EP0000005A1 - New cephalosporin derivatives, their preparations and their pharmaceutical compositions - Google Patents
New cephalosporin derivatives, their preparations and their pharmaceutical compositions Download PDFInfo
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- EP0000005A1 EP0000005A1 EP78100078A EP78100078A EP0000005A1 EP 0000005 A1 EP0000005 A1 EP 0000005A1 EP 78100078 A EP78100078 A EP 78100078A EP 78100078 A EP78100078 A EP 78100078A EP 0000005 A1 EP0000005 A1 EP 0000005A1
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- QLJUIQWECPKPHV-UHFFFAOYSA-N CC(C=CN1N)=NC1=O Chemical compound CC(C=CN1N)=NC1=O QLJUIQWECPKPHV-UHFFFAOYSA-N 0.000 description 1
- 0 CC(N1*)=NN(*)C2OC2C1=O Chemical compound CC(N1*)=NN(*)C2OC2C1=O 0.000 description 1
Classifications
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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
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- 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 I 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'-dibenzylethyl-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.
- salts are hydrohalides, for example hydrochlorides, hydrobromides, hydroiodides, and also other mineral acid salts, such as sulfates, nitrates, phosphates and the like such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates 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 formula I and their salts or hydrates of the salts can be in the syn-isomeric 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-hydroxysuccinimide 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.
- 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. So you can e.g. condense a free acid of the formula III with one of the esters corresponding to the formula II using a carbodiimide, such as dicyclohexylcarbodiimide, in an inert solvent, such as ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide and then split off the ester group.
- oxazolium salts e.g. Use N-ethyl-5-phenyl-isoxazolium-3'-sulfonate.
- a salt of an acid of formula II e.g. a trialkylammonium salt
- a reactive functional derivative of an acid of formula III as mentioned above in an inert solvent, e.g. one of the above to.
- an acid halide preferably the chloride of an acid of the formula III
- the amine of the formula II is reacted with the amine of the formula II.
- the reaction takes place - preferably in the presence of an acid-binding agent, for example 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 carried out in an aprotic organic solvent, such as, for example, dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric triamide.
- reaction of a compound of the formula II with a compound of the formula III or a reactive functional derivative thereof can expediently take place at temperatures between about -40 ° C. and room temperature, for example at about 0-10 ° C.
- 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.
- acid e.g. Hydrochloric acid, sulfuric acid, phosphoric acid or citric acid can be used.
- the 7-amino compounds of the formula II 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, be prepared with a thiol of 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 a customary manner, for example by recrystallization or by chromatographic methods using a suitable solvent or solvent mixture.
- the compounds of formula I, their salts and the hydrates of these salts are antibiotic, in particular bactericidally active. They have a broad spectrum of activity against Gram-positive and Gram-negative microorganisms, including ⁇ -lactamase-forming staphylococci and various ⁇ -lactamase-forming Gram-negative bacteria, such as e.g. Haemophilus influenzae, - Escherichia coli, Proteus and Klebsiella species.
- the compounds of formula I and 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.
- 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 (CD50, 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, for example, water, gum arabic.
- a pharmaceutical, inorganic or organic inert carrier material which is particularly suitable for parenteral administration, such as, for example, water, gum arabic.
- the pharmaceutical preparations are preferably in liquid form, for example 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.
- 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-deacetoxy-3- [ (1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl) thio] cephalosporanoic acid.
- 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).
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Abstract
Description
Die vorliegende Erfindung betrifft neue Acylderivate der allgemeinen Formel
sowie Salze dieser Verbindungen und Hydrate dieser Salze.The present invention relates to new acyl derivatives of the general formula
and salts of these compounds and hydrates of these salts.
Beispiele von Salzen der Verbindungen der Formel I 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'-Dibenzyläthyl- 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 I 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'-dibenzylethyl-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 Hydro- chloride, Hydrobromide, Hydrojodide,sowie andere Mineralsäuresalze, 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, Ascorbate 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, and also other mineral acid salts, such as sulfates, nitrates, phosphates and the like such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates 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 syn-isomeren Form
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
mit einer Säure der allgemeinen Formel
oder mit einem reaktionsfähigen funktionellen Derivat dieser Säure umsetzt und die Schutzgruppe abspaltet, oder dass man - b) eine Verbindung der allgemeinen Formel
mit einem Thiol der allgemeinen Formel
umsetzt und die Schutzgruppe abspaltet, wonach man das Reaktions produkt ggfs. in ein Salz bzw. ein Hydrat dieses Salzes überführt.
- a) a compound of the general formula
with an acid of the general formula
or reacted with a reactive functional derivative of this acid and split off the protective group, or that - b) a compound of the general formula
with a thiol of the general formula
and the protective group is split off, after which the reaction product is optionally converted into a salt or a hydrate of this salt.
Die in den Ausgangsverbindungen der Formeln II und 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-Hydroxysuccinimidester, 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-hydroxysuccinimide 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 Säure 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. So you can e.g. condense a free acid of the formula III with one of the esters corresponding to the formula II using a carbodiimide, such as dicyclohexylcarbodiimide, in an inert solvent, such as ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide and then split off the ester group. Instead of carbodiimides, oxazolium salts, e.g. Use N-ethyl-5-phenyl-isoxazolium-3'-sulfonate.
Nach einer anderen Ausführungsform setzt man ein Salz einer Säure der Formel II, 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 II, 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 III 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 Kaliumcar- bonat, 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 takes place - preferably in the presence of an acid-binding agent, for example 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 carried out in an aprotic organic solvent, such as, for example, dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric triamide.
Die Umsetzung einer Verbindung der Formel II mit einer Verbindung der Formel III oder einem reaktionsfähigen funktione: len Derivat davon kann zweckmässig bei Temperaturen zwischen etwa -40°C und Zimmertemperatur, beispielsweise bei etwa O-10°C, erfolgen.The reaction of a compound of the formula II with a compound of the formula III or a reactive functional derivative thereof can expediently take place at temperatures between about -40 ° C. and room temperature, for example at about 0-10 ° C.
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 II oder IV mit einer Verbindung der Formel III bzw. V wird die allenfalls vorhandene Schutzgruppe abgespalten.After the reaction of a compound of formula II or IV with a compound of formula III 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 salzbildenden 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. As an acid here. e.g. Hydrochloric acid, sulfuric acid, phosphoric acid or citric acid can be used.
Die als Ausgangsprodukte verwendeten 7-Aminoverbindungen der Formel II können ausgehend von einer Verbindung der Formel
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 II used as starting products can be started from a compound of the formula
be prepared with a thiol of 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 a customary manner, for example by recrystallization or by chromatographic methods using a suitable solvent or solvent mixture.
Die Verbindungen der Formel I, ihre Salze und die Hydrate dieser Salze sind antibiotisch, insbesondere bakterizid wirksam. Sie besitzen ein breites Wirkungspektrum gegen Gram-positive und Gram-negative Mikroorganismen, einschliesslich β-Lactamase bildende Staphylokokken und verschiedene β-Lactamase bildende Gram-negative Bakterien, wie z.B. Haemophilus influenzae, - Escherichia coli, Proteus- und Klebsiella-Spezies.The compounds of formula I, their salts and the hydrates of these salts are antibiotic, in particular bactericidally active. They have a broad spectrum of activity against Gram-positive and Gram-negative microorganisms, including β-lactamase-forming staphylococci and various β-lactamase-forming Gram-negative bacteria, such as e.g. Haemophilus influenzae, - Escherichia coli, Proteus and Klebsiella species.
Die Verbindungen der 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 and 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:
- Produkt A: (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
- Produkt B: (7R)-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-3-/[l-amino-l,2-dihydro-2-oxo-4-pyrimidinyl)-thio]-methyl/-3-cephem-4-carbonsäure
- Produkt C: (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
- Produkt D: (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
- Produkt E: (7R)-7-[2-(Methoxyimino)-2-(2-thienyl)acetamido]-3-/[(l,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as- triazin-3-yl)thio]methyl/-3-cephem-4-carbonsäure
- Produkt F: (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
- Produkt G: (7R)-7-/2-[(Carbamoylmethoxy)imino]-2-(2-furyl)-acetamido/-3-/[(l,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl/-3-cephem-4-carbonsäure.
- Product A: (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
- Product B: (7R) -7- [2- (2-furyl) -2- (methoxyimino) acetamido] -3 - / [l-amino-l, 2-dihydro-2-oxo-4-pyrimidinyl) thio ] -methyl / -3-cephem-4-carboxylic acid
- Product C: (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
- Product D: (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
- Product E: (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
- 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- (methoxyimino) acetamido] -3-cephem-4-carboxylic acid
- Product G: (7R) -7- / 2 - [(carbamoylmethoxy) imino] -2- (2-furyl) acetamido / -3 - / [(l, 4,5,6-tetrahydro-4-methyl-5 , 6-dioxo-as-triazin-3-yl) thio] methyl / -3-cephem-4-carboxylic acid.
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 (CD50, mg/kg).
Herstellung des Natriumsalzes der (7R)-7-[2-(2-Furyl)-2-(methoxyimino)acetamido]-3-/[(l,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl/-3-cephem-4-carbonsäure:
- 5,06 g 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 und 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 orangegefärbte 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-/[(l,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).
- 5.06 g of 2-methoxyimino-2-furyl-acetic acid (syn / anti mixture 80:20) are dissolved in 150 ml of benzene and gassed with nitrogen at 5-10 ° C with 4.2 ml of triethylamine, 2.6 ml of oxalyl chloride and 6 drops of dimethylformamide are 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 of acetone and at 0 ° C. with a solution of 11.2 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 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 matter 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 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. The orange-colored filtrate is mixed with 10 ml of a 2-n solution of 2-ethylcaproic acid sodium salt in ethyl acetate, 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- carbonic acid fails. This is filtered off, 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).
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 (7R)-7-Amino-3- desacetoxy-3-[(l-amino-l,2-dihydro-2-oxo-4-pyrimidinyl)-thio]-cephalosporansäure hergestellt. Das Produkt stellt ein beiges Pulver dar (syn/anti-Gemisch 70:30). Rf-Wert = 0,40 (DC auf Kieselgel-F254-Fertigplatten im System Butanol/Eisessig/Wasser 4:1:1; Sichtbarmachung mit UV-Licht).
- 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-deacetoxy-3 - [(l-amino-1,2-dihydro -2-oxo-4-pyrimidinyl) thio] cephalosporanic acid. The product is a beige powder (syn / anti mixture 70:30). R f value = 0.40 (TLC on silica gel F 254 finished plates in the butanol / glacial acetic acid / water 4: 1: 1 system; visualization with UV light).
Herstellung des Natriumsalzes der (7R)-7-[2-(Phenyl)-2-(methoxyimino)acetamidol-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).
- 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 of (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).
Herstellung des Natriumsalzes der (7R)-7-[2-(2-Furyl)-2-(methoxyimino)acetamido]-3-/[(l,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl/-3-cephem-4-carbonsäure: ;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:;
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).
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).
- 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 of (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).
Herstellung des Dinatriumsalzes der (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-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 ist ein praktisch farbloses Pulver (syn-Isomer).
- 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. In the salt formation 20 ml (2 equiv.) Of a 2 N solution of 2-ethylhexanoic acid A sodium salt may be used in Essigester. The product is a practically colorless powder (syn isomer).
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-[(l-äthyl-l,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-yl)thio]-cephalosporansäure hergestellt. Das Produkt ist ein beiges Pulver (syn/anti-Gemisch ca. 70:30).
- 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 - [(l-ethyl l, 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).
Herstellung des Natriumsalzes der (7R)-7-/2-[(Carbamoyl- methoxy)imino]-2-(2-furyl)acetamido/-3-/[(l,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 l,4,5,6-Tetrahydro-4-methyl-5,6-dioxo-3-mercapto-as-triazin in 200 ml Phosphatpuffer mit pH 6,4 suspendiert. Unter Stickstoffbegasung 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 O-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 400C eingeengt. Dieser konzentrierten Lösung wird Aethanol zugegeben, wobei das Natriumsalz 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/antiGemisch ca. 70:30).
- 9.76 g / α - [(carbamoylmethoxy) imino] furfuryl / cephalosporin sodium salt (syn / anti mixture approx. 70:30) together with 4.77 g, 4,5,6-tetrahydro-4-methyl-5 , 6-dioxo-3-mercapto-as-triazine suspended in 200 ml phosphate buffer with pH 6.4. The pH is adjusted to 6.4 using 1N sodium hydroxide solution while gassing with nitrogen, 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 with 2N hydrochloric acid, the reaction product precipitating 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 in vacuo. concentrated at 40 0 C. Ethanol is added to this concentrated solution, and the sodium salt precipitates. This is filtered off with suction, washed with ethanol and low-boiling petroleum ether and dried overnight at 40 ° C. in vacuo. You get that 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).
Ersetzt man die Ausgangsverbindungen durch äquivalente Mengen /a-[(Methoxy)imino]furfuryl/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 / a - [(methoxy) imino] furfuryl / cephalosporin and 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-3-mercapto-as-triazine, this gives 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. The product is identical to the compound obtained according to Example 1.
Herstellung von Trockenampullen für die intramuskuläre Verabreichung:
- Es wird in üblicher Weise ein Lyophilisat von 1 g des Natriumsalzes der (7R)-7-[2-(2-Furyl)-2-(methoxyimino)acet- amido]-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 abgefüllt. Vor der Verabreichung wird letzteres mit 2,5 ml einer 2%igen wässrigen Lidocainhydrochlorid-Lösung versetzt.
- A lyophilizate 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 (18)
sowie von Salzen dieser Verbindungen und von Hydraten dieser Salze, dadurch gekennzeichnet, dass man
mit einer Säure der allgemeinen Formel
oder mit einem reaktionsfähigen funktionellen Derivat dieser Säure umsetzt und die Schutzgruppe abspaltet, oder dass man
mit einem Thiol der allgemeinen Formel
as well as salts of these compounds and hydrates of these salts, characterized in that
with an acid of the general formula
or reacted with a reactive functional derivative of this acid and split off the protective group, or that
with a thiol of the general formula
oder ein pharmazeutisch verträgliches Salz davon bzw. ein Hydrat eines dieser Salze als wirksamen Bestandteil mit einem pharmazeutisch verträglichen Trägermaterial vermischt.10. A process for the preparation of pharmaceutical preparations, characterized in that a compound of the general formula
or a pharmaceutically acceptable salt thereof or a hydrate of one of these salts mixed as an active ingredient with a pharmaceutically acceptable carrier material.
oder an einem pharmazeutisch verträglichen Salz davon bzw. an einem Hydrat eines solchen Salzes.11. Pharmaceutical preparations, characterized in that they contain a compound of the general formula
or on a pharmaceutically acceptable salt thereof or on a hydrate of such a salt.
sowie Salze dieser Verbindungen und Hydrate dieser Salze.12. Acyl derivatives of the general formula
and salts of these compounds and hydrates of these salts.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
LU77485 | 1977-06-03 | ||
LU77485 | 1977-06-03 | ||
CH314278 | 1978-03-22 | ||
CH3142/78 | 1978-03-22 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0000005A1 true EP0000005A1 (en) | 1978-12-20 |
EP0000005B1 EP0000005B1 (en) | 1980-10-29 |
Family
ID=25692293
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP78100078A Expired EP0000005B1 (en) | 1977-06-03 | 1978-06-01 | New cephalosporin derivatives, their preparations and their pharmaceutical compositions |
Country Status (26)
Country | Link |
---|---|
EP (1) | EP0000005B1 (en) |
JP (1) | JPS5412394A (en) |
AR (1) | AR225134A1 (en) |
AT (2) | AT362501B (en) |
AU (1) | AU518648B2 (en) |
BR (1) | BR7803565A (en) |
CA (1) | CA1114808A (en) |
CU (1) | CU21118A (en) |
DE (2) | DE2824065A1 (en) |
DK (1) | DK246878A (en) |
ES (2) | ES470442A1 (en) |
FI (1) | FI781754A (en) |
FR (1) | FR2393000A1 (en) |
GB (1) | GB1599232A (en) |
GR (1) | GR73554B (en) |
HU (1) | HU182498B (en) |
IE (1) | IE46903B1 (en) |
IL (1) | IL54803A (en) |
IT (1) | IT1098306B (en) |
MC (1) | MC1195A1 (en) |
NL (1) | NL7805715A (en) |
NO (1) | NO781934L (en) |
NZ (1) | NZ187392A (en) |
PH (1) | PH14653A (en) |
PT (1) | PT68134A (en) |
SE (1) | SE7806465L (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0002605A1 (en) * | 1977-12-20 | 1979-06-27 | Eli Lilly And Company | Cephalosporin compounds and formulations containing them for use in the treatment of bacterial infections and the preparation of the cephalosporin compounds |
DE2912829A1 (en) * | 1978-03-31 | 1979-10-04 | Roussel Uclaf | O-SUBSTITUTED OXIME DERIVATIVES OF 7-AMINOTIAOYL-ACETAMIDO-CEPHALOSPORANIC ACID, THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS |
EP0045525A2 (en) * | 1978-05-30 | 1982-02-10 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Cephalosporin derivatives and process for their preparation |
EP0065748A1 (en) * | 1981-05-22 | 1982-12-01 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Process for the preparation of a cephalosporin derivative |
EP0233780A2 (en) * | 1986-02-19 | 1987-08-26 | Eli Lilly And Company | O-substituted oximino cephalosporins |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FI782683A (en) * | 1978-07-19 | 1980-01-20 | Hoffmann La Roche | KEFALOSPORINESTRAR OCH -ESTRAR |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2137899A1 (en) * | 1971-05-14 | 1972-12-29 | Glaxo Lab Ltd | |
FR2275215A1 (en) * | 1974-06-21 | 1976-01-16 | Hoffmann La Roche | NEW HETEROCYCLICAL DERIVATIVES OF DESACETOXYCEPHALOSPORIN, PROCESS FOR THEIR PREPARATION AND APPLICATION AS A MEDICINAL PRODUCT |
FR2280381A1 (en) * | 1974-08-02 | 1976-02-27 | Lilly Co Eli | NEW CEPHALOSPORIN DERIVATIVES |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1555471A (en) * | 1975-06-19 | 1979-11-14 | Glaxo Lab Ltd | 7 carbamoylalkoxyimino acetamido 3 em 4 carboxylic acidsand derivatives thereof |
GB1576625A (en) * | 1976-04-12 | 1980-10-08 | Fujisawa Pharmaceutical Co | Syn isomer 3,7 disubstituted 3 cephem 4 carboxylic acid compounds and processes for the preparation thereof |
GB1596278A (en) * | 1976-11-30 | 1981-08-26 | Glaxo Operations Ltd | 7-(-oxyimino-acetamino)cephalosporin derivatives |
-
1978
- 1978-05-25 GB GB22499/78A patent/GB1599232A/en not_active Expired
- 1978-05-25 NL NL7805715A patent/NL7805715A/en not_active Application Discontinuation
- 1978-05-26 NZ NZ187392A patent/NZ187392A/en unknown
- 1978-05-26 MC MC781305A patent/MC1195A1/en unknown
- 1978-05-26 IE IE1056/78A patent/IE46903B1/en unknown
- 1978-05-29 AU AU36588/78A patent/AU518648B2/en not_active Expired
- 1978-05-29 IL IL54803A patent/IL54803A/en unknown
- 1978-05-31 HU HU78HO2077A patent/HU182498B/en unknown
- 1978-06-01 JP JP6501078A patent/JPS5412394A/en active Pending
- 1978-06-01 FI FI781754A patent/FI781754A/en not_active Application Discontinuation
- 1978-06-01 DE DE19782824065 patent/DE2824065A1/en not_active Withdrawn
- 1978-06-01 FR FR7816468A patent/FR2393000A1/en active Granted
- 1978-06-01 EP EP78100078A patent/EP0000005B1/en not_active Expired
- 1978-06-01 SE SE7806465A patent/SE7806465L/en unknown
- 1978-06-01 GR GR56409A patent/GR73554B/el unknown
- 1978-06-01 DE DE7878100078T patent/DE2860248D1/en not_active Expired
- 1978-06-02 NO NO781934A patent/NO781934L/en unknown
- 1978-06-02 AR AR272437A patent/AR225134A1/en active
- 1978-06-02 PH PH21225A patent/PH14653A/en unknown
- 1978-06-02 AT AT403578A patent/AT362501B/en not_active IP Right Cessation
- 1978-06-02 IT IT24165/78A patent/IT1098306B/en active
- 1978-06-02 PT PT68134A patent/PT68134A/en unknown
- 1978-06-02 BR BR787803565A patent/BR7803565A/en unknown
- 1978-06-02 ES ES470442A patent/ES470442A1/en not_active Expired
- 1978-06-02 CA CA304,644A patent/CA1114808A/en not_active Expired
- 1978-06-02 DK DK246878A patent/DK246878A/en not_active Application Discontinuation
- 1978-07-03 CU CU7834929A patent/CU21118A/en unknown
-
1979
- 1979-02-27 ES ES478115A patent/ES478115A1/en not_active Expired
-
1980
- 1980-07-02 AT AT0345980A patent/AT365197B/en not_active IP Right Cessation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2137899A1 (en) * | 1971-05-14 | 1972-12-29 | Glaxo Lab Ltd | |
FR2275215A1 (en) * | 1974-06-21 | 1976-01-16 | Hoffmann La Roche | NEW HETEROCYCLICAL DERIVATIVES OF DESACETOXYCEPHALOSPORIN, PROCESS FOR THEIR PREPARATION AND APPLICATION AS A MEDICINAL PRODUCT |
FR2280381A1 (en) * | 1974-08-02 | 1976-02-27 | Lilly Co Eli | NEW CEPHALOSPORIN DERIVATIVES |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0002605A1 (en) * | 1977-12-20 | 1979-06-27 | Eli Lilly And Company | Cephalosporin compounds and formulations containing them for use in the treatment of bacterial infections and the preparation of the cephalosporin compounds |
DE2912829A1 (en) * | 1978-03-31 | 1979-10-04 | Roussel Uclaf | O-SUBSTITUTED OXIME DERIVATIVES OF 7-AMINOTIAOYL-ACETAMIDO-CEPHALOSPORANIC ACID, THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS |
EP0045525A2 (en) * | 1978-05-30 | 1982-02-10 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Cephalosporin derivatives and process for their preparation |
EP0045525A3 (en) * | 1978-05-30 | 1982-02-17 | F. Hoffmann-La Roche & Co. Aktiengesellschaft | Cephalosporin derivatives and process for their preparation |
EP0065748A1 (en) * | 1981-05-22 | 1982-12-01 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Process for the preparation of a cephalosporin derivative |
US4472574A (en) * | 1981-05-22 | 1984-09-18 | Hoffman-La Roche Inc. | Process for the manufacture of a cephem carboxylic acid derivative |
EP0233780A2 (en) * | 1986-02-19 | 1987-08-26 | Eli Lilly And Company | O-substituted oximino cephalosporins |
EP0233780A3 (en) * | 1986-02-19 | 1989-02-01 | Eli Lilly And Company | O-substituted oximino cephalosporins |
Also Published As
Publication number | Publication date |
---|---|
AU3658878A (en) | 1979-12-06 |
AR225134A1 (en) | 1982-02-26 |
GB1599232A (en) | 1981-09-30 |
FI781754A (en) | 1978-12-04 |
BR7803565A (en) | 1979-02-20 |
DE2824065A1 (en) | 1978-12-14 |
GR73554B (en) | 1984-03-14 |
SE7806465L (en) | 1978-12-04 |
DK246878A (en) | 1978-12-04 |
IL54803A (en) | 1982-01-31 |
FR2393000B1 (en) | 1982-10-29 |
MC1195A1 (en) | 1979-02-23 |
AT362501B (en) | 1981-05-25 |
IL54803A0 (en) | 1978-07-31 |
DE2860248D1 (en) | 1981-01-29 |
AU518648B2 (en) | 1981-10-15 |
NL7805715A (en) | 1978-12-05 |
ATA403578A (en) | 1980-10-15 |
IE46903B1 (en) | 1983-11-02 |
CA1114808A (en) | 1981-12-22 |
PH14653A (en) | 1981-10-14 |
ES478115A1 (en) | 1979-06-01 |
ATA345980A (en) | 1981-05-15 |
AT365197B (en) | 1981-12-28 |
IT7824165A0 (en) | 1978-06-02 |
JPS5412394A (en) | 1979-01-30 |
HU182498B (en) | 1984-01-30 |
EP0000005B1 (en) | 1980-10-29 |
ES470442A1 (en) | 1979-10-01 |
IT1098306B (en) | 1985-09-07 |
FR2393000A1 (en) | 1978-12-29 |
PT68134A (en) | 1978-07-01 |
NZ187392A (en) | 1984-05-31 |
CU21118A (en) | 1983-04-06 |
NO781934L (en) | 1978-12-05 |
IE781056L (en) | 1978-12-03 |
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