IE46903B1 - Novel cephalosporin derivatives, a process for their manufacture and pharmaceutical preparations - Google Patents

Abstract

1. Cephalosporin derivatives of the general formula see diagramm : EP0000005,P15,F1 wherein R represents furyl, thienyl or phenyl optionally substituted by halogen, hydroxy, lower alkoxy or lower alkyl, R1 represents lower alkyl or aminocarbonylmethyl and X represents a group of the formulae see diagramm : EP0000005,P15,F2 see diagramm : EP0000005,P15,F3 see diagramm : EP0000005,P15,F4 in which one of the two symbols R2 and R3 or R4 and R5 represents hydrogen and the other represents lower alkyl, carboxymethyl or sulphomethyl, as well as salts of said compounds and hydrates of said salts.

Description

in which one of the two symbols R2 and R^ or R4 and R5 represents hydrogen and the other represents lower alkyl, carboxymethyl or sulphomethyl, as well as salts of said compounds and hydrates of said salts.

Examples of salts of the compounds of formula X 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, Ν,Ν'-dibenzylethyl-ethylenediamine, alkylamines or dialkylamines) as well as salts with amino acids such as for example, salts with arginine or lysine. The salts can be morio-salts or di-salts. The second 15 salt formation takes place on the tautomeric enol form of the triazine group b, which has acid character.

The compounds of formula I also form addition salts with organic or inorganic acids. Examples of such salts are hydrohalides, for example hydrocnlorides, hydrobromides, hydriodides , as well as other mineral acid salts such as sulphates, nitrates and phosphates alkylsulphonates and mono-arylsulphonates such as ethanesulphonates, toluenesulphonates and benzene25 sulphonates and also other organic acid salts such as acetates, tartrates, maleates, citrates, benzoates, salicylates and ascorbates.46903 The salts of the compounds of formula I can be hydrated. The hydration can be effected in the course of the manufacturing process or can occur gradually as a consequence of hygrosoopic properties of an initially anhydrous salt of a compound of formula I.

The previously named 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 significance. 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^.

Preferred X-groups are the group (c) as well as the groups (a) and (b) in which one of the two symbols R2 and Rg or R^ and Rg represents hydrogen and the other represents methyl. Especially preferred X20 -groups are the l,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl group 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-225 -methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl/-3-cephem 46S03 -4-carboxylic acid and salts thereof as well as the hydrates of said salts.

The compounds of formula I as well as their salts or hydrates of the salts can exist in the syn-isomeric form R—C—CONH—( li N \>R. or in the anti-isomeric form R—C—- CONH 1 N or as mixtures of these two forms. The syn-isomeric form or mixtures in which the syn-isomeric form predominates is/are preferred.

The acyl derivatives of formula 1 as well as their salts or hydrates of these salts are manufactured in accordance with the invention by a process which is characterised by a) reacting a compound of the general formula 469 0 3 .6 wherein X has the significance given in formula I and the carboxy group can be present in protected form, with an acid of the general formula R 8^=0—COOH III wherein R and R^ have the significance given in formula I, or with a reactive functional derivative of this acid, and cleaving off the protecting group, or by in which R and R^ have the significance given in formula I and Y represents a leaving group, with a thiol of the general formula Ί 69 0 3 HS—X V wherein X has the significance given in formula I, in the presence of water, and, if desired, converting the reaction product into a salt or a hydrate of such salt.

The carboxy groups present in the starting materials of formulae II can be protected if desired; for example, by esterification to a readily 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.

As reactive functional derivatives of acids of formula III there come into consideration, for example, halides (i.e. chlorides, bromides and fluorides), azides, anhydrides, especially mixed anhydrides with strong acids, reactive esters (e.g. N-hydroxysuccinimide esters) and amides (e.g. imidazolides).

As leaving groups Y in a compound of formula IV there come into consideration, for example, halogens (e.g. chlorine, bromine or iodine), acyloxy groups (e.g. lower alkanoyl groups such as acetoxy), lower alkylsulphonyloxy or arylsulphonyloxy groups such as 6903 mesyloxy or tosyloxy, or the azido group.

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 5 known per se. Thus, for example, a free acid of formula III can be condensed with one of the mentioned esters corresponding to formula II by means of a carbodiimide such as dicyclohexylcarbodiimide in an inert solvent such as ethyl acetate, acetonitrile, dioxan, chloroform, methylene chloride, benzene or dimethylformamide and the ester group can subsequently be cleaved off. Oxazolium salts (e.g. N-ethyl-5-phenvl-isoxazolium-3'-sulphonate) can also be used as the condensation agent in place of carbodiimides.

According to another embodiment, a salt of an acid of formula II (e.g. a trialkylammonium salt) is reacted with a reactive functional derivative of an acid of formula III as mentioned'above in an 20 inert solvent (e.g. one of the solvents specified above).

According to a further embodiment, an acid halide, preferably the chloride, of an acid of formula III is reacted with the amine of formula II. The reaction is preferably carried out in the presence of an acid9 69 ϋ 3 -binding agent; for example, in the presence of aqueous alkali, preferably sodium hydroxide, or in the presence of an alkali metal carbonate such as potassium carbonate, or in the presence of a lower5 -alkylated amine such as triethylamine. Water is preferably used as the solvent, although the reaction can also be carried out in an aprotic organic solvent such as, for example, dimethylformamide, dimethyl sulphoxide or hexamethylphosphoric acid triamide.

The reaction of a compound of formula II with a compound of formula III or a reactive functional derivative thereof can be carried out conveniently at temperatures between about -40°C and room temperature, for example at about 0-10°C.

The reaction of a compound of formula IV with a thiol of formula V can be carried out in a manner known per se; for example, at a temperature between about 40 and 80°C, conveniently at about 60°C, in water or in a buffer solution with a pH of about 6 to 7, preferably 6.5.

After carrying out the reaction of a compound of formula II with a compound of formula III ΐϋ the protecting group which ntay be present is cleaved off.

When the protecting group represents a silyl -group (silyl ester), this group can be cleaved off especially readily by treating the reaction product with water. When the carboxyl group is protected by salt formation (e.g. v/ith triethylamine), then the cleavage of this salt-forming protecting group can be carried out by treatment with acid. In this case there can be used as the acid, for example, hydrochloric acid, sulphuric acid, phosphoric acid or citric acid.

The 7-amino compounds of formula II used as starting materials can be prepared starting from a compound of the formula in which Y represents a leaving group, with; a thiol of formula V. The reaction can be carried out under the same conditions as those for the starting materials IV and V. π A ayn/anti mixture of a compound of formula I which may be obtained can be separated into the corresponding syn- and anti-forms in the usual manner, for example by recrystallisation or by chromato5 graphic methods using a suitable solvent or solvent I mixture.

I From French Patent Publication No. 2,137,899 there aie known cephalosporin derivatives which can carry in the 7-position inter alia a substituent of the present type R^0N=CR-C0NH-. On the other hand, there are known from French Patent Publications Nos. 2,275,215 and 2,280,381 cephalosporin derivatives which can carry in the 3-position a substituted thiomethyl residue of the present type -CH^-S-X.

It has now been found that the novel cephalosporin derivatives of formula I as well as their salts and the hydrates of these salts, in which for the first time the mentioned substituents in the positions 7 and 3 are present simultaneously, have valuable anti20 biotic, especially bactericidal, activity. They have a wide spectrum of activity against Gram-positive and Gram-negative microorganisms, including 0-lactamase-forming Staphylococci and various 0-lactamase-forming Gram-negative bacteria such as, for example, Haemophilus 25 influenzae, Escherichia coli, Proteus species and Klebsiella species.

The compounds of formula I as well as the pharmaceutically acceptable salts and hydrated forms thereof can be used for the treatment and prophylaxis of infectious diseases. In the case of adults there comes into consideration a daily dosage of about 1 g to about 4 g. The parenteral administration of the compounds in accordance with the invention is especially preferred.

In order to demonstrate the antimicrobial 10 activity of the compounds in accordance with5 the invention, the following representative members were tested: Product A: (7R)-7-[2-(2-furyl)-2-(methoxyimino)-acetamido]-3-/Ϊ (1,2,5,6-tetrahydro-215 -methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl7-3-cephem-4-carboxylic acid Product B: (7R)-7-[2-(2-furyl)-2-(methoxyimiiio)acetamido]-3r-/'[-(l-amino-l, 2-dihydro-2-oxo-4-pyrimidinyl)-thio]-methy1/-320 -cephem-4-carboxylic acid Product C: (7R)-7-[2-(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~J[ (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—Z[ (1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl/-3-cephem-4-carboxylic acid Product P: (7R)-3-/T(1-ethyl-l,4,5,6-tetrahydro-5,610 -dioxo-as-triazin-3-yl)thio]methy 1J-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-3-cephem-4-carboxylic acid Product G: (7R)-7-/2-[(carbamoyImethoxy)imino]-2-(2-furyl)-acetamido/-3-/T(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl)thio]methy 17-3-cephem-4-carboxylic acid. 469 0 3 rH £ cn 3. ΰ ο •ri Ρ rt Μ μ fi Φ ϋ fi Ο Ο >1 Η Ο 4J •rt Ρ •rt Λ C Η ε •Η fi •rt s •rt > fi *rt •rt μ □ o 5.0 0.63 rrt CO 6 0.63 0.31 0.63 ! 0.63 1 in CM 0.31 in in 10 1.2 0.63 1.2 1.2 kD CO CO kD in m CM rrt o o rH CM ft • • • • • • • • CM O rrt o o o o o rH o o o O O in in -3* co CM T3* CM rrt © kD kfi co CO ko m Η rrt rrt o o o in in in in ft • • • • • • • • • • • CM o o o o o o o CM o o o o CM CM CM TJ· CM rrt CM rrt kD kD kD kD cn cn cn in cn cn co rH rH rH rH CM kD kD kD Q CM o o O o o o in o in o rrt. 20 rrt o o o © kD kD co co ¢0 cn in ι—I H rrt' o o o CM kD in in CJ β • • • • • • • • • • CM o o o o o o o rrt o o O o o CM CM CM rH rH CM rH * m cn rrt H rrt kD in <□ k£> d cn cn cn in in rrt CM ffl « * · • • • * • • • CM o o 0 o o o o CM o o o o CM o irt CM CM H Tf ^3· kO ko kD co kD co cn cn CM rrt rH o rH o kD in kD in < • • • • rH o o O o o o o o o CM m in O CM in rH •3* CM cn Tl* in kO r- rrt CM rH CM 00 cn fi C c c a c c c c fi fi in •rt •rt •rt •rt •rt •rt •rt rt ko rt rt rt rt rt rt rt rt rt rt fi rt rt rt rt rt rt rt k rt rt u •rt P P P P P P P P -P P P kJ rt w ft ft ft ft ft ft ft ft ft ft H rt jj φ cn rt Φ cn N rt fi P fi Φ fi Φ ΰ rt rt fi 0 cn fi P ι—1 g •rt in •rt rt cn Irt fi rH rrt *rt rt •rt fi Φ 0 •rt rt Φ in in fi 0 Λ rt cn fi Φ ft rt Cn P u rt in rt rt rH P ϋ fi rt fi 0 0 fi rrt rH Λ g > rt 0 •rt •rt rH ϋ 0 rH £ Φ •rt cn cn cn rH rH ft •rt rt fi fi 3 •rt 0 in Φ Φ 0 Φ Λ ϋ g Λ Λ P P P fi< •rt o Φ □ 0 0 0 rt fi rt •rt in rt rt rt -P Φ as H ft ft ft ft ft Activity in vivo Groups of 10 mice are infected intraperitoneally with an aqueous suspension of Proteus mirabilis. One hour after the infection the test substance is administered subcutaneously. The number of suriviving animals is determined on the 4th day. Various dosages are administered, and that dosage at which 50% of the experimental animals survive (CD5Q, mg/kg) is determined by interpolation.

Test substance A B C D E F GCD50' mg/kg 0.09 3.0 0.60 0.70 1.15 0.85 0.80 Toxicity (mice , 24 hours value) Test substanceLD50' mg/kg i.v. 500- 1000- 1000- 500- 2000- 1000- >4000 1000 2000 2000 1000 4000 2000 s.c. >4000 >4000 p.o. >5000 >5000 Pharmaceutical preparations, preferably dry ampoules, can contain the compounds of formula I, their salts or hydrated forms of these salts, optionally in admixture with another therapeutically valuable substance.

Conveniently, they are mixed with a pharmaceutical, inorganic or organic inert carrier material, especially one, which is suitable for parenteral administration, such as, for example, with water, gum arabic. The pharmaceutical preparations are preferably present in liquid form (e.g. as solutions, suspensions or emulsions). If desired, they are sterilised and/or contain adjuvants such as preserving, stabilising, wetting or emulsifying agents, salts for 1C varying the osmotic pressure or buffers.

Example 1 Preparation of the sodium salt of (7R)-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-3-/T(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio]5 methyl/-3-cephem-4-carboxylic acid: .60 g of 2-methoxyimino-2-furyl-aoetic acid (syn/anti mixture 80:20) are dissolved in 150 ml of benzene and treated at 5-10°C while gassing with nitrogen with 4.2 ml of triethylamine, 2.6 ml of oxalyl chloride and 6 drops of dimethylformamide. The mixture is stirred while gassing with nitrogen at 5-10°C for 1 hour and at 25°C for 1/2 hour and thereafter evaporated at 40°C in vacuo. The residue is suspended in 150 ml of acetone and treated at 0°C with a solution of 11.2 g of (7R)-7-amino-3-desacetoxy-3-[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanic acid in 150 ml of water, which has previously been adjusted to pH 7.5 using 2-N aqueous sodium hydroxide. The reaction mixture is stirred for 2 1/2 hours under nitrogen and at 0-10°C, the pH being held between 7.5 and 8.0 by the addition of 2-N aqueous sodium hydroxide. 500 ml of ethyl acetate are then added and the pH is adjusted to 1.5 with 2-N aqueous hydrochloric acid. After separating the organic phase, 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 sulphate and concentrated to a volume of ca 100 ml. The remainder is filtered-off from insolubles -and the orange coloured filtrate obtained is diluted with 1000 ml of ether. The amorphous (7R)-7-[2-(2-furyl)-2-(methoxyimino)acetamido] -3-/T (1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio]methy17-3-cephem-4-carboxylic acid which thereby precipitates is filtered off under suction and washed with ether and with low-boiling petroleum ether. The beige coloured product obtained is dissolved in 250 ml of ethyl acetate and insolubles are- filtered off. The orange coloured filtrate is treated with 10 mi of a 2-N solution of sodium 2-ethylcaproate in ethyl acetate, whereby 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]methyV-3-cephem-4-carboxylic acid precipitates. This is filtered off under suction, washed with ethyl acetate and low-boiling petroleum ether and dried at 25°C in vacuo for 2 days The product obtained is a beige coloured powder (syn/ anti mixture 80:20). [α]β = -108.6° (c = 0.5 in water) Rf value =0.10 (thin-layer chromatography on Kieselgel-Fgg^-finished plates in the system butanol/glacial acetic acid/water 4:1:1? visualisation with UV light).

Example 2 460 03 Preparation of the sodium salt of (7R)-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-3-/7(1-amino-l,2-dihydro-2-oxo-4-pyrimidinyl)thio]-methy17“3“cePhem-4-carboxylic acid: This compound is prepared analogously to Example 1 from 3.4 g of 2-methoxyimino-2-furyl-acetic acid and 7.11 g of (7R)-7-amino-3-desacetoxy-3-[(l-amino-1,2dihydro-2-oxo-4-pyrimidinyl)thio]-cephalosporanic acid. The product is a beige powder (syn/anti mixture 70:30), Rj, value = 0.40 (thin-layer chromatography on Kieselgel-F254~flnislied plates in the system butanol/glacial acetic acid/water 4:1:1; visualisation with UV light).

Example 3 Preparation of the sodium salt of (7R)-7-[215 -(phenyl)-2-(methoxyimino)acetamido]-3-/7(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio]methy17-3-cephem-4-carboxylic acid: This compound is prepared analogously to Example 1 from 1.8 g of 2-methoxyimino-phenyl-acetio acid (syn/ anti mixture 90:10) and 3.73 g of (7R)-7-amino-3-desacetoxy-3-[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanic acid. The product is a beige powder (syn/anti mixture 90:10). [a]^ = -135° (c - 0.5 in water). R^ value * 0.17 (thin46903 -layer chromatography on Kieselgel-F254-finished plates in the system butanol/glacial acetic acid/water 4:1:1, visualisation with OV light).

Example 4 Preparation of the sodium salt of (7R)-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-3-/1(1,4,5,6-tetrahydro -4-methyl-5,6-dioxo-as-triazin-3-yl)thio]methy17-3-cephem-4-carboxylic acid: This compound is prepared analogously to Example 1 10 from 3.4 g of 2-methoxyimino-2-furyl-acetic acid (syn/ anti mixture 80:20) and 7.46 g of (7R)-7-amino-3-desacetoxy-3-[(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanic acid. The product is a beige powder (syn/anti mixture 80:20). [α]ρΟ =44° (° = °·5 in water). Rf value = 0.34 (thin-layer chromatography on Kieselgel-P2g4-finished plates in the system butanol/glacial acetic acid/water 4:1:1; visualisation with UV light).

Example 5 Preparation of the sodium salt of (7R)-7-[2-(methoxyimino)-2-(2-thienyl)acetamido]-3-/1 (1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl/-3-cephem-4-carboxylic acid: This compound is prepared analogously to Example 1 from 1.85 g of 2-methoxyimino-2-thienyl-acetic acid (syn/anti mixture ca 70:30) and 3.71 g of (7R)-7-amino-3-desacetoxy-3-[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo5 -as-triazin-3-yl)thio]-cephalosporanic acid. The product is a beige powder (syn/anti mixture ca 70:30). [a]p = -128.2° (c = 0.5 in water). Rf value = 0.21 (thin-layer chromatography on Kieselgel-F284-finished plates in the system butanol/glacial acetic acid/water 4:1:1, visualisation with UV light).

Example 6 Preparation of the disodium salt of (7R)-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-3-/1(2,5-dihydro-2-methyl-5-oxo-6-hydroxy-as-triazin-3-yl)thio]methy17-315 -cephem-4-carboxylic acid: This compound is prepared analogously to Example 1 from 10.12 g of 2-methoxyimino-2-furyl-acetic acid (syn isomer) and 18.7 g of (7R)-7-amino-3-desacetoxy-3-[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-320 -yl)thio]-cephalosporanic acid. For the salt-formation there are used 20 ml (2 equivalents) of a 2-N solution of sodium 2-ethylcaproate in ethyl acetate. The product is an almost colourless powder (syn isomer). [α]^θ = -141.6° (c = 0.5 in water). Rf value = 0.14 (thin-layer chromatography on Kieselgel-F28^-finished plates in the system butanol/glacial acetic acid/water 4:1:1, visualisation with UV light).

Example 7 Preparation of the sodium salt of (7R)-3-/1(15 -ethyl-1,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-yl)thio]methy17-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-3-cephem-4-carboxylic acid: This compound is prepared analogously to Example 1 from 1.69 g of 2-methoxyimino-2-furyl-acetic acid (syn isomer) and 3.85 g of (7R)-7-amino-3-desacetoxy-3-[(1-ethyl-l,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-yl)thio]-cephalosporanic acid. The product is a 20 beige powder (syn/anti mixture ca 70:30). [a]Q = -47.2° (c == 0.5 in water), R^ value = 0.47 (thin-layer chromatography on Kieselgel-Fg^-finished plates in the system butanol/glacial acetic acid/'water 4:1:1, visualisation with UV light).

Example 8 Preparation of the sodium salt of (7R)-7-/*220 -[(carbamoyl-methoxy)imino]-2-(2-furyl)acetamido7-3~Π(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl7-3-cephem-4-carboxylie acid: 9.76 g of /a-[(carbamoylmethoxy)imino]furfuryl/~ cephalosporin sodium salt (syn/anti mixture ca 70:30) are suspended together with 4.77 g of 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-3-mercapto-as-triazine in 200 ml of phosphate buffer of pH 6.4. The pH is adjusted to 6.4 using 1-N sodium hydroxide while gassing with nitrogen, whereby a dark solution is obtained. This solution is stirred at pH 6.4-6.5 for 6 hours at 55-6O°C while gassing with nitrogen, the pH being held constant 10 with the aid of an autotitrator with the addition of 1-N sodium hydroxide. The reaction solution is cooled to 0-5°C and the pH is adjusted to 2 with 2-N hydrochloric acid, whereby the reaction product separates out as the acid. This is filtered off under suction, washed with ioe/water and dried at 40°C overnight in vacuo. The end product is obtained in the form of the crude acid. For purification, this is dissolved in 150 ml of methanol and the solution is boiled with active carbon for 2 minutes. The mixture 20 is filtered through a fluted filter and the orange coloured filtrate is concentrated in vacuo. The resin which thereby precipitates is separated and discarded.

The concentrated methanolic solution is poured into ether. The acid which thereby precipitates is filtered off under suction and washed with ether and with low-boiling petroleum ether. The end product is obtained in the form of the pure acid which, for conversion into the sodium salt, is dissolved in 100 ml of methanol and treated with 5 ml of a 2-N solution of ί·· .ί sodium 2-ethylcaproate in ethyl acetate. A small amount of insolubles is filtered off and the orange coloured filtrate is concentrated at 40°C in vacuo.

This concentrated solution is added to ethanol, whereby the sodium salt precipitates. This is filtered off under suction, washed with ethanol and low-boiling petroleum ether and dried at 4O°C overnight in vacuo. There is obtained the sodium salt of (75)-7-/2-[(carbamoyImethoxy)imino]-2-(2-furyl)acetamidq7-310 -/[$.,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl/-3~cePhem-4-carboxylic acid as a 20 beige powder (syn/anti mixture ca 70:30). [a]D = -30.1° (c = 1 in water). Rf = 0.29 (thin-layer chromatography on Kieselgel-f^^finished plates in the system butanol/glacial acetic acid/water 4:1:1, visualisation with UV light).

When the starting compounds are replaced by equivalent amounts of /a-[(methoxy)imino]furfuryl/oephalosporin and l,2,5,6-tetrahydro-2-methyl-5,620 -dioxo-3-mercapto-as-triazine, then there is obtained under otherwise similar conditions the sodium salt of (7R)-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-3-/[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl7-3-cephem-4-carboxylie acid. The product is identical with the compound obtained according to Example 1. 469 υ 3 Example 9 Preparation of dry ampoules for intramuscular administration: A lyophilisate of 1 g of the sodium salt of 5 (7R)-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-3-/7(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio]methy 17-3-cephem-4--carboxylic acid is prepared in the usual manner and filled into an ampoule. Prior to the administration, the latter is treated with 2.-5 ml of a 2% agueous lidocaine hydrochloride solution.

Claims (17)

1. Claims: ·

1. Cephalosporin derivatives of the general formula COOH 5 wherein R represents furyl, thienyl or phenyl optionally substituted by halogen, hydroxy, lower alkoxy or lower alkyl, R^ represents lower alkyl or aminooarbonyImethyl and X represents a group of the formula 'Ν' i '0 in which one of the two symbols R 2 and R 3 or R^ and Rg represents hydrogen and the other represents lower alkyl, carboxymethyl or sulphomethyl, as well as salts of said compounds and hydrates of said salts. 4 6 9 0 3

2. Derivatives according to claim 1, characterised in that R represents furyl, as well as salts of said compounds and hydrates of said salts.

3. Derivatives according to claim 1 or 2, 5 characterised in that R^ represents methyl, as well as salts of said compounds and hydrates of said salts.

4. Derivatives according to one of claims 1 to 3, characterised in that X represents the group (c) or one of groups (a) and (b), in which one of the two 10 symbols R 2 and R 3 or R 4 and R g represents hydrogen and the other represents methyl, as well as salts of said compounds and hydrates of said salts.

5. Derivatives according to claim 4, characterised in that X represents a l,2,5,6-tetrahydro-2-methyl-5,615 -dloxo-as-triazin-3-yl group, as well as salts of said compounds and hydrates of said salts.

6. Derivatives according to claim 4, characterised in that X represents the l,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl group, as well as salts of said 20 compounds and hydrates of said salts.

7. (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-carboxylic acid, as well as salts of said compoundand hydrates of said salts.

8. Process for the manufacture of cephalosporin derivatives of the general formula wherein R represents furyl, thienyl or phenyl optionally 5 substituted by halogen, hydroxy, lower alkoxy or lower alkyl, R^ represents lower alkyl or aminocarbonyImethyl and X represents a group of the formula R q in which one of the two symbols R 2 and Rg or R^ and R g 10 represents hydrogen and the other represents lower alkyl, carboxymethyl or sulphomethyl, as well as salts of said compounds and hydrates of said salts, which process comprises (a) reacting a compound of the general formula wherein X has the significance given in formula I and the carboxy group can be present in protected form, with an acid of the general formula R j III R,CN==C—COOH wherein R and R^ have the significance given in formula I, or with a reactive functional derivative of this acid, and cleaving off the protecting group that may be present, or 10 (b) reacting a compound of the formula R Η H R^NsssC—CONH-gh 2 —Y IV COOH wherein R and R^ have the significance given in formula I and X represents a leaving group, with a thiol of the general 4 3803 formula HS—X V wherein X has the significance given in formula I, in the presence of water, and, if desired, converting 5 the reaction product into a salt or a hydrate of such a salt.

9. A process according to claim 8, characterised in that a starting compound of formula IX is reacted with an acid of formula III or a reactive functional derivative of such acid.

10. A process according to claim 9, characterised in that the chloride of an acid of formula III is reacted with a starting compound of formula II in aqueous alkali.

11. A process according to one of claims 8 to 10 for the manufacture of compounds of formula I, in which 15 R represents furyl, and of salts thereof or of hydrates of such salts, characterised in that appropriately substituted starting compounds are used.

12. A process according to one of claims 8 to 11 for the manufacture of compounds of formula I, in which 2o R j_ represents methyl, and of salts thereof or of hydrates of such salts, characterised in that appropriately substituted starting compounds are used. Λ6903

13. A process according to one of claims 8 to 12 for the manufacture of compounds of formula I, in which X represents the group (c) or one of groups (a) and (b), in which one of the two symbols R 2 and R g or 5 R^ and R g represents hydrogen and the other represents methyl, and of salts thereof or of hydrates of such salts, characterised in that appropriately substituted starting compounds are used.

14. A process according to claim 13 for the 10 manufacture of compounds of formula I, in which X represents a l,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl group, and of salts thereof or of hydrates of such salts, characterised in that appropriately substituted starting compounds are used.

15. 15. A process according to claim 13 for the manufacture of compounds of formula I, in which X represents the l,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl group, and of salts thereof or of hydrates of such salts, characterised in that appropriately 20 substituted starting compounds are used.

16. A process according to claim 14 for the manufacture of (7R)-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-3-{[(l,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as -triazin-3-yl)thio]methyl}-3-cephem-4-carboxylic acid, 25 and of salts thereof or of hydrates of such salts, 46303 characterised in that appropriately substituted starting compounds are used.

17. Pharmaceutical compositions, characterised in that they contain a derivative of the general formula wherein R represents furyl, thienyl or phenyl optionally substituted by halogen, hydroxy, lower alkoxy or lower alkyl, R^ represents a lower alkyl or aminocarbonyImethyl x nh 2 or a h e in which one of the two symbols R 2 and R g or R^ and R g represents hydrogen and the other represents lower alkyl, carboxymethyl or sulphomethyl, or a pharmaceutically compatible salt thereof or a hydrate of such salt.