such as, for example, Haemophilus influenzae, Escherichia coli, Proteus and Klebsiella species.

Die Verbindungender Formel I sowie die pharmazeutisch verträglichen Salze und hydratisierten Formen davon können zur Behandlung und Prophylaxe von Infektionskrankheiten verwendet werden. Für den Erwachsenen kommt eine Tagesdosis von etwa 1 g bis etwa 4 g in Betracht. Die parenterale Verabreichung der erfindungsgemäßen Verbindungen ist besonders bevorzugt.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. A daily dose of approximately 1 g to approximately 4 g is suitable for the adult. The parenteral administration of the compounds according to the invention is particularly preferred.

Zum Nachweis der antimikrobiellen Wirksamkeit der erfindungsgemässen Verbindungen wurden folgende repräsentative Vertreter getestet:

Figure imgb0010
Figure imgb0011
 Aktivität in vivoThe following representative representatives were tested to demonstrate the antimicrobial activity of the compounds according to the invention:
Figure imgb0010
Figure imgb0011
 Activity in vivo

Gruppen von 10 Mäusen werden mit einer wässrigen Suspension von Proteus mirabilis intraperitoneal infiziert. Eine Stunde nach der Infektion wird die Prüfsubstanz subcutan appliziert. Die Zahl der überlebenden Tiere wird am 4. Tag bestimmt. Es werden verschiedene Dosierungen appliziert, und durch Interpolation wird diejenige Dosis bestimmt, bei der 50% der Versuchstiere überlebten (CDsa, mg/kg).

Figure imgb0012
Figure imgb0013
 Groups of 10 mice are infected intraperitoneally with an aqueous suspension of Proteus mirabilis. The test substance is applied subcutaneously one hour after the infection. The number of surviving animals is determined on the 4th day. Different doses are applied and the dose at which 50% of the test animals survived (CD sa , mg / kg) is determined by interpolation.
Figure imgb0012
Figure imgb0013

Pharmazeutische Präparate, vorzugsweise Trockenampullen, können die Verbindungen der Formel I, ihre Salze oder hydratisierte Formen dieser Salze, eventuell in Mischung mit einem anderen therapeutisch wertvollen Stoff enthalten. Zweckmässig sind sie mit einem insbesondere für die parenterale Applikation geeigneten pharmazeutischen, anorganischen oder organischen inerten Trägermaterial vermischt, wie z.B. mit Wasser, Gummi arabicum. Die pharmazeutischen Präparate leigen vorzugsweise in flüssiger Form vor, z.B. als Lösungen, Suspensionen oder Emulsionen. Gegebenenfalls sind sie sterilisiert und bzw. oder enthalten Hilfsstoffe, wie Konservierungs-, Stabilisierungs-, Netz- oder Emulgiermittel, Salze zur Veränderung des osmotischen Druckes oder Puffer.Pharmaceutical preparations, preferably dry ampoules, can contain the compounds of formula I, their salts or hydrated forms of these salts, possibly in a mixture with another therapeutically valuable substance. They are expediently mixed with a pharmaceutical, inorganic or organic inert carrier material which is particularly suitable for parenteral administration, such as e.g. with water, gum arabic. The pharmaceutical preparations are preferably in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers.

Beispiel 1example 1

Herstellung des Natriumsalzes der (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 - carbonsäure:

  • 5,60 2-Methoxyimino-2-furyl-essigsäure (syn/anti-Gemisch 80:20) werden in 150 ml Benzol gelöst und unter Stickstoff-Begasung bei 5-10°C mit 4,2 ml Triäthylamin, 2,6 ml Oxalylchlorid und 6 Tropfen Dimethylformamid versetzt. Das Gemisch wird 1 Stunde bei 5-10°C und 1/2 Stunde bei 25°C unter Stickstoff-Begasung gerührt und danach im Vakuum bei 40°C eingedampft. Der Rückstand wird in 150 ml Aceton suspendiert und bei 0°C mit einer Lösung von 11,2 g (7R) - 7 - Amino - 3 - desacetoxy - 3 - [(1,2,5,6 - tetrahydro - 2 - methyl - 5,6 - dioxo - as - triazin - 3 - yl) - thio] - cephalosporansäure in 150 ml Wasser, welche zuvor mittels 2-n wässriger Natronlauge auf ph 7,5 eingestellt worden war, versetzt. Das Reaktionsgemisch wird 2 1/2 Stunden unter Stickstoff und bei 0-10°C gerührt, wobei das pH mittels Zugabe von 2-n wässriger Natronlauge zwischen 7,5 und 8,0 gehalten wird. Dann werden 500 ml Essigester zugegeben und das pH mit 2-n wässriger Salzsäure auf 1,5 eingestellt. Nach dem Abtrennen der organischen Phase wird die wässrige Phase einmal mit Essigester extrahiert. Die vereinigten organischen Phasen werden zweimal mit gesättigter wässriger Kochsalz-Lösung gewaschen, über Natriumsulfat getrocknet und auf ein Volumen von ca. 100 ml eingeengt. Der Rückstand wird von Ungelöstem abfiltriert ud das erhaltene orangegefärbte Filtrat mit 1000 ml Aether verdünnt. Die dabei amorph ausgefallene (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 - carbonsäure wird abgenutscht und mit Aether sowie tiefsiedendem Petroläther gewaschen. Das erhaltene beige-farbene Produkt wird in 250 ml Essigester gelöst und von Ungelöstem abfiltriert. Das orangefärbte Filtrat wird mit 10 ml einer 2-n Lösung von 2-Aethylcapronsäure-Natriumsalz in Essigester versetzt, wobei das Natriumsalz der (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 - carbonsäure ausfällt. Dieses wird abgenutscht, mit Essigester und tiefsiedendem Petroläther gewaschen und 2 Tage im Vakuum bei 25°C getrocknet. Das erhaltene Produkt ist ein beigefarbenes Pulver (syn/anti-Gemisch 80:20).
    Figure imgb0014
    (c = 0,5 in Wasser). Rf-Wert = 0,10 (DC auf Kieselgel-F254-Fertigplatten im System Butanol/Eisessig/Wasser 4:1:1; Sichtbarmachung mit UV-Licht).
Preparation of the sodium salt 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 - 4 - carboxylic acid:
  • 5.60 2-methoxyimino-2-furyl-acetic acid (syn / anti mixture 80:20) are dissolved in 150 ml of benzene and with nitrogen fumigation at 5-10 ° C with 4.2 ml of triethylamine, 2.6 ml Oxalyl chloride and 6 drops of dimethylformamide were added. The mixture is stirred for 1 hour at 5-10 ° C and 1/2 hour at 25 ° C under nitrogen gas and then evaporated in vacuo at 40 ° C. The residue is suspended in 150 ml acetone and at 0 ° C with a solution of 11.2 g (7R) - 7 - amino - 3 - deacetoxy - 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 2N aqueous sodium hydroxide solution. The reaction mixture is stirred for 2 1/2 hours under nitrogen and at 0-10 ° C., the pH being kept between 7.5 and 8.0 by adding 2N aqueous sodium hydroxide solution. Then 500 ml of ethyl acetate are added and the pH is adjusted to 1.5 with 2N aqueous hydrochloric acid. After the organic phase has been separated off, the aqueous phase is extracted once with ethyl acetate. The combined organic phases are washed twice with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated to a volume of approximately 100 ml. The residue is filtered off from undissolved material and the orange-colored filtrate obtained is diluted with 1000 ml of ether. The (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 with suction and washed with ether and low-boiling petroleum ether. The beige-colored product obtained is dissolved in 250 ml of ethyl acetate and filtered off from the undissolved. 10 ml of a 2N solution of 2-ethylcaproic acid sodium salt in ethyl acetate are added to the orange-colored filtrate, the sodium salt 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 - 4 - carboxylic acid precipitates. This is abge sucked, washed with ethyl acetate and low-boiling petroleum ether and dried in vacuo at 25 ° C for 2 days. The product obtained is a beige powder (syn / anti mixture 80:20).
    Figure imgb0014
    (c = 0.5 in water). R f value = 0.10 (TLC on silica gel F 254 finished plates in the butanol / glacial acetic acid / water 4: 1: 1 system; visualization with UV light).

Beispiel 2Example 2

Herstellung des Natriumsalzes der (7R) - 7 - [2 - (2 - Furyl) - 2 - (methoxyimino)acetamido] - 3 - -/[1 - amino - 1,2 - dihydro - 2 - oxo - 4 - pyrimidinyl)thio] - methyl/ - 3 - cephem - 4 - carbonsäure:

  • Diese Verbindung wird analog Beispiel 1 aus 3,4 g 2-Methoxyimino-2-furyl-essigsäure und 7,11 g g (7R) - 7 - Amino - 3 - desacetoxy - 3 - [(1 - amino - 1,2 - dihydro - 2 - oxo - 4 - pyrimidinyl) - thio] - cephalosporansäure hergestellt. Das Produkt stellt ein beiges Pulver dar (syn/anti-Gemisch 70:30), R,-Wert = 0,40 (DC auf Kieselgel-F254―Fertigplatten im System Butanol/Eisessig/Wasser 4:1;1; Sichtbarmachung mit UV-Licht).
Preparation of the sodium salt of (7R) - 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 gg (7R) - 7 - amino - 3 - deacetoxy - 3 - [(1 - amino - 1,2 - dihydro - 2 - oxo - 4 - pyrimidinyl) - thio] - cephalosporanic acid. The product is a beige powder (syn / anti mixture 70:30), R, value = 0.40 (TLC on silica gel F 254 ert finished plates in the butanol / glacial acetic acid / water system 4: 1; 1; visualization with UV light).

Beispiel 3Example 3

Herstellung des Natriumsalzes der (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 - carbonsäure:

  • Diese Verbindung wird analog Beispiel 1 aus 1,8 g 2-Methoxyimino-phenyl-essigsäure (syn/anti-Gemisch 90:10) und 3,73 g (7R) - 7 - Amino - 3 - desacetoxy - 3 - [(1,2,5,6 - tetrahydro - 2 - methyl - 5,6 - dioxo - as - triazin - 3 - yl) - thio] - cephalosporansäure hergestellt. Das Produkt ist ein beiges Pulver (syn/anti-Gemisch 90:10).
    Figure imgb0015
    (c = 0,5 in Wasser). Rf-Wert = 0,17 (DC auf Kieselgel-F254-Fertigplatten im System Butanol/Eisessig/Wasser 4:1:1, Sichtbarmachung mit UV-Licht).
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) and 3.73 g (7R) - 7 - amino - 3 - deacetoxy - 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).
    Figure imgb0015
    (c = 0.5 in water). R f value = 0.17 (TLC on silica gel F 254 finished plates in the butanol / glacial acetic acid / water 4: 1: 1 system, visualization with UV light).

Beispiel 4Example 4

Herstellung des Natriumsalzes der (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 - carbonsäure:

  • Diese Verbindung wird analog Beispiel 1 aus 3,4 g 2-Methoxyimino-2-furyl-essigsäure (syn/anti-Gemisch 80:20) und 7,46 g (7R) - 7 - Amino - 3 - desacetoxy - 3 - [(1,4,5,6 - tetrahydro - 4 - methyl - 5,6 - dioxo - as - triazin - 3 - yl) - thio] - cephalosporansäure hergestellt. Das Produkt ist ein beiges Pulver (syn/anti-Gemisch 80:20).
    Figure imgb0016
    (c = 0,5 in Wasser). Rf-Wert = 0,34 (DC auf Kieselgel-F254-Fertigplatten im System Butanol/Eisessig/Wasser 4:1:1; Sichtbarmachung mit UV-Licht).
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:
  • 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 (7R) - 7 - amino - 3 - deacetoxy - 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).
    Figure imgb0016
    (c = 0.5 in water). R f value = 0.34 (TLC on silica gel F 254 finished plates in the butanol / glacial acetic acid / water 4: 1: 1 system; visualization with UV light).

Beispiel 5Example 5

Herstellung des Natriumsalzes der (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 - carbonsäure:

  • Diese Verbindung wird analog Beispiel 1 aus 1,85 g 2-Methoxyimino-2-thienyl-essigsäure (syn/anti-Gemisch ca. 70:30) und 3,71 g (7R) - 7 - Amino - 3 - desacetoxy - 3 - [(1,2,5,6 - tetrahydro - 2 - methyl - 5,6 - dioxo - as - triazin - 3 - yl)thio] - cephalosporansäure hergestellt. Das Produkt ist ein beiges Pulver (syn/anti-Gemisch ca. 70:30).
    Figure imgb0017
    (c = 0.5 in Wasser). Rf-Wert s 0,21 (DC auf Kieselgel-F254-Fertigplatten im System Butanol/Eisessig/Wasser 4:1:1, Sichtbarmachung mit UV-Licht).
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) and 3.71 g (7R) - 7 - amino - 3 - deacetoxy - 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 approx. 70:30).
    Figure imgb0017
    (c = 0.5 in water). R f value s 0.21 (TLC on silica gel F 254 finished plates in the butanol / glacial acetic acid / water 4: 1: 1 system, visualization with UV light).

Beispiel 6Example 6

Herstellung des Dinatriumsalzes der (7R) - 7 - [2 - (2 - Furyl) - 2 - (methoxy imino)acetamido] - 3 - /[(2,5 - dihydro - 2 - methyl - 5 - oxo - 6 - hydroxy - as - triazin - 3 - yi)thio]methy)/ - 3 - cephem - 4 - carbonsäure:

  • Diese Verbindung wird analog Beispiel 1 aus 10,12 g 2-Methoxyimino-2-furyl-essigsäure (syn-Isomer) und 18,7 g (7R) - 7 - Amino - 3 - desacetoxy - 3 - [(1,2,5,6 - tetrahydro - 2 - methyl - 5,6 - dioxo - as - triazin - 3 - yl)thio] - cephalosporansäure hergestellt. Bei der Salzbildung werden 20 ml (2 Aequiv.) einer 2-n Lösung von 2-Aethylcapronsäure-Natriumsalz in Essigester verwendet. Das Produkt is ein praktisch farbloses Pulver (syn-Isomer).
    Figure imgb0018
    (c0,5 in Wasser). Rf-Wert=0,14 (DC auf Kieselgel-F254-Fertigplatten im System Butano)/Eisessig/Wasser 4:1:1, Sichtbarmachung mit UV-Licht).
Preparation of the disodium salt of (7R) - 7 - [2 - (2 - furyl) - 2 - (methoxy imino) acetamido] - 3 - / [(2,5 - dihydro - 2 - methyl - 5 - oxo - 6 - hydroxy - as - triazin - 3 - yi) thio] methy) / - 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 of (7R) - 7 - amino - 3 - deacetoxy - 3 - [(1,2, 5,6 - tetrahydro - 2 - methyl - 5,6 - dioxo - as - triazin - 3 - yl) thio] - cephalosporanic acid. 20 ml (2 equivalents) of a 2-n solution of 2-ethylcaproic acid sodium salt in ethyl acetate are used in the salt formation. The product is a practically colorless powder (syn isomer).
    Figure imgb0018
    (c0.5 in water). R f value = 0.14 (TLC on silica gel F 254 finished plates in the Butano system) / glacial acetic acid / water 4: 1: 1, visualization with UV light).

Beispiel 7Example 7

Herstellung des Natriumsalzes der (7R) - 3 -/[(1-Aethyl - 1,4,5,6 - tetrahydro - 5,6 - dioxo - as - triazin - 3 - yl)thio]methyl/ - 7 - [2 - (2 - furyl) - 2 - (methoxyimino)acetamido] - 3 - cephem - 4 - carbonsäure:

  • Diese Verbindung wird analog Beispiel 1 aus 1,69 g 2-Methoxyimino-2-furyl-essigsäure (syn-Isomer) und 3,85 g (7R) - 7 - Amino - 3 - desacetoxy - 3 - [(1 - äthyl - 1,4,5,6 - tetrahydro - 5,6 - dioxo - as - triazin - 3 - yl)thioJ - cephalosporansäure hergestellt. Das Produkt ist ein beiges Pulver (syn/anti-Gemisch ca. 70:30).
    Figure imgb0019
     (c = 0,5 in Wasser), rf-Wert = 0,47 (DC auf Kieselgel-F254-Fertigplatten im System Butanol/Eisessig/Wasser4:1:1, Sichtbarmachung mit UV-Licht).
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 - furyl) - 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 of (7R) - 7 - amino - 3 - deacetoxy - 3 - [(1 - ethyl - 1,4,5,6 - tetrahydro - 5,6 - dioxo - as - triazin - 3 - yl) thioJ - cephalosporanic acid. The product is a beige powder (syn / anti mixture approx. 70:30).
    Figure imgb0019
     (c = 0.5 in water), r f value = 0.47 (TLC on silica gel F 254 finished plates in the butanol / glacial acetic acid / water 4: 1: 1 system, visualization with UV light).

Beispiel 8Example 8

Herstellung des Natriumsalzes der (7R) - 7 - /2 - [(Carbamoyl - methoxy)imino] - 2 - (2 - furyl)acetamido/ - 3 - /[1,4,5,6 - tetrahydro - 4 - methyl - 5,6 - dioxo - as - triazin - 3 - yl)thio]methyl/ - 3 - cephem - 4 - carbonsäure:

  • 9,76 g /α - [(Carbamoylmethoxy)imino]furfuryl/cephalosporin Natriumsalz (syn/anti-Gemisch ca. 70:30) werden zusammen mit 4,77 g 1,4,5,6-Tetrahydro-4-methyl-5,6-dioxo-3-mercapto-as-triazin in 200 ml Phosphatpuffer mit pH 6,4 suspendiert. Unter Sticksoffbegasung wird das pH mittels 1-n Natronlauge auf 6,4 gestellt, wobei eine dunkle Lösung entsteht. Diese Lösung wird 6 Stunden bei 55-60°C unter Stickstoffbegasung bei pH 6,4-6,5 gerührt, wobei das pH mit Hilfe eines Autotitrators unter Zugabe von 1-n Natronlauge konstant gehalten wird. Die Reaktionslösung wird auf 0-5°C abgekühlt und das pH mit 2-n Salzsäure auf 2 gestellt, wobei das Reaktionsprodukt als Säure ausfällt. Dieses wird abgenutscht, mit Eiswasser gewaschen und über Nacht im Vakuum bei 40°C getrocknet. Man erhält das Endprodukt in Form der rohen Säure. Zur Reinigung wird diese in 150 ml Methanol gelöst und die Lösung 2 Minuten mit Aktivkohle gekocht. Das Gemisch wird durch ein Faltenfilter filtriert und das orangefarbige Filtrat im Vakuum eingeengt. Das dabei ausgeschiedene Harz wird abgetrennt und verworfen. Die konzentrierte methanolische Lösung wird auf Aether gegossen. Die dabei ausgefallene Säure wird abgenutscht, mit Aether und tiefsiedendem Petroläther gewaschen. Man erhält das Endprodukt in Form der gereinigten Säure, die, zwecks Ueberführung in das Natriumsalz, in 100 ml Methanol gelöst wird und mit 5 ml einer 2-n Lösung von 2-Aethylcapronsäure-Natriumsalz in Essigester versetzt wird. Es wird von wenig Ungelöstem abfiltriert und das orangefarbige Filtrat im Vakuum bei 40°C eingeengt. Dieser konzentrierten Lösung wird Aethanol zugegeben, wobei das Natriumsalze ausfällt. Dieses wird abgenutscht, mit Aethanol und tiefsiedendem Petroläther gewaschen und über Nacht im Vakuum bei 40°C getrocknet. Man erhält das Natriumsalz der (7R) - 7 - /2 - [(Carbamoylmethoxy)imino] - 2 - (2 - furyl)acetamido/ - 3 - /[1,4,5,6 - tetrahydro - 4 - methyl - 5,6 - dioxo - as - triazin - 3 - yl)thio]methyl/ - 3 - cephem - 4 - carbonsäure als beiges Pulver (syn/anti-Gemisch ca. 70:30).
    Figure imgb0020
    (c=1 1 in Wasser), Rf=0,29 (DC auf Kieselgel-F254-Fertigplatten im System Butanol/Eisessig/Wasser 4:1:1, Sichtbarmachung mit UV-Licht).
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 - triazin - 3 - yl) thio] methyl / - 3 - cephem - 4 - carboxylic acid:
  • 9.76 g / α - [(carbamoylmethoxy) imino] furfuryl / cephalosporin sodium salt (syn / anti mixture approx. 70:30) together with 4.77 g 1,4,5,6-tetrahydro-4-methyl- 5,6-dioxo-3-mercapto-as-triazine suspended in 200 ml phosphate buffer with pH 6.4. With nitrogen gassing, the pH is adjusted to 6.4 using 1N sodium hydroxide solution, a dark solution being formed. This solution is stirred for 6 hours at 55-60 ° C. under nitrogen gasification at pH 6.4-6.5, the pH being kept constant with the aid of an autotitrator with the addition of 1N sodium hydroxide solution. The reaction solution is cooled to 0-5 ° C. and the pH is adjusted to 2 using 2N hydrochloric acid, the reaction product precipitating out as an acid. This is filtered off, washed with ice water and dried overnight in a vacuum at 40 ° C. The end product is obtained in the form of the crude acid. For cleaning, this is dissolved in 150 ml of methanol and the solution boiled with activated carbon for 2 minutes. The mixture is filtered through a pleated filter and the orange-colored filtrate is concentrated in vacuo. The resin that is separated out is separated off and discarded. The concentrated methanolic solution is poured onto ether. The 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 the purpose of conversion into the sodium salt, is dissolved in 100 ml of methanol and 5 ml of a 2N solution of 2-ethylcaproic acid sodium salt in ethyl acetate are added. Little undissolved matter is filtered off and the orange-colored filtrate is concentrated in vacuo at 40.degree. Ethanol is added to this concentrated solution, and the sodium salt precipitates. 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 - 5 , 6-dioxo - as - triazin - 3 - yl) thio] methyl / - 3 - cephem - 4 - carboxylic acid as a beige powder (syn / anti mixture approx. 70:30).
    Figure imgb0020
    (c = 1 1 in water), R f = 0.29 (TLC on silica gel F 254 finished plates in the butanol / glacial acetic acid / water 4: 1: 1 system, visualization with UV light).

Ersetzt man die Ausgangsverbindungen durch äquivalente Mengen /α - [(Methoxy)imino]furfu- ryl/cephalosporin und 1,2,5,6 - Tetrahydro - 2 - methyl - 5,6 - dioxo - 3 - mercapto - as - triazin, so erhält man unter sonst gleichen Bedingungen das Natriumsalz der (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 - carbonsäure. Das Produkt ist mit der gemäss Beispiel 1 erhaltenen Verbindung identisch.If the starting compounds are replaced by equivalent amounts / α - [(methoxy) imino] furfuryl / cephalosporin and 1,2,5,6 - tetrahydro - 2 - methyl - 5,6 - dioxo - 3 - mercapto - as - triazine, the sodium salt of (7R) - 7 - [2 - (2 - furyl) - 2 - (methoxyimino) acetamido] - 3 - / [1,2,5,6 - tetrahydro - 2 - methyl is obtained under otherwise identical conditions - 5,6 - dioxo - as - triazin - 3 - yl) thio] methyl / - 3 - cephem - 4 - carboxylic acid. The product is identical to the compound obtained according to Example 1.

Beispiel 9Example 9 Herstellung von Trockenampullen für die intramuskuläre Verabreichung; - Manufacture of dry ampoules for intramuscular administration; -

Es wird in üblicher Weise ein Lyophilisat von 1 g des Natriumsalzes der (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 - carbonsäure hergestellt und in eine Ampulle abge- .füllt. Vor der Verabreichung wird letzteres mit 2,5 ml einer 2%igen wässrigen Lidocainhydrochlorid-Lösung versetzt.A lyophilisate of 1 g of the sodium salt 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 filled into an ampoule. Before administration, the latter is mixed with 2.5 ml of a 2% aqueous lidocaine hydrochloride solution.

Claims (17)

1. Cephalosporin derivatives of the general formula
Figure imgb0041
wherein R represents furyl, thienyl or phenyl optionally substituted by halogen, hydroxy, lower alkoxy or lower alkyl, R, represents lower alkyl or aminocarbonylmethyl and X represents a group of the formulae
Figure imgb0042
in which one of the two symbols R2 and R3 or R4 and R5 represents hydrogen and the other represents lower alkyl, carboxymethyl or sulphomethyl, as well as salts of said compounds and hydrates of said salts.
2. Derivatives according to claim 1, characterized in that R represents furyl, as well as salts of said compounds and hydrates of said salts.
3. Derivatives according to claim 1 or 2, characterized in that R1 represents methyl, as well as salts of said compounds and hydrates of said salts.
4. Derivatives according to one of claims 1 to 3, characterized in that X represents the group (c) or one of groups (a) and (b), in which one of the two symbols R2 and R3 or R4 and R5 represents hydrogen and the other represents methyl, as well as salts of said compounds and hydrates of said salts.
5. Derivatives according to claim 4, characterized in that X represents a 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl group, as well as salts of said compounds and hydrates of said salts.
6. Derivatives according to claim 4, characterized in that X represents the 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl group, as well as salts of said compounds and hydrates of said salts.
7. (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 said compound and hydrates of said salts.
8. Process for the manufacture of cephalosporin derivatives of the general formula
Figure imgb0043
wherein R represents furyl, thienyl or phenyl optionally substituted by halogen, hydroxy, lower alkoxy or lower alkyl, R1 represents lower alkyl or aminocarbonylmethyl and X represents a group of the formulae
Figure imgb0044
 in which one of the two symbols R2 and R3 or R4 and R5 represents hydrogen and the other represents lower alkyl, carboxymethyl or sulphomethyl, as well as salts of said compounds and hydrates of said salts, which process comprises
(a) reacting a compound of the general formula
Figure imgb0045
wherein X has the significance given in formula I and the carboxy group can be present in protected form, with an acid of the general formula
Figure imgb0046
wherein R and R, have the significance given in formula I, or with a reactive functional derivative of this acid, and cleaving off the protecting group that may be present, or
(b) reacting a compound of the formula
Figure imgb0047
wherein R and R, have the significance given in formula I, Y represents a leaving group and the carboxy group can be present in protected form, with a thiol of the general formula
Figure imgb0048
wherein X has the significance given in formula I, and cleaving off the protecting group that may be present and if desired, converting the reaction product into a salt or a hydrate of such salt.
9. A process according to claim 8, characterized in that a starting compound of formula II is reacted with an acid of formula III or a reactive functional derivative of such acid.
10. A process according to claim 9, characterized in that the chloride of an acid of formula III is reacted with a starting compound of formula II in aqueous alkali.
11. A process according to one of claims 8 to 10 for the manufacture of compounds of formula I, in which R represents furyl, and of salts thereof or of hydrates of such salts, characterized in that appropriately substituted starting compounds are used.
12. A process according to one of claims 8 to 11 for the manufacture of compounds of formula I, in which R, represents methyl, and of salts thereof or of hydrates of such salts, characterized in that appropriately substituted starting compounds are used.
13. A process according to one of claims 8 to 12 for the manufacture of compounds of formula I, in which X represents the group (c) or one of groups (a) and (b), in which one of the two symbols R2 and R3 or R4 and R5 represents hydrogen and the other represents methyl, and of salts thereof or of hydrates of such salts, characterized in that appropriately substituted starting compounds are used.
14. A process according to claim 13 for the manufacture of compounds of formula I, in which X . represents a 1,2,5,6-tetrahydro-2-methyi-5,6-dioxo-as-triazin-3-yt group, and of salts thereof or of hydrates of such salts, characterized in that appropriately substituted starting compounds are used.
15. A process according to claim 13 for the manufacture of compounds of formula I, in which X represents the 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl group, and of salts thereof or of hydrates of such salts, characterized in that appropriately substituted starting compounds are used.
16. A process according to claim 14 for the manufacture 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 - 4 - carboxylic acid, and of salts thereof or of hydrates of such salts, characterized in that appropriately substituted starting compounds are used.
17. Pharmaceutical compositions, characterized in that they contain a derivative of the general formula
Figure imgb0049
wherein R represents furyl, thienyl or phenyl optionally substituted by halogen, hydroxy, lower alkoxy or lower alkyl, R, represents a lower alkyl or aminocarbonylmethyl and X represents a group of the formulae
Figure imgb0050
in which one of the two symbols R2 and R3 or R4 and R5 represents hydrogen and the other represents lower alkyl, carboxymethyl or sulphomethyl, or a pharmaceutically compatible salt thereof or a hydrate of such salt.
EP78100078A 1977-06-03 1978-06-01 New cephalosporin derivatives, their preparations and their pharmaceutical compositions Expired EP0000005B1 (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
NO782998L (en) * 1978-07-19 1980-01-22 Hoffmann La Roche CEPHALOSPORINESTERS AND EATERS.
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
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