DK166728B1 - ANALOGY PROCEDURE FOR THE PREPARATION OF CEPHALOSPORIN DERIVATIVES AND THE BASIC MATERIAL USED IN THE PROCEDURE - Google Patents

Abstract

For the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE 1. A process for the manufacture of acyl derivatives of general formula I see diagramm : EP0030294,P12,F1 in which R represents hydrogen or a readily hydrolyzable ester group, as well as of salts of these compounds and hydrates of these compounds or of their salts by reating a halide of general formula II see diagramm : EP0030294,P12,F2 in which R has the significance given above and Y represents a halogen atom, or a salt of this compound with thiourea and, if desired, converting a compound of formula I obtained into a salt or hydrate or into a hydrate of this salt, characterized in that X signifies one of the groups see diagramm : EP0030294,P13,F3 in which R' represents hydrogen or a readily hydrolysable ether group.

Description

DK 166728 B1DK 166728 B1

Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte cephalosporinderivater med den almene formel I,The present invention relates to an analogous process for the preparation of novel cephalosporin derivatives of general formula I,

Η HΗ H

I t^NI t ^ N

CH3ON=C—CONH—i—rCH3ON = C-CONH-i-r

5 N—A —f-J. sy—CHj!—S—X IN-A-f-J. its — CH₂! —S — X I

Jl \) & γJl \) & γ

13 COOR13 COOR

hvor X betegner en af grupperne (a) eller (b),where X represents one of the groups (a) or (b),

Η3εγίγο H3C.rVΗ3εγίγο H3C.rV

(a) (b) 10 R betegner hydrogen eller en let hydrolyserbar estergruppe, og R' betegner hydrogen eller en let hydrolyserbar ethergruppe, eller salte af disse forbindelser eller hydrater af disse forbindelser eller salte deraf.(a) (b) R represents hydrogen or a readily hydrolyzable ester group, and R 'represents hydrogen or a light hydrolyzable ether group, or salts of these compounds or hydrates of these compounds or salts thereof.

Når R i gruppen (b) betegner hydrogen, foreligger denne i tautomer 15 ligevægt med gruppen (a).When R in the group (b) represents hydrogen, it is in equilibrium in tautomer 15 with the group (a).

Som let hydrolyserbare estergrupper R i forbindelserne med formlen X skal forstås R-grupper på carboxylfunktionen, hvilke foreligger i form af en let hydrolyserbar estergruppe. Eksempler på sådanne estergrupper, som kan være af sædvanlig art, er lavere alkanoyloxyalkyl, 20 f.eks. acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl og 1-pivaloy-loxyethyl, lavere alkoxycarbonyloxyalkyl, f.eks. methoxycarbonyloxy-methyl, 1-ethoxycarbonyloxyethyl og 1-isopropoxycarbonyloxyethyl, lactonylgrupper, f.eks. phthalidyl og thiophthalidyl, lavere alkoxy- DK 166728 B1 2 methyl, f.eks. methoxymethyl, eller lavere alkanoylaminomethyl, f.eks. acetamidomethyl.As readily hydrolyzable ester groups R in the compounds of formula X are understood to be R groups on the carboxyl function which are in the form of a readily hydrolyzable ester group. Examples of such ester groups which may be of a conventional nature are lower alkanoyloxyalkyl, e.g. acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl, lower alkoxycarbonyloxyalkyl, e.g. methoxycarbonyloxy-methyl, 1-ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethyl, lactonyl groups, e.g. phthalidyl and thiophthalidyl, lower alkoxy- methyl, e.g. methoxymethyl, or lower alkanoylaminomethyl, e.g. acetamidomethyl.

Som let hydrolyserbare ethergrupper R i forbindelserne med formlen I skal forstås R-grupper ved 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-5 triazin-3-ylgruppen (b)'s enoliske funktion, hvilke foreligger i form af en let hydrolyserbar ethergruppe. Som ethergrupper.kan anvendes de samme grupper som nævnt ovenfor for de let hydrolysefbare estergrupper. Repræsentanter for sådanne ethere er f.eks. også de lavere alkanoyloxyalkylethere, f.eks. acetoxymethyl-, pivaloyloxymethyl-, Ι-ΙΟ acetoxyethyl- og 1-pivaloyloxyethylether, de lavere alkoxycarbony-loxyalkylethere, f.eks. methoxycarbonyloxymethyl-, 1-ethoxycarbon-yloxyethyl- og 1-isopropoxycarbonyloxyethylether, lactonyletherne, f.eks. phthalidyl- og thiophthalidyletheren, de lavere alkoxymethyl-ethere, f.eks. methoxymethyletheren, eller de lavere alkanoylamino-15 methylethere, f.eks. acetamidomethyletheren.As readily hydrolysable ether groups R in the compounds of formula I are understood to be R groups by the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-5-triazin-3-yl group (b) which are in the form of a readily hydrolyzable ether group. As ether groups, the same groups as mentioned above can be used for the easily hydrolyzable ester groups. Representatives of such ethers are e.g. also the lower alkanoyloxyalkyl ethers, e.g. acetoxymethyl, pivaloyloxymethyl, Ι-ΙΟ acetoxyethyl and 1-pivaloyloxyethyl ether, the lower alkoxycarbonyloxyalkyl ethers, e.g. methoxycarbonyloxymethyl, 1-ethoxycarbonyl yloxyethyl and 1-isopropoxycarbonyloxyethyl ether, the lactonyl ethers, e.g. the phthalidyl and thiophthalidyl ether, the lower alkoxymethyl ethers, e.g. the methoxymethyl ether, or the lower alkanoylamino methyl ethers, e.g. acetamidomethyletheren.

Eksempler på salte af forbindelserne med formlen I er alkalimetalsalte såsom natrium- eller kaliumsalte, ammoniumsalte, jordalkalimetalsal te såsom calciumsalte, salte med organiske baser såsom salte med aminer, f.eks. salte med N-ethyl-piperidin, procain, dibenzylamin, 20 N,N'-dibenzylethylethylendiamin, alkylaminer eller dialkylaminer, samt salte med aminosyrer såsom salte med arginin eller lysin. Saltene kan være monosalte eller disalte. Den anden saltdannelse kan optræde i forbindelser med hydroxygruppen af 2,5-dihydro-6-hydroxy-2-methyl-5 -oxo-as-triazin-3-ylgruppen.Examples of salts of the compounds of formula I are alkali metal salts such as sodium or potassium salts, ammonium salts, alkaline earth metal salts such as calcium salts, salts with organic bases such as salts with amines, e.g. salts with N-ethyl-piperidine, procaine, dibenzylamine, N, N'-dibenzylethylethylenediamine, alkylamines or dialkylamines, and salts with amino acids such as salts with arginine or lysine. The salts may be monosaltic or disaltic. The second salt formation can occur in compounds with the hydroxy group of the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group.

25 Forbindelserne med formlen I danner ligeledes additianssalte med organiske eller uorganiske syrer. Eksempler på sådanne salte er hydrohalogenider, f.eks. hydrochlorider, hydrobromider og hydroiodi-der samt andre mineralsyresalte såsom sulfater, nitrater og phosp-hater, alkyl- eller monoarylsulfonater såsom ethansulfonater, toluen-30 sulfonater og benzensulfonater eller andre organiske syresalte såsom acetater, tartrater, maleater, citrater, benzoater, salicylater og ascorbater.The compounds of formula I also form addition salts with organic or inorganic acids. Examples of such salts are hydrohalides, e.g. hydrochlorides, hydrobromides and hydroiodides and other mineral acid salts such as sulphates, nitrates and phosphates, alkyl or monoarylsulphonates such as ethane sulphonates, toluene sulphonates and benzenesulphonates or other organic acid salts such as acetates, tartrates, maleate, citrates, benzoates, salicates .

Forbindelserne med formlen I (herunder deres salte, let hydrolyserbare estere og ethere) kan være hydratiserede. Hydratiseringen kan DK 166728 B1 3 ske under fremstillingsprocessen eller efterhånden optræde som en følge af et først vandfrit produkts hygroskopiske egenskaber.The compounds of formula I (including their salts, easily hydrolyzable esters and ethers) may be hydrated. The hydration may occur during the manufacturing process or eventually occur as a result of the hygroscopic properties of a first anhydrous product.

De her omhandlede forbindelser kan foreligge i den syn-isomere form (Z-form)The compounds of this invention may be in the syn-isomeric form (Z-form)

N-i-C-CONH-SN-i-C-CONH-S

Jjl n 0CH3 5 eller i den anti-isomere form (E-form) N-r-C-CONH-\ //Ti 'Jjl n OCH3 5 or in the anti-isomeric form (E form) N-r-C-CONH- \ // Ti '

/N/ N

CH3.OCH3.O

eller som blandinger af disse to former. Der foretrækkes den syn-isomere form eller blandinger, hvori den syn-isomere form dominerer.or as mixtures of these two forms. The syn-isomeric form or mixtures in which the syn-isomeric form predominates are preferred.

Foretrukne produkter er (6R,7R)-7-(2-(2-amino-4-thiazolyl)-2-(Z-me-thoxyimino)acetamido) - 3* ((2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-10 triazin-3-yl)thio)-methyl)-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-en-2-carboxylsyre samt saltene deraf og de tilsvarende hydrater.Preferred products are (6R, 7R) -7- (2- (2-amino-4-thiazolyl) -2- (Z-methoxy-amino) acetamido) -3 * ((2,5-dihydro-6-hydroxy) 2-methyl-5-oxo-as-triazin-3-yl) thio-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid and the salts thereof and the corresponding hydrates.

Fra den på nærværende ansøgnings prioritetsdato ikke offentligt tilgængelige danske patentansøgning nr. 2226/79 kendes en fremgangsmåde til fremstilling af cephalosporinderivater; den foreliggende 15 opfindelse angår imidlertid en yderligere og fra de kendte fremgangsmåder forskellig fremgangsmåde til fremstilling deraf. En anden fremgangsmåde er beskrevet i DE-A 2 900 961, hvor slutprodukterne dog indeholder andre substituenter i 3-stillingen.From the Danish patent application no. 2226/79, which is not publicly available on the priority date of the present application, a method for preparing cephalosporin derivatives is known; However, the present invention relates to a further and different method from the known processes for its preparation. Another method is described in DE-A 2 900 961, however, where the final products contain other substituents at the 3-position.

Fra DE-A 2 715 385, DE-A 2 707 565 og DE-A 2 900 961 kendes cephalo-20 sporinderivater, der ligesom cephalosporinderivaterne ifølge den foreliggende opfindelse, bærer en 7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyamino)acetamido]-gruppe. Cephalosporinderivaterne ifølge den DK 166728 β1 4 foreliggende opfindelse adskiller sig dog karakteristisk gennem konfigurationen af substituenten i 3-stillingen, hvorved nye forbindelser med overraskende virkningsfordele fremkommer.From DE-A 2 715 385, DE-A 2 707 565 and DE-A 2 900 961 are known cephalo-20 sporine derivatives which, like the cephalosporin derivatives of the present invention, carry a 7- [2- (2-amino-4-thiazolyl) ) -2- (Z-methoxyamino) acetamido] group. However, the cephalosporin derivatives of the present invention differ characteristically through the configuration of the substituent at the 3-position, whereby new compounds having surprising efficacy benefits emerge.

Den foreliggende opfindelse angår en analogifremgangsmåde til frem-5 stilling af cephalosporinderivater med den almene formel I,The present invention relates to an analogous process for the preparation of cephalosporin derivatives of general formula I,

HHHH

m 4 a c h3ON=C—CONH--1 /i H2N^v xm 4 a c h3ON = C — CONH - 1 / i H2N ^ v x

^ COOR^ COOR

hvor R betegner.hydrogen eller en let fraspaltelig estergruppe, samt 10 salte af disse forbindelser eller hydrater af disse forbindelser eller salte deraf, ved hvilken et halogenid med den almene formel II,wherein R represents hydrogen or a readily cleavable ester group, and 10 salts of these compounds or hydrates of these compounds or salts thereof, wherein a halide of the general formula II,

Η HΗ H

! I! IN

CH3ON=C—CONH—-X ^ CO C^J-NVsx^-~CH2—S—X li ch2yCH3ON = C — CONH —— X 2 CO C 2 J-NVsx 2 - ~ CH 2 —S — X li ch 2 y

COORCOOR

15 hvor R har den ovenfor anførte betydning, og Y betegner halogen, eller et salt af denne forbindelse, omsættes med thiourinstof, og en vunden forbindelse med den almene formel I, om ønsket, omdannes til et salt eller hydrat eller et hydrat af dette salt, hvilken fremgangsmåde er ejendommelig ved, at X betegner en af grupperne (a) og 20 (b), DK 166728 B1 5 H3CvyNY°Rl (a) (b) hvor R' betegner hydrogen eller en let fraspaltelig ethergruppe.Wherein R is as defined above and Y represents halogen, or a salt of this compound, is reacted with thiourea and a won compound of general formula I, if desired, is converted to a salt or hydrate or hydrate of this salt , which method is characterized in that X represents one of groups (a) and 20 (b), wherein R 'represents hydrogen or an easily decomposable ether group.

Det ved fremgangsmåden ifølge den foreliggende opfindelse anvendte 5 halogenid med den almene formel II kan f.eks. fremstilles ved, at en primær amin med den almene formel III,The halide of the general formula II used in the process according to the present invention may e.g. is prepared by a primary amine of the general formula III,

Η HΗ H

! h2N—-[! H 2 N - [

tf—nn^x>L--ch2--s—X IIItf-nn ^ x> L - ch2 - s-X III

COORCOOR

10 hvor X og R har den ovenfor angivne betydning, omsættes med en halogeneret carboxylsyre med den almene formel IV,10 wherein X and R are as defined above are reacted with a halogenated carboxylic acid of the general formula IV,

CH30N=C—COOHCH30N = C-COOH

CO iv i ch2y 15 hvor Y betegner halogen, eller med et reaktivt derivat af denne forbindelse. Den halogenerede carboxylsyre med den almene formel IV anvendes enten i fri form i nærværelse af et kondensationsmiddel, f.eks. et N,N'-disubstitueret carbodiimid såsom N,N'-dicyclohexyl- DK 166728 B1 6 carbodiimid eller en azolidforbindelse såsom N,N'-carbonyldiimidazol eller N,N'-thionyldiimidazol eller også i form af et syrehalogenid såsom syrechloridet eller -bromidet i form af et syreanhydrid såsom et syreanhydrid med en kulsyremonoester, f.eks. monomethyl- eller 5 monoisopropylcarbonat, eller i form af en aktiveret ester såsom p-nitrophenylesteren, 2,4-dinitrophenylesteren, N-hydroxysuccinimide-steren eller N-hydroxyphthalimidesteren. Omsætningen sker generelt i et inert organisk opløsningsmiddel, f.eks. i et haldgeneret carbon-hydrid såsom chloroform, dichlormethan eller carbontetrachlorid, i en 10 ether, f.eks. tetrahydrofuran eller dioxan, i dimethylformamid, dimethylacetamid, vand eller blandinger deraf. Reaktionstemperaturen ligger især i området fra ca. -50°C til +40°C, fortrinsvis mellem ca. -10°C og +10°C.CO iv in ch 2y 15 where Y represents halogen, or with a reactive derivative of this compound. The halogenated carboxylic acid of general formula IV is used either in free form in the presence of a condensing agent, e.g. an N, N'-disubstituted carbodiimide such as N, N'-dicyclohexyl carbodiimide or an azolid compound such as N, N'-carbonyldiimidazole or N, N'-thionyl diimidazole or also in the form of an acid halide or acid chloride or acid chloride or acid chloride in the form of an acid anhydride such as an acid anhydride with a carbonic acid monoester, e.g. monomethyl or monoisopropyl carbonate, or in the form of an activated ester such as the p-nitrophenyl ester, 2,4-dinitrophenyl ester, N-hydroxysuccinimide ester or N-hydroxyphthalimide ester. The reaction is generally carried out in an inert organic solvent, e.g. in a halogenated hydrocarbon such as chloroform, dichloromethane or carbon tetrachloride, in an ether, e.g. tetrahydrofuran or dioxane, in dimethylformamide, dimethylacetamide, water or mixtures thereof. The reaction temperature is in particular in the range of approx. -50 ° C to + 40 ° C, preferably between ca. -10 ° C and + 10 ° C.

Det i henhold til den foreliggende opfindelse anvendte halogenid med 15 den almene formel II kan også fremstilles ved, at en forbindelse med den almene formel V,The halide of the general formula II used in accordance with the present invention may also be prepared by a compound of the general formula V,

Η HΗ H

f CH3ON=C—CONH—-'<f CH3ON = C — CONH —- <

CO ^—ch2—s X VCO 2 —ch 2 —s X V

ch3CH3

COORCOOR

20 hvor X og R har den ovenfor angivne betydning, halogeneres. Det hertil anvendte udgangsprodukt med formlen V kan på sin side fremstilles ved, at den ovenfor definerede primære amin med formlen III omsættes med 3-oxo-2-methoxyiminosmørsyre eller med et reaktivt derivat af denne forbindelse. Denne omsætning forløber i det væsent-25 lige på samme måde som den ovenfor beskrevne acylering af den primære amin med den halogenerede carboxylsyre med formlen IV eller med et reaktivt derivat deraf. Halo generingen af det vundne acyleringspro-dukt med formlen V fører til de ovenfor definerede halogenider med formlen II og sker fortrinsvis ved behandling med det tilsvarende 30 halogen eller thionylhalogenid, f.eks. med chlor, brom eller sul- furylchlorid, fortrinsvis i et inert opløsningsmiddel såsom et halo- DK 166728 B1 7 generet carbonhydrid, f.eks. dichlormethan, dichlorethan, chloroform, dichlorethylen eller carbontetrachlorid eller en lavere alkancar-boxylsyre såsom eddikesyre eller et aromatisk opløsningsmiddel såsom benzen eller toluen. Reaktionstemperaturen ligger generelt mellem ca.Wherein X and R have the meaning given above are halogenated. The starting product of formula V used for this can in turn be prepared by reacting the above defined primary amine of formula III with 3-oxo-2-methoxyiminobutyric acid or with a reactive derivative of this compound. This reaction proceeds in substantially the same manner as the acylation of the primary amine described above with the halogenated carboxylic acid of formula IV or with a reactive derivative thereof. The halo generation of the obtained acylation product of formula V leads to the above-defined halides of formula II and preferably occurs by treatment with the corresponding halogen or thionyl halide, e.g. with chlorine, bromine or sulfuryl chloride, preferably in an inert solvent such as a halo generated hydrocarbon, e.g. dichloromethane, dichloroethane, chloroform, dichloroethylene or carbon tetrachloride or a lower alkanecarboxylic acid such as acetic acid or an aromatic solvent such as benzene or toluene. The reaction temperature is generally between ca.

5 0°C og 60°C.5 ° C and 60 ° C.

De ovenfor beskrevne mellemprodukter med formlen II samt fremstillingen deraf ud fra udgangsforbindelser med formlen ΙΓΙ eller V udgør ligeledes en del af den foreliggende opfindelse.The intermediates of formula II described above as well as their preparation from starting compounds of formula ΙΓΙ or V also form part of the present invention.

Omsætningen ifølge den foreliggende opfindelse af halogenidet med 10 formlen II eller et salt deraf med thiourinstof forløber fortrinsvis i et inert opløsningsmiddel, f.eks. i en lavere alkanol såsom ethanol, i en lavere keton såsom acetone, i en ether såsom tetrahydrofuran eller dioxan, i dimethylformamid eller dimethylacetamid, i vand, eller i blandinger deraf. Reaktionstemperaturen ligger generelt i 15 området fra ca, 0°C til 60°C, fortrinsvis ved stuetemperatur. Som halogenid med formlen II kan anvendes chloridet, bromidet, fluoridet eller iodidet, idet der fortrinsvis anvendes chloridet eller bromidet. Der kan anvendes den fri syre med formlen II, men valgfrit også et salt deraf, hvorhos der kan anvendes de samme salte som de ovenfor 20 beskrevne salte af forbindelserne med formlen I.The reaction of the present invention of the halide of formula II or a salt thereof with thiourea preferably proceeds in an inert solvent, e.g. in a lower alkanol such as ethanol, in a lower ketone such as acetone, in an ether such as tetrahydrofuran or dioxane, in dimethylformamide or dimethylacetamide, in water, or in mixtures thereof. The reaction temperature is generally in the range of from about 0 ° C to 60 ° C, preferably at room temperature. As the halide of formula II, the chloride, bromide, fluoride or iodide may be used, preferably using the chloride or bromide. The free acid of formula II can be used, but optionally also a salt thereof, whereby the same salts as the salts described above of the compounds of formula I. can be used.

Fremstillingen af saltene eller hydraterne af forbindelserne med formlen I eller hydraterne af disse salte kan ske på i og for sig kendt måde, f.eks. ved omsætning af carboxylsyren med formlen I med en ækvivalent mængde af den ønskede base, hensigtsmæssigt i et op-25 løsningsmiddel såsom vand eller i et organisk opløsningsmiddel såsom ethanol, methanol, acetone og lignende. Ved anvendelse af et andet ækvivalent af base sker saltdannelsen også ved en eventuelt tilstedeværende tautomer enolform (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-ylgruppen X), hvorhos der opstår et disalt. Saltdannelse-30 stemperaturen er ikke kritisk. Den ligger generelt ved stuetemperatur, men kan også ligge lidt derover eller derunder, omtrent i området fra 0eC til 50°C.The preparation of the salts or hydrates of the compounds of formula I or the hydrates of these salts can be carried out in a manner known per se, e.g. by reacting the carboxylic acid of formula I with an equivalent amount of the desired base, conveniently in a solvent such as water or in an organic solvent such as ethanol, methanol, acetone and the like. Using another equivalent of base, the salt formation also occurs with a tautomeric enol form (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group X) present, if any, which occurs. disalt. Salt formation-temperature is not critical. It is generally at room temperature, but may also be slightly above or below, approximately in the range of 0 ° C to 50 ° C.

Fremstillingen af hydraterne sker for det meste automatisk under fremstillingsfremgangsmåden eller som følge af et først vandfrit pro DK 166728 B1 8 dukts hygroskopiske egenskaber. Til en tilsigtet fremstilling af et hydrat kan et helt eller delvist vandfrit produkt (carboxylsyre med formlen I eller ester, ether eller salt deraf) udsættes for en fugtig atmosfære, f.eks. ved fra ca. +10°C til +40°C.The hydrates are usually produced automatically during the manufacturing process or as a result of a first anhydrous prodrug hygroscopic properties. For an intended preparation of a hydrate, a completely or partially anhydrous product (carboxylic acid of formula I or ester, ether or salt thereof) may be exposed to a humid atmosphere, e.g. know from approx. + 10 ° C to + 40 ° C.

5 En eventuelt vunden syn/anti-blanding af en forbindelse med formlen I kan på sædvanlig måde opspaltes i de tilsvarende syn- og antiformer, f.eks. ved omkrystallisation eller ved chromatografiske metoder under anvendelse af et egnet opløsningsmiddel eller en egnet opløsnings-middelb1ånding.An optionally obtained syn / anti-mixture of a compound of formula I can be split in the usual manner into the corresponding syn and antiforms, e.g. by recrystallization or by chromatographic methods using a suitable solvent or solvent mixture.

10 Forbindelserne med formlen I samt de tilsvarende salte eller hydrater af disse produkter er antibiotisk, især baktericidt virksomme. De besidder et bredt virkningsspektrum mod grampositive og gramnegative mikroorganismer, herunder /3-lactamaseproducerende stafylokokker og forskellige ^3-lactamaseproducerende gramnegative bakterier såsom 15 Pseudomonas aeruginosa, Haemophilus influenzae, Escherichia coli,The compounds of formula I as well as the corresponding salts or hydrates of these products are antibiotic, especially bactericidal. They possess a broad spectrum of action against gram-positive and gram-negative microorganisms, including β-lactamase-producing staphylococci and various β-lactamase-producing gram-negative bacteria such as Pseudomonas aeruginosa, Haemophilus influenzae, Escherichia coli,

Serratia marcescens, Proteus- og Klebsiella-arter.Serratia marcescens, Proteus and Klebsiella species.

Forbindelserne med formlen I samt de tilsvarende let hydrolyserbare estere, ethere og salte eller hydraterne af disse forbindelser kan anvendes til behandling og profylakse af infektionssygdomme. Til 20 voksne kan anvendes en dagsdosis på fra ca. 0,1 g til ca. 2 g. Den parenterale administration af de her omhandlede forbindelser foretrækkes især.The compounds of formula I as well as the corresponding readily hydrolyzable esters, ethers and salts or the hydrates of these compounds can be used for the treatment and prophylaxis of infectious diseases. For 20 adults a daily dose of approx. 0.1 g to approx. 2 g. The parenteral administration of the compounds of this invention is particularly preferred.

Til påvisning af den antimikrobielle virkning hos de her omhandlede produkter vurderes virkningen in vitro (mindste inhiberende koncen-25 tration i pg/ml) for (6R,7R)-7-(2-(2-amino-4-thiazolyl)-2-(Z-methoxy-imino)acetamido)-3-(((2,5-dihydro-6-hydroxy-2-methyl- 5-oxo-as-tria-zin-3-yl)thxo)-methyl)-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-en-2-carboxylsyre (herefter benævnt A), en repræsentativ forbindelse for de i henhold til den foreliggende opfindelse fremstillelige forbind-30 eiser. Resultaterne er sammenfattet i den nedenstående tabel: DK 166728 B1 9To detect the antimicrobial effect of the products herein, the effect in vitro (minimum inhibitory concentration in pg / ml) of (6R, 7R) -7- (2- (2-amino-4-thiazolyl) -2) is assessed. - ((Z-methoxy-imino) acetamido) -3 - (((2,5-dihydro-6-hydroxy-2-methyl-5-oxo-az-triazin-3-yl) thxo) -methyl) - 8-Oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (hereinafter referred to as A), a representative compound of the compounds of the present invention. The results are summarized in the table below: DK 166728 B1 9

TABELTABLE

Testorganismer - ATest organisms - A

5 Haemophilus influenzae Stamme 1 0,085 Haemophilus influenzae Strain 1 0.08

Stamme 2 0,005Strain 2 0.005

Stamme 3 0,005Strain 3 0.005

Stamme 4 ' -0,005Strain 4 '-0.005

Stamme 5 0,0025 10 Stamme 6 0,0025Strain 5 0.0025 10 Strain 6 0.0025

Stamme 7 0,0025Strain 7 0.0025

Klebsiella pneumoniae 1,2Klebsiella pneumoniae 1,2

Escherichia coli Stamme 1 0,02Escherichia coli Strain 1 0.02

Stamme 2 0,6 15 Proteus mirabilis Stamme 1 <0,01Strain 2 0.6 15 Proteus mirabilis Strain 1 <0.01

Stamme 2 <0,01Strain 2 <0.01

Proteus vulgaris <0,01Proteus vulgaris <0.01

Proteus rettgeri <0,01Proteus justice <0.01

Staphylococcus aureus Stamme ATCCStaphylococcus aureus Strain ATCC

20 6538 2,56538 2.5

Penicillin- resistent stamme 2,5Penicillin-resistant strain 2.5

Pseudomonas aeruginosa Stamme 1 0,3 25 Stamme 2 10Pseudomonas aeruginosa Strain 1 0.3 25 Strain 2 10

Stamme 3 2,5Strain 3 2.5

Stamme 4 5Tribe 4 5

Stamme 5 5Tribe 5 5

Stamme 6 10 30 _ DK 166728 B1 10 TABEL fortsatStrain 6 10 30 _ DK 166728 B1 10 TABLE continued

Testorganismer -- ATest organisms - A

5 Pseudomonas aeruginosa Stamme 7 5Pseudomonas aeruginosa Strain 7 5

Serratia marcescens 0,08Serratia marcescens 0.08

Den antibakterielle virkning in vivo vurderes som følger:The antibacterial effect in vivo is assessed as follows:

Grupper på 5 mus inficeres intraperitonealt med en vandig suspension 10 af Escherichia coli. Tre gange, dvs. 1 time, 2,5 time og 4 timer efter infektionen, administreres teststoffet subcutant i fysiologisk kogsaltopløsning. Antallet af overlevende dyr bestemmes på fjerdedagen. Der administreres forskellige doseringer, og ved interpolation bestemmes den dosis, ved hvilken 50% af forsøgsdyrene overlever 15 (CD5Q-værdi, mg/kg).Groups of 5 mice are infected intraperitoneally with an aqueous suspension 10 of Escherichia coli. Three times, ie At 1 hour, 2.5 hours and 4 hours after infection, the test substance is administered subcutaneously in physiological saline. The number of surviving animals is determined on the fourth day. Different dosages are administered and by interpolation the dose is determined at which 50% of the test animals survive 15 (CD5Q value, mg / kg).

TABELTABLE

Teststof ATest substance A

20 CD50-værdi mg/kg 0,00520 CD50 value mg / kg 0.005

Toxicitettoxicity

Teststof ATest substance A

25 _ LD50-værdi, mg Ag intravenø st 250-50 subcutant >4000 peroralt >5000 30 _ 1125 _ LD50 value, mg Ag intravenous 250-50 subcutaneously> 4000 orally> 5000 30 _ 11

De forbindelser, der kan fremstilles i henhold til den foreliggende opfindelse, kan anvendes som lægemidler, f.eks. i form af farmaceutiske præparater, der indeholder dem eller salte deraf-i blanding med et til enteral eller parenteral administration egnet farmaceutisk, 5 organisk eller uorganisk inert bæremateriale, f.eks. vand, gelatine, gummi arabicum, lactose, stivelse, magnesiumstearat, talkum, vegetabilske olier, polyalkylenglycoler eller vaseline. De farmaceutiske præparater kan foreligge i fast form, f.eks. som tabletter, dragéer, suppositorier eller kapsler, eller i flydende form, f.eks. som op-10 løsninger, suspensioner eller emulsioner. De er eventuelt steriliserede og/eller indeholder hjælpestoffer såsom konserverings-, stabiliserings-, befugtnings- eller emulgeringsmidler, salte til ændring af det osmotiske tryk, anæstetika eller puffere. De kan også indeholde andre terapeutiske værdifulde stoffer. Forbindelserne med 15 formlen I samt saltene eller hydraterne deraf anvendes fortrinsvis til parenteral administration og tilberedes til dette formål fortrinsvis som lyofilisater eller tørpulvere til fortynding med sædvanlige agenter såsom vand eller isotonisk kogsaltopløsning. De let hydrolyserbare estere eller ethere af forbindelserne med formlen I og 20 saltene eller hydraterne deraf kan også anvendes til enteral administration.The compounds which can be prepared according to the present invention can be used as drugs, e.g. in the form of pharmaceutical compositions containing them or salts thereof in admixture with a pharmaceutical, organic or inorganic inert carrier suitable for enteral or parenteral administration, e.g. water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols or vaseline. The pharmaceutical compositions may be in solid form, e.g. as tablets, dragees, suppositories or capsules, or in liquid form, e.g. as solutions, suspensions or emulsions. They are optionally sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, salts for changing osmotic pressure, anesthetics or buffers. They may also contain other therapeutically valuable substances. The compounds of formula I and their salts or hydrates are preferably used for parenteral administration and are preferably prepared for this purpose as lyophilisates or dry powders for dilution with usual agents such as water or isotonic boiling salt solution. The easily hydrolyzable esters or ethers of the compounds of formula I and the salts or hydrates thereof can also be used for enteral administration.

Fremgangsmåden ifølge den foreliggende opfindelse belyses nærmere ved følgende eksempler:The process of the present invention is further illustrated by the following examples:

EKSEMPELEXAMPLE

25 28,8 g (6R,7R)-7-(4-brom-2-((Z)-methoxyimino)acetoacetamido)-3- (((2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triaz in-3-yl)thio)meth-yl)) -8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylsyre opløses i 400 ml absolut ethanol. Opløsningen tilsættes 7,6 g thiourinstof. Efter 15-20 minutters omrøring ved 25°C begynder reaktionsproduktet 30 at udkrystallisere af den orange opløsning som hydrobromid. Efter 1,5 times omrøring isoleres det sidstnævnte ved sugefiltrering og vaskes med 200 ml alkohol og 200 ml lavtkogende petroleumsether i den nævnte rækkefølge og tørres natten over i højvakuum ved 35-40°C. Herved fås 22 g praktisk taget farveløst hydrobromid. Dette opløses sammen med DK 166728 B1 12 15,7 g natriumacetat- trlhydrat i en blanding af 110 ml vand og 110 ml acetone. Til denne opløsning sættes 140 ml acetone til let uklarhed.28.8 g (6R, 7R) -7- (4-bromo-2 - ((Z) -methoxyimino) acetoacetamido) -3- (((2,5-dihydro-6-hydroxy-2-methyl-5) -oxo-as-triazin-3-yl) thiolmethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid is dissolved in 400 ml of absolute ethanol. To the solution is added 7.6 g of thiourea. After 15-20 minutes of stirring at 25 ° C, reaction product 30 begins to crystallize from the orange solution as hydrobromide. After 1.5 hours of stirring, the latter is isolated by suction filtration and washed with 200 ml of alcohol and 200 ml of low boiling petroleum ether in said order and dried overnight in high vacuum at 35-40 ° C. This gives 22 g of practically colorless hydrobromide. This is dissolved together with DK 166728 B1 12 15.7 g of sodium acetate trihydrate in a mixture of 110 ml of water and 110 ml of acetone. To this solution, add 140 ml of acetone to light cloudiness.

Kort derefter begynder reaktionsproduktet at krystallisere. Blandingen omrøres i 30 minutter, og derefter tildryppes i løbet af yderlig-5 ere 30 minutter 180 ml acetone, hvorhos krystallisationen fuldendes. Reaktionsproduktet isoleres ved sugefiltrering, vaskes med 250 ml 85%'s vandig acetone, 250 ml acetone og 250 ml lavtkogende petrole-umsether i den nævnte rækkefølge og tørres til slut i vakuum ved 25 C. Der fås 19,6 g (59,3% af det teoretiske) praktisk taget farve-10 løst dinatriumsalt af (6R,7R)-7-(2-(2-amino-4-thiazolyl)-2-(Z-meth-oxyimino)acetamido) -3-(((2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio)methyl)-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-en-2- carboxylsyre, som omkrystalliseres af vand-acetone. Herved fås 17,3 g 25 (52,3% af det teoretiske) rent stof, [a] p = -150,8° (c = 1 i vand).Shortly thereafter, the reaction product begins to crystallize. The mixture is stirred for 30 minutes and then, for a further 30 minutes, 180 ml of acetone are added dropwise, the crystallization being completed. The reaction product is isolated by suction filtration, washed with 250 ml of 85% aqueous acetone, 250 ml of acetone and 250 ml of low boiling petroleum ether in the above order and finally dried in vacuo at 25 C. 19.6 g (59.3 % of theoretical) practically color-dissolved disodium salt of (6R, 7R) -7- (2- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) acetamido) -3 - (( (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio) methyl) -8-oxo-5-thia-l-azabicyclo [4.2.0] oct- 2-ene-2-carboxylic acid, which is recrystallized from water-acetone. There is thus obtained 17.3 g of 25 (52.3% of theory) of pure matter, [a] p = -150.8 ° (c = 1 in water).

15 1H-NMR-Spektrum (DMS0-d6): S = 3,47 (N-CH3) (s) (3H), 3,49 (2-CH2)1 H NMR Spectrum (DMSO-d6): S = 3.47 (N-CH3) (s) (3H), 3.49 (2-CH2)

OCHOCH

(AB-q/centreringsværdi; = Jgem = ca. 18 Hz) (2H) , 3,85 [= N 3, (Z)] (s) (3H), 4,37 (3-CH2~S) (AB-q/centreringsværdi; Jgem = 12,5 Hz) (2H), 5,04 (H-6) (d,JH_6)H_7 = 4,5 Hz (IH), 5,59 (H-7) (q, JH.7,NH = 8 Hz, JH-7,h-6 = 4>5 Hz) (1H)> 6>75 (thiazolyl-H) (s) (IH), 7,29 20 (-NH2) (b) (2H), 9,52 (-C0-NH-) (d, JNHjH-7 “ 8 Hz) (IH).(AB-q / centering value; = Jgm = about 18 Hz) (2H), 3.85 [= N 3, (Z)] (s) (3H), 4.37 (3-CH2 ~ S) (AB -q / centering value; Jgm = 12.5 Hz) (2H), 5.04 (H-6) (d, JH_6) H_7 = 4.5 Hz (1H), 5.59 (H-7) (q, JH.7, NH = 8 Hz, JH-7, h-6 = 4> 5 Hz) (1H)> 6> 75 (thiazolyl-H) (s) (1H), 7.29 (-NH2) ( b) (2H), 9.52 (-CO-NH-) (d, JNH2H-7 "8 Hz) (1H).

Den som udgangsforbindelse anvendte (6R,7R)-7-(4-brom-2-((Z)-meth-oxyimino)acetoacetamido)-3-(((2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio)methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylsyre kan fremstilles som følger: 25 592,1 g aceteddikesyre-tert.butylester opløses i 560 ml iseddike. Til denne opløsning dryppes ved 5-10°C i løbet af 2,5 time en opløsning af 290,6 g natriumnitrit i 655 ml vand. Den vundne gule suspension omrøres i 30 minutter ved 20°C, tilsættes 940 ml vand og omrøres i yderligere 2 timer. Blandingen tilsættes 900 ml vand og 900 g is og 30 ekstraheres i en udrøringsbeholder tre gange med hver gang 1 liter ethylacetat. De forenede ethylacetatekstrakter vaskes tre gange med hver gang 1 liter vand, tilsættes derefter 5 liter vand og indstilles med natriumhydrogencarbonat til en pH-værdi på 6,8. Efter fraskillel-se af den vandige fase vaskes endnu en gang med vand. Derefter tørres 35 ethylacetatopløsningen over natriumsulfat og inddampes ved 40°C i 13 vakuum. Herved fås (2)-2-hydroxyimino-3-oxosmørsyre- tert.butyles ter i form af en gul olie, som tørres i endnu 9 timer i højvakuum ved 40eC. Udbyttet er 626,65 g (89,2% af det teoretiske).The starting compound (6R, 7R) -7- (4-bromo-2 - ((Z) -methoxy-amino) acetoacetamido) -3 - (((2,5-dihydro-6-hydroxy-2-methyl) 5-oxo-as-triazin-3-yl) thiolmethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid can be prepared as follows: Dissolve 1 g of acetic acid tert.butyl ester in 560 ml of glacial acetic acid. To this solution, a solution of 290.6 g of sodium nitrite in 655 ml of water is dropped at 5-10 ° C over 2.5 hours. The yellow suspension obtained is stirred for 30 minutes at 20 ° C, 940 ml of water is added and stirred for a further 2 hours. The mixture is added with 900 ml of water and 900 g of ice and extracted into a stirrer three times with 1 liter of ethyl acetate each time. The combined ethyl acetate extracts are washed three times with 1 liter of water each time, then 5 liters of water are added and adjusted with sodium bicarbonate to a pH of 6.8. After separation of the aqueous phase, wash again with water. The ethyl acetate solution is then dried over sodium sulfate and evaporated at 40 ° C in 13 vacuum. There is thus obtained (2) -2-hydroxyimino-3-oxo-butyric acid tert.butylester in the form of a yellow oil, which is dried for another 9 hours in high vacuum at 40 ° C. The yield is 626.65 g (89.2% of theory).

626,65 g (Z)-2-hydroxyimino-3-oxosmørsyre-tert,butylester opløses i 5 2,86 liter acetone. Opløsningen afkøles til 5°C og tilsættes por tionsvis 703,5 g kaliumcarbonat. Til den gule opløsning tildryppes uden afkøling i løbet af 1 time 322 ml dimethylsulfat,-hvorhos temperaturen i blandingen ikke bør stige over 25°C. Den lysbeige suspension omrøres ved 20-25°C i ca. 4 timer, til der tyndtlagschro-10 matografisk ikke længere kan påvises noget udgangsmateriale. Derefter hældes blandingen ud på 7 liter vand og ekstraheres tre gange med hver gang 1 liter ethylacetat. De forenede ethylacetatekstrakter vaskes tre gange med hver gang 1 liter vand, tørres over natriumsulfat og inddampes ved 40°C i vakuum. Den som remanens vundne, gule 15 olie tørres endnu 6 timer i højvakuum ved 40°C og destilleres derefter. Herved fås 577 g (Z)-2-methoxyimino-3-oxosmørsyre-tert.butyl-ester (85,6% af det teoretiske) i form af en gul olie med kogepunkt 57°C/0,02 mmHg.626.65 g (Z) -2-hydroxyimino-3-oxo-butyric acid, butyl ester is dissolved in 2.86 liters of acetone. The solution is cooled to 5 ° C and 703.5 g of potassium carbonate are added portionwise. To the yellow solution is added dropwise 322 ml of dimethyl sulphate without cooling during one hour - where the temperature of the mixture should not rise above 25 ° C. The light beige suspension is stirred at 20-25 ° C for approx. 4 hours until thin layer chromatography can no longer detect any starting material. The mixture is then poured into 7 liters of water and extracted three times with 1 liter of ethyl acetate each time. The combined ethyl acetate extracts are washed three times with 1 liter of water each time, dried over sodium sulfate and evaporated at 40 ° C in vacuo. The yellow oil obtained as the residue is dried for another 6 hours in high vacuum at 40 ° C and then distilled. There are thus obtained 577 g (Z) -2-methoxyimino-3-oxo-butyric acid tert.butyl ester (85.6% of theory) in the form of a yellow oil of boiling point 57 ° C / 0.02 mmHg.

1H-NMR-Spektrum (CDC13): δ = 1,55 [-C(CH3)3] (s) (9H), 2,36 (CH3-C0) 20 (s) (3H), 4,01 [=N0CH3, (Z)] (s) (3H).1 H NMR Spectrum (CDCl3): δ = 1.55 [-C (CH3) 3] (s) (9H), 2.36 (CH3-CO) (s) (3H), 4.01 [= NOCH3, (Z)] (s) (3H).

86 g (Z)-2-methoxyimino-3-oxosmørsyre-tert.butylester opløses i 400 ml trifluoreddikesyre. Opløsningen lades henstå i 1 time ved 25°C og inddampes derefter i vakuum ved 35°C. Den olieagtige remanens krystalliseres af ether/petroleumsether. Herved fås 50 g (80,6% af det 25 teoretiske) gullig, vandopløselig (Z)-2-methoxyimino-3-oxosmørsyre, smeltepunkt 80-85°C.Dissolve 86 g of (Z) -2-methoxyimino-3-oxo-butyric acid tert-butyl ester in 400 ml of trifluoroacetic acid. The solution is allowed to stand for 1 hour at 25 ° C and then evaporated in vacuo at 35 ° C. The oily residue is crystallized by ether / petroleum ether. There is obtained 50 g (80.6% of the theoretical) yellowish, water-soluble (Z) -2-methoxyimino-3-oxo-butyric acid, mp 80-85 ° C.

ΟΡΗ NMR-Spektrum (CDC13): δ = 2,43 (CH3-C0) (3H), 4,14 [= N 3, (Z)] (s) (3H), 10,47 (OH) (s) (IH).ΟΡΗ NMR Spectrum (CDCl 3): δ = 2.43 (CH 3 -CO) (3H), 4.14 [= N 3, (Z)] (s) (3H), 10.47 (OH) (s) (I H).

145 g (Z)-2-methoxyimino-3-oxosmørsyre opløses i 1000 ml alkohol- og 30 vandfrit dichlormethan. Til denne opløsning sættes 10 ml 30%'s brom-brintesyre i iseddike. Derefter tildryppes i løbet af ca. 2 timer en opløsning af 37,5 ml brom i 112,5 ml dichlormethan, hvorhos reaktionsblandingens temperatur ved let køling holdes på 20-25°C. Der- DK 166728 B1 14 efter gennemblæses reaktionsblandingen kraftigt med nitrogen til fjernelse af hydrogenbromid. Derefter tilsættes 250 g is, 250 ml vand og 2 liter ether i den nævnte rækkefølge. Den vandige-fase fraskilles og kasseres. Den organiske fase vaskes med 250 ml vand og 250 ml 5 mættet natriumchloridopløsning, tørres over natriumsulfat og inddampes i vakuum. Som remanens fås 170 g brunt olie, som krystalliseres af carbontetrachlorid. Herved fås 100 g (44,6% af det teoretiske) praktisk taget farveløs (Z)-4-brom-2-methoxyimino’-3-oxosmørsyre.Dissolve 145 g of (Z) -2-methoxyimino-3-oxobutyric acid in 1000 ml of alcohol and anhydrous dichloromethane. To this solution is added 10 ml of 30% hydrochloric acid in glacial acetic acid. Then drip over the course of approx. 2 hours a solution of 37.5 ml of bromine in 112.5 ml of dichloromethane, keeping the temperature of the reaction mixture with light cooling at 20-25 ° C. Then the reaction mixture is vigorously purged with nitrogen to remove hydrogen bromide. Then 250 g of ice, 250 ml of water and 2 liters of ether are added in the order mentioned. The aqueous phase is separated and discarded. The organic phase is washed with 250 ml of water and 250 ml of 5 saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. As the residue, 170 g of brown oil are obtained, which is crystallized by carbon tetrachloride. This gives 100 g (44.6% of theory) of practically colorless (Z) -4-bromo-2-methoxyimino'-3-oxo-butyric acid.

NMR-Spektrum (CDC13): 5 “ 4’24 [“ N °CH3, (Z)] (s) (3H), 4,41 (-CH2-) 10 (s) (2H), 11,00 (OH) (s) (IH).NMR Spectrum (CDCl3): δ 4'24 ["N ° CH3, (Z)] (s) (3H), 4.41 (-CH2-) (s) (2H), 11.00 (OH) ) (s) (1H).

37,1 g (7R)-7-amino-3-desacetoxy-3-[(2,5-dihydro-6-hydroxy-2-methyl- 5-oxo-as-triazin-3-yl)thiol]-cephalosporansyre suspenderes i 800 ml ethylacetat og tilsættes 100 ml N,0-bis(trimethylsilyl)acetamid.37.1 g (7R) -7-amino-3-desacetoxy-3 - [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-az-triazin-3-yl) thiol] -cephalosporanoic acid is suspended in 800 ml of ethyl acetate and 100 ml of N, O-bis (trimethylsilyl) acetamide is added.

Blandingen omrøres under udelukkelse af fugt i 30 minutter ved 25°C, 15 hvorved der opstår en lysegul opløsning. Til denne til -10°C afkølede opløsning dryppes i løbet af 30 minutter ved -10-0°C en opløsning af (Z)-4-brom-2-methoxyimino-3-oxosmørsyrechlorid, som er fremstillet ud fra 22,4 g (Z)-4-brom-2-methoxyimino-3-oxosmørsyre i 300 ml alkohol-og vandfrit dichlormethan og 20,8 g phosphorpentachlorid ved 8-10°C.The mixture is stirred under moisture exclusion for 30 minutes at 25 ° C to give a pale yellow solution. To this solution cooled to -10 ° C, a solution of (Z) -4-bromo-2-methoxyimino-3-oxo-butyric acid chloride prepared from 22.4 g is added over 30 minutes at -10 ° C. (Z) -4-Bromo-2-methoxyimino-3-oxo-butyric acid in 300 ml of alcohol and anhydrous dichloromethane and 20.8 g of phosphorus pentachloride at 8-10 ° C.

20 Reaktionsblandingen omrøres i 30 minutter ved 0-5°C og 1 time ved 25eC. Der tilsættes under omrøring 1 liter ethylacetat og 500 ml vand. Den vandige fase og det harpiksagtige mellemlag kasseres. Den organiske fase vaskes 6 gange med hver gang 500 ml vand, tørres over natriumsulfat og inddampes i vakuum ved 40° C til et volumen på 200 25 ml. Dette orangefarvede koncentrat dryppes under omrøring til 1,8 liter ether, hvorved reaktionsproduktet udfældes amorft. Dette isoleres ved sugefiltrering, vaskes med 1 liter ether og 1 liter lavt-kogende petroleumsether i den nævnte rækkefølge og tørres natten over ved 35°C. Herved fås 37,2 g (64,4% af det teoretiske) (6R,7R)-7-30 (4-brom-2-[(Z)-methoxyimino]acetoacetamido)-3-([(2,5-dihydro-6-hy droxy- 2-methyl-5-oxo-as-triazin-3-yl) thio]methyl)-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-en-2-carboxylsyre som beige, amorft produkt 25 med [a] p = -223,1’ (c = 1 i methanol).The reaction mixture is stirred for 30 minutes at 0-5 ° C and 1 hour at 25 ° C. With stirring, 1 liter of ethyl acetate and 500 ml of water are added. The aqueous phase and the resinous intermediate layer are discarded. The organic phase is washed 6 times with 500 ml of water each time, dried over sodium sulfate and evaporated in vacuo at 40 ° C to a volume of 200 25 ml. This orange colored concentrate is dripped with stirring to 1.8 liters of ether, whereby the reaction product precipitates amorphously. This is isolated by suction filtration, washed with 1 liter of ether and 1 liter of low-boiling petroleum ether in the above order and dried overnight at 35 ° C. There is thus obtained 37.2 g (64.4% of theory) (6R, 7R) -7-30 (4-bromo-2 - [(Z) -methoxyimino] acetoacetamido) -3 - ([(2.5 dihydro-6-hydroxy-2-methyl-5-oxo-az-triazin-3-yl] thio] methyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene 2-carboxylic acid as beige amorphous product with [a] p = -223.1 '(c = 1 in methanol).

1H-NMR-Spektrum (DMS0-d6): δ - 3,60 (N-CH3) (s) (3H), 3,63 (2-CH2) ΟΓΗ 35 (AB-q/centreringsværdi; J =18 Hz) (2H), 4,07 [= N 3, (Z)] (s)1 H NMR Spectrum (DMSO-d6): δ - 3.60 (N-CH3) (s) (3H), 3.63 (2-CH2) ΟΓΗ 35 (AB-q / centering value; J = 18 Hz) (2H), 4.07 [= N 3, (Z)] (s)

g6IRg6IR

Claims (17)

15 (3H), 4,25 (3-CH2-S) (AB-q/centreringsværdi; Jgem = 13 Hz) (2H), 4,62 (Br-CH2-) (s) (2H), 5,15 (H-6) (d,JH_6)H_7 = 5 Hz) (IH), 5,78 (H-7) (q, = 8 Hz> “ JH-7,H-6 = 5 Hz) (1H)> (NH) (d>JNH,H-7 = 8 Hz> <1H)> U’12 ('C00H °S -OH) (b) (2H).(3H), 4.25 (3-CH2-S) (AB-q / centering value; Jgem = 13 Hz) (2H), 4.62 (Br-CH2 -) (s) (2H), 5.15 (H-6) (d, JH_6) H_7 = 5 Hz) (1H), 5.78 (H-7) (q, = 8 Hz> "JH-7, H-6 = 5 Hz) (1H)> (NH) (d> JNH, H-7 = 8 Hz> <1H)> U'12 ('C00H ° S -OH) (b) (2H). 5 ANVENDELSESEKSEMPEL Fremstilling af tørampuller til intramuskulær administration: På sædvanlig måde fremstilles et lyofilisat af 1 g af dinatriumsaltet af (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-([ (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl) -10 8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-en-2-carboxylsyre og fyldes i en ampul. Før administrationen tilsættes lyofilisatet 2,5 ml af en 20%'s vandig lidocainhydrochloridopløsning.EXAMPLE OF USE Preparation of dry ampoules for intramuscular administration: In a usual manner, a lyophilisate of 1 g of the disodium salt of (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) acetamido is prepared ] -3 - ([(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-az-triazin-3-yl) thio] methyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid and filled into a vial. Prior to administration, the lyophilisate is added 2.5 ml of a 20% aqueous lidocaine hydrochloride solution. 1. Analogifremgangsmåde til fremstilling af cephalosporinderivater 15 med den almene formel I, Η H ! UK CH3ON=C—CONH—— j-i - ^ COOR hvor R betegner hydrogen eller en let hydrolyserbar estergruppe, 20 eller salte af disse forbindelser eller hydrater af disse forbindelser eller salte deraf, ved hvilken et halogenid med den almene formel II, DK 166728 B1 16 HH f CH30N==C—CONH—-r Ί CO J>-CH2—S—X ch2v •COOR hvor R har den ovenfor angivne betydning, og Y betegner halogen, 5 eller et salt af denne forbindelse omsættes med thiourinstof, og en vunden forbindelse med formlen I, om ønsket, omdannes til et salt eller et hydrat eller et hydrat af dette salt, kendetegnet ved, at X betegner én af grupperne (a) og (b), (a) ' (b) 10 hvor R' betegner hydrogen eller en let fraspaltelig ethergruppe.1. Analogous Process for Preparation of Cephalosporin Derivatives 15 of General Formula I, Η H! UK CH3ON = C-CONH-ji - ^ COOR wherein R represents hydrogen or a readily hydrolyzable ester group, 20 or salts of these compounds or hydrates of these compounds or salts thereof, wherein a halide of the general formula II, DK 166728 B1 16 HH f CH30 N == C — CONH —- r Ί CO J> -CH 2 —S — X ch 2v • COOR wherein R is as defined above and Y represents halogen, 5 or a salt of this compound is reacted with thiourea, and a won compound of formula I, if desired, is converted into a salt or hydrate or hydrate of this salt, characterized in that X represents one of groups (a) and (b), (a) '(b) R 'represents hydrogen or an easily decomposable ether group. 2. Fremgangsmåde ifølge krav 1, kendetegnet ved, at R og R' betegner hydrogen.Process according to claim 1, characterized in that R and R 'are hydrogen. 3. Fremgangsmåde ifølge krav 1 eller 2, 15 kendetegnet ved, at Y betegner brom.Process according to claim 1 or 2, characterized in that Y represents bromine. 4. Fremgangsmåde ifølge et hvilket som helst af kravene 1-3, kendetegnet ved, at udgangsforbindelsen med den almene formel II foreligger i syn-form (Z-form). 1 2 3 Fremgangsmåde ifølge et hvilket som helst af kravene 1-4, 2 20 kendetegnet ved, at halogeni det med formlen II fremstilles 3 ved omsætning af en primær amin med den almene formel III, 17 Η Η HjN-j-kS —2-x 111 COOR hvor X og R har den i krav 1 angivne betydning, med en halogeneret 5 carboxylsyre med den almene formel IV, CH3ON=C—COOH CO ch2y hvor Y betegner halogen, eller med et reaktivt derivat af denne e 10 forbindelse,Process according to any one of claims 1-3, characterized in that the starting compound of the general formula II is in syn-form (Z-form). Process according to any one of claims 1-4, 2, characterized in that halogeno of formula II is prepared 3 by reaction of a primary amine of general formula III, 17 Η Η HjN-j-kS -2 -x111 COOR wherein X and R are as defined in claim 1, with a halogenated carboxylic acid of the general formula IV, CH3ON = C-COOH CO ch2y where Y represents halogen, or with a reactive derivative of this compound, 6. Fremgangsmåde ifølge krav 5, kendetegnet ved, at R og R' betegner hydrogen.Process according to claim 5, characterized in that R and R 'are hydrogen. 7. Fremgangsmåde ifølge krav 5 eller 6, kendetegnet ved, at Y betegner brom. 15 8, Fremgangsmåde ifølge et hvilket som helst af kravene 5-7, kendetegnet ved, at den halogenerede carboxylsyre med formlen IV eller et reaktivt derivat deraf foreligger i syn-form (Z-form). 1 Fremgangsmåde ifølge et hvilket som helst af kravene 5-8, 20 kendetegnet ved, at der anvendes syrechloridet af den halogenerede carboxylsyre med formlen IV. DK 166728 B1 18Process according to claim 5 or 6, characterized in that Y represents bromine. A process according to any one of claims 5-7, characterized in that the halogenated carboxylic acid of formula IV or a reactive derivative thereof is in syn-form (Z-form). Process according to any one of claims 5-8, 20, characterized in that the acid chloride of the halogenated carboxylic acid of formula IV is used. DK 166728 B1 18 10. Fremgangsmåde ifølge et hvilket som helst af kravene 1-4, kendetegnet ved, at halogenidet med formlen II fremstilles ved halogenering af en forbindelse med den almene formel V, Η H f ! CH3ON=C—CONH—-'<Process according to any one of claims 1-4, characterized in that the halide of formula II is prepared by halogenating a compound of the general formula V, Η H f! CH3ON = C-CONH - '< 5 CO ^—CH2—S X v ch3 COOR hvor X og R har den i krav 1 angivne betydning.CO 2 - CH 2 - S X v ch 3 COOR wherein X and R have the meaning set forth in claim 1. 11. Fremgangsmåde ifølge krav 10, kendetegnet ved, at R og R' betegner hydrogen.Process according to claim 10, characterized in that R and R 'are hydrogen. 12. Fremgangsmåde ifølge krav 10 eller 11, kendetegnet ved, at forbindelsen med formlen V foreligger * i syn-form (Z-form).Process according to claim 10 or 11, characterized in that the compound of formula V is * in syn-form (Z-form). 13. Forbindelser med den almene formel II, Η H ! CH3ON=C—CONH—-X ^13. Compounds of General Formula II, Η H! CH3ON = C-CONH-X 15. I 11 CQ ^-CH2-3-X ch2y COOR hvor Y betegner halogen, X betegner en af grupperne (a) og (b), 19 η c Ν s. * μ .no' Ν γ' S "^.Α0 ~^νΑ0 (a) <b> R betegner hydrogen eller en let hydrolyserbar estergruppe, og R' betegner hydrogen eller en let hydrolyserbar ethergruppe, samt salte-5 ne deraf.15. In 11 CQ ^ -CH2-3-X ch2y COOR where Y denotes halogen, X denotes one of the groups (a) and (b), 19 η c Ν s. * Μ .no 'Ν γ' S "^. Ner0 ~ ^ νΑ0 (a) <b> R represents hydrogen or an easily hydrolyzable ester group, and R 'represents hydrogen or an easily hydrolyzable ether group, and its salts. 14. Forbindelse ifølge krav 13, kendetegnet ved, at R og R' betegner hydrogen.A compound according to claim 13, characterized in that R and R 'are hydrogen. 15. Forbindelse ifølge krav 13 eller 14, kendetegnet ved, at Y betegner brom.Compound according to claim 13 or 14, characterized in that Y represents bromine. 16. Forbindelse ifølge krav 13, kendetegnet ved, at den er (6R,7R)-7-((4-brom-2-[(Z)-methoxyimino]acetoacetamido) - 3- ([ (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as -triazin-3-yl)thio]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylsyre samt saltene deraf.Compound according to claim 13, characterized in that it is (6R, 7R) -7 - ((4-bromo-2 - [(Z) -methoxyimino] acetoacetamido) - 3- ([(2,5-dihydro) 6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid as well as the salts thereof.