GB1599232A - 7-(2-oximinoacetamido)-cephalosporin derivatives - Google Patents

Description

PATENT SPECIFICATION ( 11)1 599 232

C ( 21) Application No 22499/78 ( 22) Filed 25 May 1978 ( 31) Convention Application No77485 ( 19) ( 32) Filed 3 June 1977 ( 31) Convention Application No 3142/78 kiw ( 32) Filed 22 March 1978 in _ ( 33) Luxembourg (LU) Switzerland (CH) ( 44) Complete Specification published 30 Sept 1981 ( 51) INT CL' C 07 D 501/36; A 61 K 31/545 ( 52) Index at acceptance C 2 C 1314 1470 1510 1601 1651 214 215 220 226 22 Y 246 247 250 252 253 254 256 25 Y 28 X 292 29 Y 30 Y 321 32 Y 33 Y 342 346 34 Y 351 352 366 367 373 37 Y 519 614 62 672 RO(I ROY AA RP PATENTS ACT 1949 SPECIFICATION NO 1599232

The following amendments were allowed under Section 29 on 18 October 1982:Page 3, delete line 12, Page 10, delete line 12 insert group, Page 3, delete line 16, Page 10, delete line 16 insert in water or in a buffer solution having a p H of about 6 to 7, and Page 3, line 19, delete materials of formulae 11 and IV insert material of formula 11 Page 4, line 9, delete in a polar solvent such as an alcohol (e g a Page 4, delete line 10 Page 4, line 11, delete sulphoxide, but preferably Page 4, lines 14 and 15 delete or of the reaction of a compound of formula IV with a thiol of formula V, Page 4, line 17, delete Where the Page 4, delete lines 18 to 21 Page 4, lines 25 and 26, delete and the carboxy group can be present in protected form THE PATENT OFFICE December 1982 Bas 94063/8 halogen, hydroxy, lower alkoxy or lower alkyl, R, represents alkyl or aminocarbonylmethyl and X represents a group of the formula' FR F Q4 N N N N N, or 13 (a) (b) (c) in which one of the two symbols R 2 and R 3 or R 4 and R 5 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 I are alkali metal salts such as the sodium and potassium salt, the ammonium salt, alkaline earth metal salts such 70 v PATENT SPECIFICATION 11 599 232 eq ( 21) Application No 22499/78 ( 22) Filed 25 May 1978 Co ( 31) Convention Application No77485 ( 19)) ( 32) Filed 3 June 1977 ( 31) Convention Application No 3142/78 ( 32) Filed 22 March 1978 in - ( 33) Luxembourg (LU) Switzerland (CH) ( 44) Complete Specification published 30 Sept 1981 ( 51) INT CL 3 C 07 D 501/36; A 61 K 31/545 ( 52) Index at acceptance C 2 C 1314 1470 1510 1601 1651 214 215 220 226 22 Y 246 247 250 252 253 254 256 25 Y 28 X 292 29 Y 30 Y 321 32 Y 33 Y 342 346 34 Y 351 352 366 367 373 37 Y 519 614 628 672 801 80 Y AA RP ( 54) 7-( 2-OXIMINOACETAMIDO)-CEPHALOSPORIN DERIVATIVES ( 71) We, F HOFFMANN-LA ROCHE & CO, AKTIENGESELLSCHAFT, a Swiss Company of 124-184 Grenzacherstrasse, Basle, Switzerland, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: 5

The present invention relates to acyl derivatives More particularly, the invention is concerned with acyl derivatives, a process for the manufacturing thereof and pharmaceutical preparations containing same.

The acyl derivatives provided by the present invention are compounds of the general formula lo R H N I (I) R 1 ON=C-CONHjh I O' CH 2 S-X COOH wherein R represents furyl, thienyl or phenyl optionally substituted by halogen, hydroxy, lower alkoxy or lower alkyl, R 1 represents alkyl or aminocarbonylmethyl and X represents a group of the formula R 2 R 4 o 1 1 - 1 N 1 N N X N z NH 2 J O N ' 44 O or R 3 (a) (b) (c) in which one of the two symbols R 2 and R 3 or R 4 and R 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 I are alkali metal salts such as the sodium and potassium salt, the ammonium salt, alkaline earth metal salts such 20 2 1,599,232 2 as the calcuim salt, salts with organic bases such as salts with amines (e g salts with N-ethyl-piperidine, procaine, dibenzylamine, N,N'dibenzylethylethylenediamine, alkylamines or dialkylamines) as well as salts with amino acids (e g salts with arginine or lysine) The salts can be mono-salts or di-salts Di-salts are formed when the compounds of formula I contain a group of formula (b) in the tautomeric enol 5 form, said form being acidic _ The compounds of formula I also form acid addition salts with organic or inorganic acids Examples of such salts are hydrohalides (e g hydrochlorides, hydrobromides and hydroiodides) as well as other mineral acid salts (e g sulphates, nitrates and phosphates, alkylsulphonates and monoarylsulphonates (e g ethane 10 sulphonates, toluenesulphonates and benzenesulphonates) and other organic acid salts (e g acetates, tartrates, maleates, citrates, benzoates, salicylates and ascorbates).

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 15 consequence of the hygroscopic properties of an initially anhydrous salt of a compound of formula I.

The aforementioned lower alkyl groups are either straight-chain or branchedchain and contain up to 7 carbon atoms (e g methyl, ethyl, n-propyl, isopropyl, npentyl and n-heptyl) The lower alkoxy groups have an analogous significance The 20 halogen atom is fluorine, chlorine, bromihe or iodine with chlorine and bromine being preferred.

Preferred groups denoted by R are furyl, thienyl and phenyl, especially furyl.

R, preferably represents methyl X preferably represents the group of formula (c) or a group of formula (a) or (b) in which one of the two symbols R: and R 3 or R 4 25 and R 5 represents hydrogen and the other represents methyl Especially preferred groups denoted by X are the i,2,5,6-tetrahydro-2-methyl-5,6-dioxo-astriazin-3-yl group and the 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl group.

Preferred acyl derivatives provided by the present invention are the compound (R) 7 l 2 ( 2 furyl) 2 (methoxyimino)acetamidol 3 ll( 1,2,5,6 30 tetrahydro 2 methyl 5,6 dioxo as triazin 3 yl)thiolmethyll 3 cephem 4 carboxylic acid and salts thereof as well as the hydrates of said salts.

The compounds of formula I as well as their salts and hydrates of said salts can exist in the syn-isomeric form R-C-CON H A 35 11 N OR, or in the anti-isomeric form R-C-CONH N / Ri O or as mixtures of these two forms The syn-isomeric form is preferred as are mixtures in which the syn-isomeric form predominates.

According to the process provided by the present invention, the acyl 40 derivatives aforesaid (i e the compounds of formula I as well as their salts and hydrates of said salts) are manufactured by (a) reacting a compound of the general formula H H H 2 N N J CH 2-S-X (O) COOH 1 i 1 i j g 1 I,, i 3,,_ _ Wherein X has the significance given earlier and the carboxy group can be present in protected form, with an acid of the general formula R R,O -C-COOH (III) wherein R and R, have the significance given earlier, 5 or with a reactive functional derivative of this acid and, where required, cleaving off the protecting group, or (b) reacting a compound of the general formula R H H R ON= C-CONH 10' ' CH 2-Y 10 (IV) COON wherein R and R, have the significance given earlier, Y represents a leaving group and the carboxy group can be present in protected form, with a thiol of the general formula HS-X (V) wherein X has the significance given earlier, 15 and, where required, cleaving off the protecting group, and (c) if desired, converting the reaction product into a salt or a hydrate of such a salt.

The carboxy groups present in the starting materials of formulae II and IV can be protected is desired; for example, by esterification to form a readily cleavable 20 ester such as a silyl ester (e g the trimethylsilyl ester) The carboxy group can also be protected by salt formation with an inorganic base or a tertiary organic base such as triethylamine -' Examples of reactive functional derivatives of acids of formula III include halides (i e chlorides, bromides and fluorides), azides, anhydrides, especially 25 mixed anhydrides with strong acids, reactive esters, (e g Nhydroxysuccinimide esters) and amides (e g imidazolides).

Examples of leaving groups denoted by Y in compounds of formula IV include halogen atoms (e g chlorine, bromine or iodine)', cyloxy groups (e g C,-C 7 alkanoyl groups such as acetoxy), lower alkylsulphonyloxy or aylsulphonyloxy 30 groups (e g mesyloxy or tosyloxy) and the azido group o, The reaction of a compound of formula II with an acid of formula HI or a reactive derivative thereof can be carried out in a manner known per se Thus, for example, a free acid of formula III can be condensed with one of the aforementioned esters of a compound of formula II in the presence of a ctrbodiimide 35 (e.g dicyclohexylcarbodiimide) in an inert solvent (e g ethyl acetate, acetonitrile, dioxan, chloroform, methylene chloride, benzene or dimethylformamide) and the ester group can subsequently be cleaved off Oxazolium salts (e g N-ethyl5phenyl-isoxazolium-3 '-sulphonate) can be used in the place of carbodiimides.

I 40 According to another embodiment, a salt of an acid of formula II (e g a 40 trialkylammonium salt) is reacted with a reactive functional derivative of an acid of formula III as mentioned earlier in an inert solvent (e g one of the solvents specified earlier).

According to a further embodiment, an acid halide, preferably the acid chloride, of an acid of formula III is reacted with an amine of formula II The 45 reaction is preferably carried out in the presence of an acid-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 lower-alkylated amine such as triethylamine Water is preferably 1.599232 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 a 5 temperature between -40 C and room tem'perature, for example at 0 -100 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 40 C and 80 C, conveniently at about 60 C, in a polar solvent such as an alcohol (e g a C,-C 7 alkanol such as ethanol or propanol), dimethylformamide or dimethyl 10 sulphoxide, but preferably in water or in a buffer solution having a p H of about 6 to 7, preferably 6,5.

After completion of the reaction of a compound of formula II with an acid of formula III or a reactive derivative thereof or of the reaction of a compound of formula IV with a thiol of formula V, any protecting groub present is cleaved off 15 Where the protecting group is a silyl group (silyl ester), this group can be cleaved off especially readily by treating the reaction product with water Where the carboxyl group of an acid of formula IV is protected by salt formation (e g with 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 20 example, hydrochloric acid, sulphuric acid, phosphoric acid or citric acid.

The starting materials of formula II hereinbefore can be prepared by reacting a compound of the general formula H H S H 2 N + S (VI) e N_ CH 2-Y COOH wherein Y has the significance given earlier and the carboxy group can be 25 present in protected form, with a thiol of formula V hereinbefore The reaction can be carried out under the same conditions as described earlier in connection with the reaction of a compound of formula IV with a thiol of formula V.

A syn/anti mixture of a compound of formula I which may be obtained can be 30 separated into the corresponding syn and anti-forms in the usual manner; for example, by recrystallisation or by chromatographic methods using a suitable solvent or solvent mixture.

The compounds of formula I, their salts and the hydrates of said salts have antibiotic, especially bactericidal, activity They have a wide spectrum of activity 35 against gram-positive and gram-negative microorganisms, including /lactamase forming Staphylococci and various 1-lactamase forming gram-negative bacteria such as, for example, Haemophilus influenzae, Escherichia coli, Proteus species and Klebsiella species.

The compounds of formula I as well as their pharmaceutically acceptable 40 salts and hydrates of said salts can be used for the treatment and prophylaxis of infectious diseases In the case of adults a daily dosage of about I g to about 4 g may be administered Administration by the parenteral route is especially preferred.

In order to demonstrate the antimicrobial activity of the compounds provided by the present invention, the following representative compounds were tested: 45 Compound A: ( 7 R) 7 l 2 ( 2 furyl) 2 (methoxyimino)acetamidol 3 ll( 1,2,5,6tetrahydro 2 methyl 5,6 dioxo as triazin 3 yl)thiolmethyll 3 cephemr 4 carboxylic acid.

Compound B: ( 7 R) 7 l 2 ( 2 furyl) 2 (methoxyimino)acetamidol 3 ll(I 1 amino 1,2 dihydro 2 oxo 4 50 pyrimidinyl)thiolmethyll 3 cephemr 4 carboxylic acid.

Compound C: ( 7 R) 7 l 2 (phenyl) 2 (methoxyimino)acetamidol 3 ll( 1,2,5,6tetrahydro 2 methyl 5,6 dioxo as triazin 3 yl)thiolmethyll 3 cephem 4 carboxylic acid.

1,599232 Compound D:

Compound E:

Compound F:

Compound G:

1,599,232 ( 7 R) 7 l 2 ( 2 furyl) 2 (methoxyimino)acetamidol 3 ll( 1,4,5,6tetrahydro 4 methyl 5,6 dioxo as triazin 3 yl)thiolmethyll 3 cephem 4 carboxylic acid.

( 7 R)7 l 2 (methoxyimino) 2 ( 2 thienyl)acetamidol 3 ll( 1,2,5,6tetrahydro 2 methyl 5,6 dioxo as triazin 3 yl)thiolmethyll 3 cephem 4 carboxylic acid.

( 7 R) 3 ll(l ethyl-l,4,5,6, tetrahydro 5,6 dioxo as triazin 3 yl)thiolmethyll 7 l 2 ( 2 furyl) 2 (methoxyimino)acetamidol 3 cephem 4 carboxylic acid.

( 7 R) 7 l 2 l(carbamoylmethoxy)iminol 2 ( 2 furyl)acetamidol 3 ll( 1,4,5,6 tetrahydro 4 methyl 5,6dioxo as triazin 3 yl)thiolmethyll 3 cephem 4carboxylic acid.

Activity in vitro: Minimum Inhibitory Concentration (pg/ml) A B C D E F G Haemophilus influenzae strain 1 1 2 2 5 2 5 2 5 2 5 2 5 5 0 strain 2 0 16 0 63 0 16 0 31 0 16 0 31 0 63 strain 3 0 16 0 63 0 16 0 31 0 16 1 2 0 31 strain 4 0 16 0 31 0 16 0 31 0 16 0 16 0 63 strain 5 0 08 0 31 0 08 0 16 0 08 0 08 0 31 strain 6 0 16 0 31 0 08 0 16 0 08 0 08 0 63 strain 7 0 08 0 31 0 08 0 16 0 08 0 16 0 63 Klebsiella pneumoniae 10 20 20 5 40 40 2 5 Escherichia coli strain 1 0 63 2 5 1 2 0 16 2 5 1 2 0 31 strain 2 40 20 10 5 20 80 5 Proteus mirabilis strain 1 2 5 10 10 10 10 20 5 strain 2 5 40 20 20 20 40 10 Proteus vulgaris 5 40 10 1 2 10 20 1 2 Proteus rettgeri 0 63 2 5 0 63 0 63 2 5 10 ' 0 63 Staphylococcus aureus ATCC 6538 2 5 0 16 2 5 0 63 2 5 5 1 2 Penicillin resistant strain 5 1 2 2 5 0 63 2 5 5 1 2 Activity in vivo Groups of 10 mice are infected intraperitoneally with an aqueous suspension of Proteus mirabilis One hour after the infection the test compound is administered subcutaneously The number of surviving mice is determined on the 4th day Various dosages of test compound are administered and the dosage at which 50 of the mice survive (C Do,, mg/kg) is determined by interpolation.

1,599,232 Test compound A B C D E F G CD 50, mg/kg 0 09 3 O 0 60 O 70 1 15 0 85 0 80 Toxicity (mice, 24 hour values) Test compound A B C D E F G -LD 50, 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 pharmaceutically acceptable salts or hydrates of said salts, optionally in admixture with another therapeutically valuable substance.

Such compounds, salts or hydrates are conveniently mixed with pharmaceutical 5 inorganic or organic inert carrier material, especially one which is suitable for parenteral administration, such as, for example, water or gum arabic The pharmaceutical preparations are preferably made up in liquid form (e g as solutions, suspensions or emulsions) The pharmaceutical preparations may be sterilised and/or may contain adjuvants such as preserving agents, stabilising agents, wetting lo agents, emulsifying agents, salts for varying the osmotic pressure or buffers.

The following Examples illustrate the process provided by the present invention:

Example 1.

i 5 Preparation of the sodium salt of ( 7 R) 7 l 2 ( 2 furyl) 2 15 (methoxyimino)acetamidol 3 ll( 1,2,5,6 tetrahydro 2 methyl 5,6 dioxo as triazin 3 yl)thiolmethyll 3 cephem 4 carboxylic acid 5.06 of 2-methoxyimino-2-furyl-acetic 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 dimethyl 20 formamide The mixture is stirred while gassing with nitrogen at 5 -10 C for I hour and at 25 C for 0 5 hour and then evaporated at 10 C in vacuo The residue is suspended in 150 ml of acetone and treated at O C with a solution of 11 2 g of ( 7 R)7 amino 3 desacetoxy 3 l( 1,2,5,6tetrahydro 2 -methyl 5,6 dioxo as triazin 3 yl)thiolcephalosporanic acid in 150 ml of wafer, which has 25 previously been adjusted to p H 7 5 using 2-N aqueous sodium hydroxide _The mixture is stirred at 0 -o 10 C for 2 5 hours under nitrogen, the p H being held between 7 5 and 8 0 by the addition of 2-N aqueous sodium hydroxirde 500 ml of ethyl acetate are then added and the p H is adjusted to 1 5 with 2 N aqueous hydrochloric acid After separating the organic phase, the aqueous phase is 30 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 Insolubles are filtered off and the orange coloured filtrate obtained is diluted with 1000 ml of ether The amorphous ( 7 R) 7 l 2 ( 2 furyl) 2 (methoxyimino)acetamidol 3 ll( 1,2,5,6tetrahydro 35 2 methyl 5,6 dioxo as triazin 3 yl)thiolmethyll 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 ml of a 2-N solution of sodium 2-ethyl 40 caproate in ethyl acetate, whereby the sodium salt of ( 7 R) 7 l 2 ( 2 furyl) 2 (methoxyimino)acetamidol 3 ll( 1,2,5,6tetrahydro 2 methyl 5,6 dioxo as triazin 3 yl)thiolmethyll 3 cephem 4 carboxylic acid precipitates This is filtered off under suction, washed with ethyl acetate and lowboiling 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); lal 12 O=108 6 (c= 0 5 in water); R 1 value = O 10 lthin-layer chromatography on Kieselgel-F 214finished plates in butanol/glacial acetic acid/water ( 4:1:1), visualisation with 5 ultraviolet lightl.

Example 2.

Preparation of the sodium salt of ( 7 R) 7 l 2 ( 2 furyl) 2 (methoxyimino)acetamidol 3 ll( 1 i amino 1,2 dihydro 2 oxo 4pyrimidinyl)thiolmethyll3 cephem 4 carboxylic acid This salt is prepared in a manner analogous to that described in Example I from 3 4 g of 2 methoxyimino 2 furyl acetic acid and 7 11 g of ( 7 R) 7 amino 3 -' desacetoxy 3 1 ( 1 amino 1,2 dihydro 2 oxo 4pyrimidinyl)thiolcephalosporanic acid The product is a beige powder (syn/anti mixture 70:30); R, value= 0 40 lthin-layer chromatography on Kieselgel-F 254 15 finished plates in butanol/glacial acetic acid/water ( 4:1:1), visualisation with ultraviolet lightl.

Example 3.

Preparation of the sodium salt of ( 7 R) 7 l 2 (phenyl) 2 (methoxyimino)acetamidol 3 ll( 1,2,5,6tetrahydro 2 methyl 5,6 dioxo 20 as triazin 3 yl)thiolmethyll 3 cephem 4 carboxylic acid This salt is prepared in a manner analogous to that described in Example I from 1 8 g of 2-methoxyimino-phenylacetic acid (syn/anti mixture 90:10) and 3 75 g of ( 7 R) 7 amino 3 desacetoxy 3 l( 1,2,5,6 tetrahydro 2 methyl 5,6 dioxo as triazine 3 yl)thiolcephalosporanic acid The product is a beige 25 powder (syn-anti mixture 90:10); lal 2 = 135 o (c = O 5 in water); R 1 value = O 17 lthin-layer chromatography on Kieselgel-F 2 4-finished plates in butanol/glacial acetic acid/water ( 4:1:1), visualisation with ultraviolet lightl.

0 Example 4.

Preparation of the sodium salt of ( 7 R) 7 l 2 ( 2 furyl) 2 30 (methoxyimino)acetamidol 3 ll( 1,4,5,6 tetrahydro 4 methyl 5,6 dioxo as triazin 3 yl)thiolmethyll 3 cephemr 4 carboxylic acid This salt is prepared in a manner analogous to that described in Example I from 3 4 g of 2-methoxyimino-2-furyl-acetic acid (syn/anti mixture 80:20) and 7 46 g of ( 7 R) 7 amino 3 desacetoxy 3 l( 1,4,5,6tetrahydro 4 methyl 35 5,6 dioxo as triazin 3 yl)thiolcephalosporanic acid The product is a beige powder (syn/anti mixture 80:20); lal 1 =-44 (c = O 5 -in water); 'R value =O 34 lthin-layer chromatography on Kieselgel-F 2 4-finished plates in butanol/glacial acetic acid/water ( 4:1:1), visualisation with urtraviolet lightl.

Example 5 40

Preparation of the sodium salt of ( 7 R) 7 'l 2 (methoxyimino) 2 ( 2 thienyl)acetamidol 3 ll( 1,2,5,6 tetrahydro 2 methyl 5,6 dioxo as triazin 3 yl)thiolmethyll 3 cephem 4 carboxylic acid 'This salt is prepared in a manner analogous to that described in Example I from 1 85 g of 2-methoxyimino-2-thienyl-acetic acid (syn/anti mixture ca 70 30) and 45 3.71 g of ( 7 R) 7 amino 3 desacetoxy 3 l( 1,2,5,6tetrahydro 2 methyl 5,6 dioxo as triazin 3 yl)thiolcephalosporanic acid The product is a beige powder (syn/anti mixture ca 70:30); lal Jo =-128 2 (c = 0 5 in water); R, value= 0 21 lthin-layer chromatography on Kieselgel-F 2,-finished plates in butanol/glacial acetic acid/water ( 4:1:1), visualisation with ultraviolet lightl 50 Example 6.

Preparation of the disodium salt of ( 7 R) 7 12 ( 2 furyl) 2(methoxyimino)acetamidol 3 ll( 2,5 dihydro 2 methyl 5 oxo 6hydroxy as triazin 3 yl)thiolmethyll 3 cephem 4 carboxylic acid This salt is prepared in a manner analogous to that described in Example 1 55 from 10 12 g of 2-methoxyimino-2-furyl-acetic acid (syn isomer) and 18 7 g of ( 7 R)7 amino 3 desacetoxy 3 l( 1,2,5,6tetrahydro 2 methyl 5,6 dioxo as triazin 3 yl)thiol cephalosporanic acid For the salt-formation there are used 20 ml ( 2 equivalents) of a 2-N solution of sodium 2ethylcaproate in ethyl acetate The product is an almost colourless powder (syn isomer); 60 1.599232 8 1,599,232 lall =-141 6 (c= 0 5 in water; R, value= O 14 lthin-layer chromatography on Kieselgel-F 2,-finished plates in butanol/glacial acetic acid/water ( 4:1:1), visualisation with ultraviolet lightl.

Example 7.

Preparation of the sodium salt of ( 7 R)3 llMl_ 4,5,6tetrahydro 5,6 dioxo as 5 triazin 3 yl)thiolmethyll 7 l 2 ( 2 -furyl)2 (methoxyimino)acetamidol 3 cephem 4 carboxylic acid This acid is prepared in a manner analogous to that described in Example I from 1.69 g of 2-methoxyimino-2-furyl-acetic acid (syn isomer) and 3 85 g of ( 7 R) 7 amino 3 desacetoxy 3 l( 1 ethyl 1,4,5,6 tetrahydro 5,6 dioxo as 10 triazin 3 yl)thiolcephalosporanic acid The product is a beige powder (syn/anti mixture ca 70:30); lcall =-47 2 (c= 0 5 in water); R 1 value= 0 47 lthin-layer chromatography on Kieselgel-F 2,4-finished plates in butanol/glacial acetic acid/water ( 4:1:1), visualisation with ultraviolet lightl.

Example 8 15

Preparation of the sodium salt of ( 7 R) 7 l 2 l(carbamoylmethoxy) iminol 2 ( 2 furyl)acetamidol 3 l{( 1,4,5,6 tetrahydro 4 methyl 5,6 dioxo as triazin 3 yl)thiolmethyll 3 cephem 4 carboxylic acid 9.76 g of 7-la-l(carbamoylmethoxy)iminolfurfuryllcephalosporanic acid sodium salt (syn/anti mixture ca 70:30) are suspended together with 4 77 g of 20 1,4,5,6 tetrahydro 4 methyl 5,6 dioxo 3 mercapto as triazine in 200 ml of phosphate buffer having a p H of 6 4 The p H is adjusted to 6 4 using I-N sodium hydroxide while gassing with nitrogen, whereby a dark solution is obtained.

This solution is stirred at p H 6 4 6 5 for 6 hours at 55 -60 C while gassing with nitrogen, the p H being held constant with the aid of an autotitrator with the 25 addition of I-N sodium hydroxide The solution is cooled to 0 0-5 C and the p H is adjusted to 2 with 2-N hydrochloric acid, whereby the product separates out as the acid This is filtered off under suction, washed with ice/water and dried at 40 C overnight in vacuo The product is obtained in the form of the crude acid For purification, this crude acid is dissolved in 150 ml of methanol and the solution is 30 boiled with active carbon for 2 minutes The mixture is filtered through a fluted filter and the orange coloured filtrate is concentrated in vacuo The resin which thereby precipitates is separated and rejected The concentrated methanolic solution is poured into ether The acid which thereby precipitates if filtered off under suction and washed with ether and with low-boiling petroleum ether The 35 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 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 40 This salt is filtered off under suction, washed with ethanol and lowboiling petroleum ether and dried at 40 C overnight in vacuo There is obtained the sodium salt of ( 7 R) 7 l 2 (carbamoylmethkxy) iminol 2 ( 2 furyl)acetamidol 3 ll( 1,4,5,6tetrahydro 4 methyl 5,6,dioxo as triazin 3 yl)thiolmethyll 3 cephem 4 carboxylic, acid in the form of a 45 beige powder (syn/anti mixture ca 70:30); lal 2 =-30 = o (c= 1 in water) Rvalue= 0 29 lthin-layer chromatography on iieselgel-F 2 _-finished plates in butanol/glacial acetic acid/water ( 4:1:1), visualisation with ultraviole lightl.

When the starting materials used in the preceding paragraph are replaced by equivalent amounts of 7 la l(methoxy) iminolfurfuryllcephalosporanic acid 50 and 1,2,5,6, tetrahydro 2 methyl 5,6 dioxo 3 mercapto as triazine, then there is obtained under otherwise similar conditions the sodium salt of ( 7 R) 7 l 2 ( 2 furyl) 2 (methoxyimino)acetamidol 3 ll( 1,2,5,6tetrahydro 2 methyl 5,6 dioxo as triazin 3 yl)thiolmethyll 3 cephem 4 carboxylic acid This salt is identical with the salt obtained according to Example 1 55 The following Example illustrates the preparation of a pharmaceutical preparation provided by the present invention:

Example A.

Preparation of dry ampoules for intramuscular administration A lyophilisate of I g of the sodium salt of ( 7 R) 7 l 2 ( 2 furyl) 2 60 (methoxyimino)acetamidol 3 l( 1,2,5,6 tetrahydro 2 methyl 5,6 dioxo as triazin 3 yl)thiolm(ethyll 3 cephem carboxylic acid is 1,599,232 prepared in the usual manner and filled into an ampoule Prior to the administration, the latter is treated with 2 5 ml of 2 % aqueous lidocaine hydrochloride solution.

Claims (1)

1. WHAT WE CLAIM IS:

   : 5 1 Compounds of the general fozmula 5 R R l ON=C-CONH (I) H 2-S-X COOH wherein R represents furyl, thienyl or phenyl optionally subsfituted by halogen, hydroxy, lower alkoxy or lower alkyl, R, represents alkvl or aminocarbonylmethyl and X represents a group of the formula o P 2 P 4 O N N KN 2 10 O 10 1 1 R 3 (a) (b) (c) 0 in which one of the two symbols R 2 and R 3 or R 4 and R, represents hydrogen and the other represents lower alkyl, carboxymethyl or sulphomethyl, as well as salts of said compounds and hydrates of said salts.

   2 Compounds as set forth in claim 1, wherein R represents furyl, as well as 15salts of said compounds and hydrates of said salts 15 3 Compounds as set forth in claim I or claim 2, wherein R, represents methyl, as well as salts of said compounds and hydrates of said salts.

   4 Compounds as set forth in any one of claims I to 3 inclusive, wherein X represents the group of formula (c) or a group of formula (a) or (b) in which one of o 20 the two symbols R 2 and R 3 or R 4 and Rs represents hydrogen and the other 20 represents methyl, as well as salts of said compounds and hydrates of said salts.

   Compounds as set forth in claim 4, wherein X represents the 1,2,5,6 tetrahydro 2 methyl 5,6 dioxo as triazfin3 yl group, as well as salts of said compounds and hydrates of said salts 25 6 Compounds as set forth in claim 4, wherein X represents the 1,4,5,6 25 tetrahydro 2 methyl 5,6 dioxo as triazin 3 'yl group, as well as salts of said compounds and hydrates of said salts.

   7 ( 7 R)7 l 2 ( 2 Furyl) 2 (methoxyimino)acetamido P 3 ll( 1,2,5,6 tetrahydro 2 methyl 5,6 dioxo as triazin 3 yl)thiolmethyll 3 o 30 cephem 4 carboxylic acid as well as salts of this compound and hydrates of said30 salts.

   8 A process for the manufacture of the acyl derivatives claimed in claim I, which process comprises (a) reacting a compound of the general formula H H 235 35H 2 N 5 (II) NCOOHH 2-S-X 0 COON wherein X has the significance given earlier and the carboxy group can be present in protected form, with an acid of the general formula R I _ R 1 ON=C-COOH (III) wherein R and R, have the significance given in claim 1, 5 or with a reactive functional derivative of this acid and, where required, cleaving off the protecting group, or (b) reacting a compound of the general formula R H H R 1 ON=C-CONH U -CH 2-Y (IV) 10 CH 2-y' (IV) 10 COOH wherein R and R, have the significance given in claim 1, Y represents a leaving group and the carboxy group can be present in protected form, with a thiol of the general formula HS-X (V) wherein X has the significance given in claim I, 15 and, where required, cleaving off the protecting group, and (c) if desired, converting the reaction product into a salt or a hydrate of such a salt.

   9 A process according to claim 8, wherein a compound of formula II is reacted with an acid of formula III or a reactive functional derivative thereof 20 A process according to claim 9, wherein an acid chloride of an acid of formula III is reacted with a compound of formula II in aqueous alkali.

   1 11 A process according to any one of claims 8 to 10 inclusive, wherein there is manufactured a compound of formula I in which R represents furyl or a salt thereof or a hydrate of such a salt 25 12 A process according to any one of claims 8 to 11 inclusive, wherein there is manufactured a compound of formula I in which R, represents methyl or a salt thereof or a hydrate of such a salt 13 A process according to any one of claims 8 to 12 inclusive, wherein there is manufactured a compound of formula I in which X represents the group of the 30 formula (c) or a group of the formula (a) or (b) in which one of the two symbols R and R 3 or R 4 or R 5 represents hydrogen and the other represents methyl or a salt thereof or a hydrate of such a salt, r 14 A process according to claim 13, wherein there is manufactured a compound of formula I in which X represents the 1,2,5,6-tetrahydro-2methyl-5,6 35 dioxo-as-triazin-3-yl group or a salt thereof or a hydrate of such a salt.

   A process according to claim 13, wherein there is manufactured a compound of formula I in which X represents the 1,4,5,6-tetrahydro-4methyl-5,6-dioxo-as-triazin-3-yl group or a salt thereof or a hydrate of such a salt.

   16 A process according to claim 14, wherein there is manufactured ( 7 R) 7 40 l 2 ( 2 furyl) 2 (methoxyimino)acetamidol 3 ll( 1,2,5,6tetrahydro 2 methyl 5,6 dioxo as triazin 3 yl) thiolmethyll 3 cephem 4 carboxylic acid or a salt thereof or a hydrate of such a salt.

   17 A process for the manufacture of the acyl derivatives set forth in claim 1, substantially as hereinbefore described with reference to any one of Examples I to 45 8.

   18 An acyl derivative as set forth in claim 1, when manufactured by the process claimed in any one of claims 8 to 17 inclusive or by an obvious chemical equivalent thereof.

   1,599,232 11 1,599,232 1 19 A pharmaceutical preparation containing as essential active ingredient a compound of formula I given in claim I or a pharmaceutically acceptable salt thereof or a hydrate of one of said salts.

   For the Applicants, CARPMAELS"& RANSFORD, Chartered Patent Agents, XJ O 43, Bloomsbury Square, London WC I A 2 RA.

   Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1981.

   Published by the Patent Office, 25 Southampton Buildings, London, WC 2 A l AY, from which copies may be obtained.