NZ190532A - Cephalosporin derivatives preparation and pharmaceutical compositions - Google Patents

Abstract

Compounds of the general formula <IMAGE> [wherein X represents the 1,2,5,6- tetrahydro-2-methyl-5,6-dioxo-as- triazin-3-yl group, the 2,5-dihydro-6- hydroxy-2-methyl-5-oxo-as-triazin-3- yl group of the 1,4,5,6-tetrahydro-4- methyl-5,6-dioxo-as-triazin-3-yl group] and readily hydrolysable esters, readily hydrolysable ethers and salts thereof and hydrates of these compounds have broad-spectrum anti-bacterial activity.

Description

New Zealand Paient Spedficaiion for Paient Number 1 90532 J 905 w ol jzk, I k3ij Sf-5 „ .-," rr, mz - - Priority Datsfc): 2Q.:S 3 & T& ~3cTB.

Ccmp'.cU -- pacification Filed:. . ass:. Q ^ ."3<&- • • ■ Pub;ic2t-jn Date:...*' P.O. Journal, No. \\S\<\ AHtNDED under Sectlonyt_.....^J-^—Of tfce Patents Act 1953 from//. assist/.!'it commissioner OF PATENTS NEW ZEALAND PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION ACYL DERIVATIVES 3®? We, F. HOFFMANN-LA ROCHE & CO. AKTIENGESELLSCHAFT, 124-184 Grenzacherstrasse, Basle, Switzerland, a Swiss company hereby declare the invention for whichXL / we pray that a patent may Q&^kbe granted to yao^us, and the method by which it is to be performed, MAY ke Particularly described in and by the following statement:- * li - 1 - (followed by page la) - la- 190532 ■ - i RAM 4410/120 The present invention relates t^ acyl derivatives, More particularly, the invention is^concerned with cephalo- / sporin derivatives, a process fojf the manufacture thereof The invention is further concerxafed with the use of said cephalosporin derivatives. and pharmaceutical preparations containing same.

The cephalosporin derivatives provided by/ the present / X invention are compounds of the general formu/a / h h ch3on=c—conh V , wherein X represents/the 1,2,5,6-tetra-hydro-2-methyl-5,6-daoxo-as-triazin-3-yl group or the corresponding tautomeric form thereof, the 2y8-dihydro-6-hydroxy-2-methyl--5-oxo-as-tri/azin-3-yl group, or the 1,4,5,6--tetrahydro-4-methyl-5,6-dioxo-as-triazin-3--yl group,' as well as readily hydrolysable esters, readily hydrolysable ethers and salts of these compounds and hydrates of the compounds of formula I or of their esters, ethers and salts. Mn/5■d■7 D ^ 1 905 3 ^ • *' r' ' ' " * » ^ 1 , - - - 2 - As readily hydrolysable esters of the compounds of formula I there are to be understood compounds of formula X in which the carboxy group is present in the form of a readily hydrolysable ester grow. Examples of such esters, which can be of the conventional type, are the lower alkanoyloxyalkyl esters (eyg. the acetoxymethyl, pivaloyl-oxymethyl, 1-acetoxyethyl/and 1-pivaloyloxyethyl ester), the lower alkoxycarbonylox^alkyl esters (e.g. the methoxycar- / /' bonyloxymethy1, l-ethpxycarbonyloxyethyl and 1-isopropoxy- / / carbonyloxyethyl ester), the lactonyl esters (e.g. the / ' phthalidyl and thi'ophthalidyl ester) , the lower aikoxymethyl esters (e.g. the^methoxymethyl ester) and the lower alkanoylaminomethyl esters (e.g. the acetamidomethyl ester).

Other esters/(e.g. the benzyl and cyanomethyl esters) can / also be used. xs readily hydrolysable ethers of the compounds of formula I there are to be understood compounds of formula I wherein X represents the 2,5-d£hydro-6-hydroxy-2-methyl-5--oxo-as-triazin-3-yl group i/n which the enolic OH group is present in the form of a^readily hydrolysable ether group. Possible ether groups are the same ether groups which have already been mentioned earlier in connection with the readily hydrolysable ester groups. Examples of such ethers are the lower alkanoyloxyalkyl ethers (e.g. the acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl ether), the lower alkoxycarbonyloxyalky1 ethers (e.g. the methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and 1Q f\ C -5 ^ 'W ^ [ncvv - V^'r;] - 3 - l-isopropoxycarbonyloxyethyl ether), the lactonyl ethers (e.g the phthalidyl and thiophthalidyl ether), the lower alkoxy-methyl ethers (e.g. the methoxymethyl ether) and the lower alkanoylaminomethyl ethers (e.g./the acetamidomethyl ether).

Examples of salts of compounds of formula I are alkali metal salts such as the spdium salt and the potassium salt, /' the ammonium salt, alkafline earth metal salts such as the / / calcium salt, salts .with organic bases such as salt^with // amines (e.g. salts*with N-ethyl-piperidine, procaine, // / dibenzylamine, N,N1-dibenzylethylethylenediamine, alkyl- / , amines or diadkylamines), and salts with am^rio acids (e.g. / salts with/arginine or lysine). The sal£s can be mono- -salts or di-salts. The second salt formation can occur in coiripounds with the hydroxy moietVof the 2,5-dihydro-6- / / -h^droxy-2-methyl-5-oxo-as-triazin-3-yl group.

The compounds of formed, a I also form acid addition salts with organic or inorganic acids. Examples of such salts are hydrohalides/fe.g. hydrochlorides, hydrobromides and hydroiodides), other mineral acid salts such as sulphates, nitrates, phosphates and the like, alkyl-sulphonates and monoarylsulphonates such as ethanesul-phonates, toluenesulphonates, benzenesulphonates and the like and other organic acid salts such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like. 190532 NOV The compounds of formula I and their salts, readily hydrolysable esters and readily hydrolysable ethers can be hydrated. The hydration can be effected in the course of the manufacturing process or can occur gradually as a result of the hygroscopic properties of an initially anhydrous product.

/ / The cephalosporin derivatives provided by the present / invention can exist in the svn-isomeric form c conh or in the anti-isomeric form h2n or as mixtures of these two forms. The syn-isomeric form ,/ is preferred, as aj£e mixtures in which the syn-isomeric form predominates.

Preferred cephalosporin derivatives provided by the present invention are: NOto 1 (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_7-8-oxo-5-thia-l-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid and salts thereof as well as the corresponding hydrates.

According to the process provided by the present invention, the cephalosporin derivatives aforesaid are manufactured by (a) cleaving o£f the protecting group R (and, if desired, also a carooxy protecting group which/may be present) in a compound of the c h3 0n^=c conh // \\ d? RHJ II :ooh , wherein X has the significance given earlier, R represents a cleavable protecting group and the carboxy group can be present in protected ^orm, or (b) for the manufacture of a readily hydrolysable ester or ether of a compound of formula I, subjecting a carboxylic acid or an enol of formula I to a corresponding esterification or etherification, or (c) for the manufacture of salts or hydrates of a compound of formula I or hydrates of said salts, converting a compound of formula I into a, salt or hydrate or into a hydrate of said salt.

If desired, the c^drboxy group present in the starting /, can be protected; for example, by fgfrm a readily cleavable ester/such as a materials of formula esterification to silyl ester (e.g./the trimethylsilyl ester). /The carboxy group can also loe protected in the form of one of the aforementioned reaaily hydrolysable esters. Furthermore, the carboxy grofap can be protected by salt formation with an inorganic/ or tertiary organic base such as triethylamine.

PossiJo^e protecting groups denoted^/by R are, for example, protecting groups which are cleavable by acid hydrolysis (e/g. the tert.butoxycarbonyl/or trityl groups) or by basic ydrolysis (e.g. the trifluproacetyl group). Preferred protecting groups denoted/by R are the chloroacetyl, bromo- acetyl and iodoacetyl groups, especially the chloroacetyl / group. These last-mentioned protecting groups can be cleaved off by treatment with thiourea.

The starting materials of formula II hereinbefore can be prepared, for example, by N-acylating a corresponding 7--amino compound, namely by reacting a compound of the general formula - la- 190532 The present invention relates to acyl derivatives. More particularly, the invention is concerned with cephalosporin derivatives, a process for the manufacture thereof and pharmaceutical preparations containing same. The invention is further concerned with the use of said cephalosporin derivatives.

The cephalosporin derivatives provided by the present invention are a compound of the general formula h h c H3on —-conh ch2 s x cooh , wherein X represents the 1,2,5,6-tetra- hydro-2-methvl-5,6-dioxo-as-triazin-3-yl group or the corresponding tautomeric form thereof, the 2,5-dihydro-6-hydroxy-2-methyl--5-oxo-as-triazin-3-yl group, as well as readily hydrolysable esters / ethers and salts of this compound and hydrates of the compound of formula I or of its esters / ethers and salts. 190532 .C- ^ As readily hydrolysable esters of the compound of formula I there are to be understood compounds corresponding to formula I in which the carboxy group is present in the form of a readily hydrolysable ester group. Examples of such esters, 5 which can be of the conventional type, are the lower alkanoyloxyalkyl esters (e.g. the acetoxymethyl, pivaloyl-oxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl ester), the lower alkoxycarbonyloxyalkyl esters (e.g. the methoxycar-bonyloxymethyl, 1-ethoxycarbonyXoxyethyl and 1-isopropoxy-10 carbonyloxy ethyl ester) , the lactonyl esters (e.g. the phthalidvl and thiophthalidvl ester) , the lower alkoxymethyl esters (e.g. the methoxymethyl ester) and the lower alkanoylaminomethyl esters (e.g. the acetamidomethyl ester). Other esters (e.g. the benzyl and cyanomethyl esters) can 15 also be used.

As readily hydrolysable ethers of the compound of formula I there are to be understood ccsnpounds corresponding to formula I wherein X represents the 2,5-dihydro-6-hydroxy-2-methyl-5--oxo-as-triazin-3-yl group in which the enolic OH group is 20 present in the form of a readily hydrolysable ether group. Possible ether groups are the same ether groups which have already been mentioned earlier in connection with the readily hydrolysable ester groups. Examples of such ethers are the lower alkanoyloxyalkyl ethers (e.g. the acetoxy-25 methyl, pivaloyloxymethy 1, 1-acetoxyethyl and 1-pivaloyloxy-ethyl ether), the lower alkoxycarbonyloxyalkyl ethers (e.g.,,., the methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyeth.y Ir'and fl< (i *£. *, . 190532 3 1-isopropoxycarbonyloxyethyl ether), the lactonyl ethers (e.c. the phthalidvl ana thiophthalidyl ether), the lower alkoxy-methyl ethers (e.g. the methoxymethyl ether) and the lower alkanoylaminomethyl ethers (e.g. the acetamidomethyl ether). metal salts such as the sodium salt and the 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, 10 dibenzylamine, N,N1-dibenzylethylethylenediamine, alkyl- amines or dialkylamin.es) , and salts with amino acids (e.g. salts with arginine or lysine). The salts can be mono- • -salts or di-salts. The second salt formation can occur in compounds with the hydroxy moiety of the 2,5-dihydro-6-15 -hydroxy-2-methyl-5-oxo-as-triazin-3-yi group.

The compound of formula I also forms acid addition salts with organic or inorganic acids. Examples of such salts are hydrohalides (e.g. hydrochlorides, hydrcbromides and hydroiodides), other mineral acid salts such as 20 sulphates, nitrates, phosphates and the like, alkvl- sulphonates and monoarylsulphonates such as ethanesul-phonates, toluenesulphonates, benzenesulphonates and the like and other organic acid salts such as acetates, tartrates, maleates, citrates, benzoates, salicylates, 25 ascorbates and the like.

Examples of salts of the compound of formula I are alkali 190532 4 The compound of formula I and its salts and readily hydrolysable esters / ethers can be hydrated.

The hydration can be effected in the course of the manufacturing process or can occur gradually as a result of the hygroscopic properties of an initially anhydrous product.

The cephalosporin derivatives provided by the present invention can exist in the syn-isomeric form or as mixtures of these two forms. The syn-isomeric fora is preferred, as are mixtures in which the syn-isomeric form predominates.

Preferred cephalosporin derivatives provided by the present invention are: och3 or in the anti-isomeric form choo / \' ;> 190532 r".7\ ^ » " tr'W: ■ . (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-y1) thio] me thy l_7-8-oxo-5-thia-l-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid and salts thereof as well 5 as the corresponding hydrates.

According to the process provided by the present invention, the cephalosporin derivatives aforesaid are manufactured by desired, also a carboxy protecting group which may be present) in a compound of the general formula (a) cleaving off the protecting group R (and, if h h II cooh , wherein X has the significance given earlier, R represents a cleavable protecting group and the carboxy group can be present in protected form, or (b) for the manufacture of a readily hydrolysable ester / ether of the compound of formula I, subjecting same to a corresponding esterification / etherification, or 19053 r p t1 (c) for the manufacture of salts or hydrates of the compound of formula I or hydrates of said salts, converting the compound of formula I into a salt or hydrate or into a hydrate of said salt.

If desired, the carboxy group present in the starting materials of formula II can be protected; for example, by esterification to form a readily cleavable ester such as a silyl ester (e.g. the trimethylsilyl ester). The carboxy group can also be protected in the form of one of the aforementioned readily hydrolysable esters. Furthermore, the carboxy group can be protected by salt formation with an inorganic or tertiary organic base such as triethylamine. Possible protecting groups denoted by R are, for example, protecting groups which are cleavable by acid hydrolysis (e.g. the tert.butoxycarbony 1 or trityl groups) or by basic hydrolysis (e.g. the trifluoroacetyl group). Preferred protecting groups denoted by R are the chloroacetyl, bromo-acetyl and ioaoacetyl groups, especially the chloroacetyl group. These last-mentioned protecting groups can be cleaved off by treatment with thiourea.

The starting materials of formula II hereinbefore can be prepared, for example, by N-acylating a corresponding 7--amino compound, namely by reacting a compound of the general formula 1 90o 3 2 h h c h 2 s1 *x III cooh , wherein X has the significance given earlier and the carboxy group and/or the amino group can be present in protected form, with an acid of the general formula c h3:on=c cooh rhn IV , wherein R has the significance given earlier, or with a reactive functional derivative of this acid and, if desired, cleaving off a carboxy protecting group which may be present.

If desired, the carboxy group present in the 7-amino compounds of formula III can be protected in the same 15 manner as mentioned hereinbefore in connection with the starting materials of formula II. The amino group in the compounds of formula III can be protected, for example, by a silyl protecting group such as the trimethylsilyl group. 190532 Examples of reactive functional derivatives of acids of formula IV are halides (i.e. chlorides, bromides and fluorides), azides, anhydrides, especially mixed anhydrides with strong acids, reactive esters (e.g. N-hydroxysuccin-5 imide esters) and amides (e.g. imidazolides).

The reaction of a 7-amino compound of formula III with an acid of formula IV or a reactive functional derivative thereof can be carried out in a manner known per se. Thus, for example, a free acid of formula IV can be reacted with 10 an aforementioned ester of a compound of formula III in the presence of a carbodiimide such as dicyclohexylcarbodiimide in an inert solvent such as ethyl acetate, acetonitrile, dioxan, chloroform, methylene chloride, benzene or dimethyl-formamide and subsequently the ester group can be cleaved 15 off. Oxazolium salts (e.g. N-ethyl-5-phenyl-isoxazolium 3'-sulphonate) can be used in place of carbodiimides in the foregoing reaction.

According to another embodiment, a salt of an acid of formula III (e.g. a triaIky1ammonium salt such as the tri-20 ethylammonium salt) is reacted with a reactive functional derivative of an acid of formula IV as mentioned earlier in an inert solvent (e.g. one of the aforementioned solvents).

According to a further embodiment, an acid halide, preferably the chloride, of an acid of formula IV is reacted 25 with an amine of formula III. The reaction is preferably ' •'"90532 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 5 alkylamine such as triethylamine. As the solvent there is preferably used water, optionally in admixture with an inert organic solvent such as tetrahydrofuran or dioxan. The reaction can also be carried out in an aprotic organic solvent such as dimethylformamide, dimethyl sulphoxiae or hexa-10 methylphosphoric acid triamide. When a silylated compound of formula III is used, the reaction is carried out in an anhydrous medium.

The reaction of a 7-amino compound of .formula III with an acid of formula IV or a reactive functional derivative 15 thereof can conveniently be carried out at a temperature between -40°C and room temperature, for example at substantially 0°-10°C. '90532 In accordance with embodiment (a) of the process . provided by the present invention, the amino protecting group denoted by R in a compound of formula II is cleaved off. Protecting groups which are cleavable by acid hydrolysis are preferably removed with the aid of a lower alkanecarboxylic acid which may be halogenated. In particular, formic acid or trifluoroacetic acid is used. The acid hydrolysis is generally carried out at room temperature, although it can be carried out at a slightly elevated or slightly reduced temperature, for example a temperature in the range of 0°C to +40°C. Protecting groups which are cleavable under alkaline conditions are generally hydrolysed with a dilute aqueous alkali metal hydroxide solution at 0°C to 30°C. The chloroacetyl, bromoacetyl and iodoacetyl protecting groups can be cleaved off by means of thiourea in an acid, neutral or alkaline medium at "about 0°-30°C. Hydrogenolytic cleavage (e.g. cleavage of the benzyl group) is unsuitable in this case, since the oxime group is reduced to the amino group during the hydrogenolysis.

After carrying out embodiment (a) of the process, a carboxy protecting group present in the resulting product can be cleaved off if desired. When the protecting group is a silyl group (silyl ester), this group can be cleaved 190532 _NOV7 halide. The esterification/etherification is preferably carried out in an. inert organic solvent such as dimethyl- acetamide, hexamethylphosphoric acid triamide, . dimethyl" sulphoxide or, especially, dimetliylformamide. The reaction is preferably carried out at temperature in the range of 0°-40°C.

The manufactureyOf the salts and hydrates of compounds of formula I or theynydrates of said salts/in accordance with embodiment Cc) of the process provided by the present / / / / invention can bfe carried out in a manner known per se? for / /. example, by reacting a carboxylic ^cid of formula I with an equivalent^amount of the desired/base, conveniently in a solvent/such as water or an organic solvent (e.g. ethanol, / methanol, acetone and the ldke). When a second equivalent base is used, salt formation also takes place on a tautomeric enol form w^ich may be present (2,5-dihydro-6--hydroxy-2-methyl-5/oxo-as-triazin-3-yl group X), whereby a di-salt is forme^u The temperature at which the salt formation is serried out is not critical. The salt formation is generally carried out at room temperature, but it can be carried out at a temperature slightly above or below room temperature, for example in the range of 0°C to +50°C.

The manufacture of the hydrates usually takes place ^25 ►Jutomatically in the course of the manufacturing process or as ^ ® a result of the hygroscopic properties of an initially 19053 off especially readily by treatment with water. Lower alkanoyloxyalkyl, alkoxycarbonyloxyalkyl, lactonyl, alkoxy-methyl and alkanoylaminomethyl esifers are preferably cleaved enzymatically with the aid of suitable esterase at substantially 20°-40°C. When the carboxyy^roup is protected by salt formation (e.g. with trie thiamine) , then the cleavage of this salt-forming proteg/^ing group can be carried <yat. by treatment with an acidf. Acids which can be used" for this purpose are, for example, hydrochloric acid, ^ulphuric acid, phosphoric acid or citric acid.

The ca/boxy protecting group can/be cleaved off in the same manngt as just described also jfrior to the cleavage of the projecting group denoted by In order to manufacture a readily hydrolysable ester 15 of a carboxylic acid of £6rmula I in accordance with embodiment (b) of the /rocess provided by the present invention, a carboxylic acid of formula I is preferably reacted with a cqz^responding halide, preferably an iodide, containing the/aesired ester group. The reaction can be 20 accelerated with the aid of a base such as an alkali metal hydroxide, an alkali metal carbonate or an organic amine (e.g. triethylamine). If the 2,5-dihydro-6-hydroxy-2--methyl-5-oxo-as-triazin-3-yl group with its enolic function is present, this is etherified with the formation of a co-rresponding readily hydrolysable ether. In this case at Oji there is preferably used an excess of the corresponding - -- -- * yy-n - 11 - 190532 £i off especially readily by treatment with water. Lower alkanoyloxyalkyl, alkoxycarbonyloxyalkyl, lactonyl, alkoxy-methyl and alkanoylaminomethyl esters are preferably cleaved enzymatically with the aid of a suitable esterase at substantially 20°-40°C. When the carboxy group 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 an acid. Acids which can be used for this purpose are, for example, hydrochloric acid, sulphuric•acid, phosphoric acid or citric acid.

The carboxy protecting group can be cleaved off in the same manner as just described also prior to the cleavage of the protecting group denoted by R.

In order to manufacture a readily hydrolysable ester of the carboxylic acid of formula I in accordance with embodiment (b) of the process provided by the present invention, a carboxylic acid of formula I is preferably reacted with a corresponding halide, preferably an iodide, containing the desired ester group. The reaction can be accelerated with the aid of a base such as an alkali metal hydroxide, an alkali metal carbonate or an organic amine (e.g. triethylamine). The 2,5-dihydro-6-hydroxy-2-raethyl-5--oxo-as-triazin-3-yl group with its enolic function is ether-ified with the formation of a corresponding readily hydrolysable ether. (The so-obtained, simultaneously esterified and etherified products are hereinbefore and hereinafter termed "readily hydrolysable esters / ethers".) In this case^^T^r?^ /rv- ^ there is preferably used an excess of the corresponda-rtg I s^o,, 190532 7 A (r^- r " r- I r~>,i FJ! halide. The esterification/etherification is preferably carried out in an. inert organic solvent such as aimethyl- acetamiae, hexamethylphosphoric acid triamide, . dimethyl sulphoxide or, especially, dimethylformamide. The reaction is preferably carried out at a temperature in the range of 0°-40°C.

The manufacture of the salts and hydrates of tlie ccnpound of formula I or the hydrates of said salts in accordance with embodiment (c) of the process provided by the present invention can be carried out in a manner known per se; for example, by reacting a carboxylic acid of formula I with an equivalent amount of the desired base, conveniently in a solvent such as water or an organic solvent (e.g. ethanol, methanol, acetone ana the like). When a second equivalent of base is used, salt formation also takes place on the tautomeric enol form (2,5-dihydro-6--hydroxy-2-methyl-5-oxo-as-triazin-3-yl group X), whereby a di-salt is formed. The temperature at which the salt formation is carried out is not critical. The salt formation is generally carried out at room temperature, but it can be carried out at a temperature slightly above or below room temperature, for example in the range of 0°C to +50°C.

The manufacture of the hydrates usually takes place automatically in the course of the manufacturing process or as a result of the hygroscopic properties of an initially- "v C--" ft* <2 0 7 <L/, - e X _ 13 _ 190532 anhydrous product. For the controlled manufacture of a hydrate, a completely or partially anhydrous carboxylic acid of formula I or ester, ether or salt thereof can be exposed to a moist atmosphere, e.g. at substantially + 10°C to +40°C.

The 7-amino compounds of formula III hereinbefore can be prepared by reacting a compound of the general formula h h H2 Y V cooh , wherein Y represents a leaving atom or group, with a thiol of the general formula HS X VI wherein X has the significance given earlier.

Examples of leaving atoms and groups denoted by Y in a compound of formula V are halogen atoms (e.g. a chlorine, brcmine or iodine atom), acyloxy groups (e.g. lower alkanoyloxy groups such as the acetoxy group), lower alkylsulphonyloxy or arylsul-phonyloxy groups (e.g. the mesyloxy or tosyloxy groups) and the azido group.

The reaction of a compound of formula V with a thiol of formula VI 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 water or in a buffer solution having a pH of substantially 6 to 7, preferably 6.5. u NOW AJ.'.Li.'-. '90532 A syn/anti mixture of a compound of formula I which may be obtained can be separated into the corresponding syn and anti forms in the customary manner,, for example by recrystallisation or by chromatographical methods using a suitable solvent or solvent mixture.

The compounds of formulae I and II as well as the corresponding readily hWrolysable esters, readily hydrolysable ethers ana salts and the hydrates of same have antibiotic, especially bactericidal, activity./ They possess a broad spectrum of activity againsii gram-positive and gram-negative microorganisms, including 0-lactamase- -forming Stapfiylococci and various /3-lafctamase-forming / / gram-negat^ive bacteria such as, for example, Pseudomonas aerugino la, Haemophilus influenzal/^ Escherichia coli, Serratla marcescens and Proteus-^and Klebsiella species. ./ >rmu The compounds of formulae I and II as well as the corresponding readily hydrolysable esters, readily iers and hydrolysable ethers salts and the hydrates of same can be used for the treatment and prophylaxis of infectious diseases. A daily dosage of substantially 0.1 g to substantially 2 g is envisaged for adults. "The parenteral administration of the compounds provided by the present invention is especially preferred.

In order to demonstrate the antimicrobial activity of O the compounds provided by the present invention, the following representatives were tested: 190532 - 14 ~ A syn/anti mixture of the compound of formula I which may be obtained can be separated into the corresponding syn and anti forms in the customary manner, for example by recrystallisation or by chrcmatographical methods using a 5 suitable solvent or solvent mixture.

The compounds of formulae I and II as well as the corresponding readily hydrolysable asters / ethers and salts and the hydrates of same have antibiotic, especially bactericidal, activity. They possess a ]_0 broad 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, Pseudomonas aeruginosa, Haemophilus influenzae, Escherichia coli, 15 Serratia marcescens and Proteus and Klebsiella species.

The compounds of formulae I and II as well as the corresponding readily hydrolysable esters / ethers and salts and the hydrates of same can be used for the treatment and prophylaxis of infectious diseases. A daily dosage of substantially 0.1 g to substantially 2 g is envisaged for adults. The parenteral administration of the compounds provided by the present invention is especially preferred.

In order to demonstrate the antimicrobial activii 25 the compounds provided by the present invention, the/ following representatives were tested: Compound A: IS Z6 - (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)thiol -methyl_7-8-oxo-5-thia-l-azabicyclo[4.2.0]oct--2-ene-2-carboxylic acid.

Compound B: (6R,7R)-l-£~ 2-[2-(2-Chloroacetamido)-4-thia-zolyl]-2-(Z-methoxyimino)acetamido_/-3--/~1(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as--triazin-3-yl)thio]methyl_7-8-oxo-5-thia-l--azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, Activity in vitro: Minimum inhibitory concentration (ng/ml) A- ifT - *90532 A B Haemophilus influenzae strain 1 0.08 1.2 — strain 2 0.005 0.3 strain 3 0.005 0.16 strain 4 0.005 0.16 — strain 5 0.0025 0.08 w strain 6 0.0025 0.16 strain 7 0.0025 0.16 Klebsiella pneumoniae 1.2 Escherichia coli strain 1 0.02 0.16 strain 2 0.6 Proteus mirabilis strain 1 <0.01 0.08 strain 2 <0.01 0.16 Proteus vulgaris <0.01 0.16 Proteus rettgeri <0.01 0.16 Staphylococcus aureus strain ATCC 653 8 2.5 2.5 W Penicillin-resistant strain 2.5 Pseudomonas aeruginosa strain 1 0. 3 1.2 strain 2 >80 0 20 strain 3 2.5 40 strain 4 80 strain 5 80 strain 6 80 <*■ strain 7 80 Serratia marcescens 0.08 2.5 190532 Activity in vivo c, Groups of 5 mice are infected intraperitoneally with an aqueous suspension of Escherichia coli. The test substance is administered subcutaneously in physiological 5 sodium chloride solution three times, i.e. 1 hour, 2.5 hours and 4 hours, after the infection. The number of surviving animals is determined on the fourth day. Various dosages are administered and the dosage at which 50% of the test animals survive (CD^, mg/kg) is determined by interpolation.

Test substance A B CD50, mg/kg <0.005 0.16 Toxicity Test substance A B LD5q, mg/kg i.v. s. c. ' p.o. 250-500 >4000 >5000 250-500 2000-4000 >5000 The cephalosporin derivatives provided by the present invention can be used as medicaments, for example in the form of pharmaceutical preparations which contain them in 20 association with a compatible carrier material. This carrier material can be an organic or inorganic inert carrier material which is suitable for enteral or parenteral administration such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable a. 190 oils, polyalkyleneglycols, petroleum jelly etc. The pharmaceutical preparations can be made up in solid form (e.g. as tablets, drag<£es, suppositories or capsules) or in liquid form (e.g. as solutions, suspensions or emulsions). ■ 5 The pharmaceutical preparations may be sterilised and/or may contain adjuvants such as preserving, stabilising, wetting or emulsifying agents, salts for varying the osmotic pressure, anaesthetics or buffers. The pharmaceutical preparations can also contain other therapeutically valuable 10 substances. The compounds of formula I and their salts and hydrates are especially suitable for parenteral administration and for this purpose they are preferably made up in the form of lyophilisates or dry powders for dilution with customary agents such as water or isotonic sodium 15 chloride solution. The readily hydrolysable esters and readily hydrolysable ethers of the compounds of formula I and their salts or hydrates are also suitable for enteral administration. | 90 C ^ ^ - xr- The following Examples illustrate the process provided by the present invention: Example 1 Manufacture of the 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_7-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2--carboxylic acid. .3 g of (6R,7R) — 7—2-[2-(2-chloroacetamido)-4--thiazolyl]-2-(Z-methoxyimino)acetamido_7-3-/~~ [(2,5-dihydro--6-hydroxy-2-methy1-5-oxo-as-triazin-3-yl)thio]methy1_7~ 8--oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (fraction I, see hereinafter) are suspended in 150 ml of water together with 5 g of thiourea. While gassing well with nitrogen and stirring thoroughly the pH is adjusted to 6.8-7.0 with saturated sodium hydrogen carbonate solution, there being obtained an orange coloured solution. The pH of the solution is kept constant at 6.8 for 6 hours by adding sodium hydrogen carbonate solution by means of an autotitrator. Thereafter, a further 2.5 g of thiourea are added and the solution is stirred for a further 3 hours, the pH being kept at 6.8 by adding saturated sodium hydrogen carbonate solution. Thereafter, the red solution is stored overnight in a refrigerator, whereby it becomes darker. The pH of this solution is adjusted to 2.0-2.5 by adding & 190532 100% formic acid, whereby the substance separates out. The precipitate is filtered off under suction and washed with 100 ml of 10% formic acid. The mother liquor is discarded. The brownish material on the suction filter is suspended in 200 ml of water and the pH is adjusted to 7 with triethylamine, a brown solution being obtained. This solution is stirred with 2 g of active carbon for 30 minutes, the carbon is filtered off and the filtrate, which is still brown, is adjusted to pH 3.5 with 100% formic acid while stirring well. The substance which thereby precipitates out is filtered off under suction, washed with 50 ml of 10% formic acid and discarded. The dark yellow filtrate is adjusted to pH 2-2.5 with 100% formic acid, whereby the substance precipitates out. This precipitate is filtered off under suction, washed with ice-water and dried. For conversion into the disodium salt, the cephalosporin acid obtained is suspended in a mixture of 40 ml of acetone and 40 ml of water and treated with 20 ml of a 2-N solution of the sodium salt of 2-ethylcaproic acid in ethyl acetate. 50 ml of acetone are added to the thus-obtained orange coloured solution, whereby there separates out a brown resin which is separated off by filtration. The yellow filtrate is stirred for 30 minutes, whereby the disodium salt crystallises. The mixture is treated portionwise with 50 ml of acetone and stored overnight in a refrigerator. The crystallisate is filtered off under suction, washed successively with an acetone/water mixture (85:15), pure acetone and low-boiling petroleum ether and dried overnight at 40°C 1 90S in vacuo. The title substance is obtained in the form of beige crystals; ^a]^ = ""144° (c = 0.5 in water). The nuclear magnetic resonance spectrum and the microanalysis correspond to the structure indicated.

The (6R,7R)-7-/_ 2-[2-(2-chloroacetamido)-4-thiazolyl]- -2-(Z-methoxyimino)acetamido_7-3-/~[(2,5-dihydro-6-hydroxy--2-methyl-5-oxo-as-triazin-3-yl)thio]methyl_7-8-oxo-5-thia--1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid used as the starting material can be prepared as follows: -methoxyimino)-acetic acid are suspended in 240 ml of methylene chloride. 13.39 ml of triethylamine are added to this suspension, a light brown solution being obtained.

This solution is cooled to 0°-5°C and treated with 16.72 g of phosphorus pentachloride. The mixture is stirred/at 0°-5°C and for 20 minutes without cooling. The resulting yellow solution is evaporated at 35°C in vacuo. The evaporation residue is shaken twice with n-heptane and the latter is decanted off. The resinous residue is treated 20 with 240 ml of tetrahydrofuran and the undissolved triethylamine hydrochloride is filtered off. The yellow filtrate contains the acid chloride. 22.24 g of 2-(2-chloroacetamido-thiazol-4-yl)-2-(Z- for 5 minutes 22 g of (7R)-7-amino-3-desacetoxy-3-[(2,5-dihydro-6--hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]-cephalo-sporanic acid are suspended in a mixture of 300 ml of water e. 1 90532 ->r- and 150 ml of tetrahydrofuran. 2-N sodium hydroxide is ^ g\ added dropwise to the suspension with the aid of an auto- titrator while gassing well with nitrogen until a brown-red ) solution having a pH of 8 is obtained. This solution is 5 cooled to 0°-5°C and treated dropwise during 15 minutes with the solution of the acid chloride in tetrahydrofuran prepared as described in the preceding paragraph. Thereafter, the mixture is stirred at 25°C for 2.5 hours. The pH of the mixture is held constant at 8 by adding 2-N sodium 10 hydroxide. The almost black solution is freed from tetrahydrofuran at 40°C in vacuo. 100 ml of 2-N sulphuric acid are now added. The substance which thereby precipitates out is filtered off under suction, washed with water and filtered off well under suction. The moist brown material 15 on the suction filter is dissolved in 1.5 litres of acetone. The dark solution is filtered off through Hyflo from a small amount of dark undissolved material, treated with carbon, stirred for 30 minutes and again filtered through Hyflo. The orange-red filtrate is dried over sodium sulphate, con-20 centrated in vacuo and evaporated with ethyl acetate. A black resin thereby precipitates out. This resin is filtered off and discarded. The 2-phase filtrate which still contains water is subjected to azeotropic distillation three times with benzene at 40°C in vacuo. The substance which 25 thereby precipitates out is filtered off under suction and dried at 40°C in vacuo. This substance is stirred up twice with 1 litre of acetone each time, there remaining a brown resin which is discarded. The combined orange coloured « 1905 3 - •- acetone extracts are concentrated to ca 150 ml at 40°C in vacuo, a brown resin being filtered off and discarded. The filtrate is treated with 1 litre of ethyl acetate and concentrated at 40°C in vacuo. The substance which thereby 5 precipitates out is filtered off under suction, washed with ethyl acetate and then with ether [(6R,7R)[2-(2--chloroacetamido)-4-thiazolyl]-2-(Z-methoxyimino)acetamido_/--3-jT~[ (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-10 -2-carboxylic acid, fraction I; a beige, amorphous acid]. This fraction I can be used directly for the manufacture of the desired cephalosporin derivative.

The ethyl acetate mother liquor is concentrated extensively at 40°C in vacuo, diluted with ether and the 15 precipitated substance is filtered off under suction C(6R, 7R)-1~l_ 2- [2- (2-chloroacetamido) -4-thiazolyl] -2- (Z-methoxyimino) acetamido_7-3-j/ [(2,5-dihydro-6-hydroxy-2-methyl-5--oxo-as-triazin-3-yl)thio]methyl_7-8-oxo-5-thia-l-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid, fraction II; a 20 light beige amorphous acid, somewhat purer than fraction I according to thin-layer chromatography].

For the manufacture of the disodium salt, 3.5 g of the acid (fraction II) are dissolved in a mixture of 20 ml of acetone and 11 ml of water. The solution is treated 25 with 7 ml of a 2-N solution of the sodium salt of 2-ethyl-caproic acid in ethyl acetate, whereby the disodium salt (*>•*> 1 905 3 2 crystallises. A further 25 ml of acetone are now added fy? portionwise and the mixture is stored in a deep-freeze cabinet for 2 hours. Thereafter, the crystallisate is filtered off under suction, washed successively with 25 ml of an ice-cold acetone^water mixture (80:20), pure acetone and low-boiling petroleum ether and dried overnight at 40°C in a high vacuum. /There is obtained the disodium salt of (6R,7R)-7-/ 2-2-chloroacetamido)-4-thiazolyl]-2-(Z--methoxyimino) afcetamido_7~3-/—[(2,5-dihyaro-6-hydroxy-2-10 -methyl-5-oxo^as-triazin-3-yl)thi0]methyl_7-870X0-5-thia-l--azabicyclar[4.2.0] oct-2-ene-2-carboxylic aodfd in the form of // light ye]/low crystals; Ca^D = -142.7° /c = 1 in water).

The nuclear magnetic resonance spectrujn and the microanalysis correspond to the structur^indicated.

V Example 2 Manufacture of the podium salt of (6R,7R)-7-[2-(2--amino-4-thiazolyl) -2-6methoxyimino)acetarrd.do>8-oxo-3-/I (1,4, 5,6-tetrahydro-4-met$!yl-5,6-dioxo-as-triazin-3-yl)thio]-methyl_7-5-thia-l^azabicyclo[4.2.0]oct-2-ene-2-carboxylic 20 acid. 19 g of (6R,7R)-7-/ 2-[2-(2-chloroacetamido)-4-thiazolyl] -2-(methoxyimino)acetamido]-8-oxo-3-/ [(1,4,5,6--tetrahydro-4-methy1-5,6-dioxo-as-triazin-3-yl)thio]-methyl_7-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic 25 acid are suspended in 150 ml of water together with 9.5 g of *€ 19 now .;,:y!-y- zd i ~ ^ ~ thiourea. The pH is adjusted to 6.8 with 5% sodium hydrogen carbonate solution while gassing with nitrogen and stirring, there being obtained a yellow-orange solution. The pH of the solution is held constant at 6.8-7.0 for 6 5 hours by adding sodium hydrogen carbonate solution by means of an autotitrator. 100% formic acid is added to the orange coloured solution untM the pH is. 3.5. The precipitated material is filtered off under suction and washed with 100 ml of 1Q& formic acid. This material is 10 denoted as(l). The filtrate is adjusted to pH/2.5 by adding 100% formicyacid, whereby additional substance precipitates outy The mixture is held iiycin ice-bath for 1 hour, the precipitated substance is thenr filtered off and washed withyi. small amount of ice-w^er. This material is 15 denoted as fraction I. The aforementioned orange-brown materi is suspended in 25Cyinl of water. The sus- pensg^on is adjusted to pH 7 with 2-N sodium hydroxide, there being obtained an orange-thrown solution. Additional 100% formic acid is added toythis solution until the pH is 3.5. . 20 The material which thereby precipitates out is filtered off under suction and discarded. The filtrate is adjusted to pH 2.5 with 100% formic acid, whereby additional substance precipitates out. The mixture is held in an ice-bath for 1 hour, the precipitated substance is then filtered off under 25 suction and washed with a small amount of ice-water. This material is denoted as fraction II. Fractions I and II are suspended together in 500 ml of ethanol and evaporated in a rotary evaporator in order to remove water. After adding :'ncw 3ed u_ —1 - 1 9053 ether, the mixture is filtered under suction and the ^ Q\ Q,^>' a.T>v precipitate is washed successively with ether and low- -boiling petroleum ether. There is thus obtained the title substance in the form of a yellowish solid material which is 5 denoted as A. / The mother liquors apfa washings of fractions I and II are concentrated from a JTolume of ca 1.7 litres to 250 ml, the pH is adjusted to/2.5 with 100% formic acid and the solution is stored ^overnight in a refrigerator, whereby 10 further substanc^ crystallises. This is f/ltered off under suction and washed with a small amount oW water. The residue on^Oie suction filter is azeo^ropically distilled with ethanol. There is obtained sjzflid, almost colourless title ylubstance which is denoted^s B. B is purer than A 15 according to thin-layer chromatography, In order to obtain/pure title substance, the acid B is suspended in 150 ml of^methanol and treated while stirring with 10 ml of a 2-Nysolution of the sodium salt of 2-ethyl- -caproic acid in ^thyl acetate. After ca 10 minutes, there results a solution which is treated with 100 ml of ethanol.

The mixture is extensively concentrated at 40°C in vacuo.

The sodium salt precipitates out in amorphous form after adding ethanol. This salt is filtered off under suction, washed successively with ethanol and low-boiling petroleum ether and dried at 40°C in a high vacuum. There is obtained amorphous the.title substance in the form of an almost colourless/ powder; = -42.9° (c = 1 in water). w* XL lnicv • • . -2%"- 190532 The title substance exists as a Z/E mixture (90:10) o\ .\Ji according to the nuclear magnetic resonance spectrum. The microanalysis likewise agrees with the structure indicated.

The (6R,7R)-l-£~[2-(2-chloroacetamido)-4-thiazolyl]--2-(methoxyimino)acetamido_/-8-oxo-3-/~[(1,4,5,6-tetra- hydro-4-methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl 7-5- / -thia-1-azabicyclo[4.2.0]oct-2-qne-2-carboxylic acid used as the starting material can be prepared as follows: 44 g of (7R)-7-aiid<no-3-desacetoxy-3-[ (1,4 ,5 ,6-tetra-10 hydro-4-methy1-5,6-di6xo-as-triazin-3-yl)thio]-cephalo- sporanic acid arey^uspended in a mixture of 600^1 of water and 300 ml of tetrahydrofuran. 2-N sodium^hydroxide is / 7. added dropwise to the suspension with the/aid of an auto-titrator wnile gassing well with nitrogen until a brown 15 solutiipn having a pH of 7.8 is obtained. This solution is cooled to 0°-5°C and treated dr^giwise during 15 minutes with a solution of 2-(2-chloroacetamido-thiazol-4-yl)-2-(Z- // -methoxyimino)-acetic acid/chloride in tetrahydrofuran (prepared from 44.5 g of^the corresponding acid in a manner 20 analogous to that described in Example 1). Thereafter, the mixture is stirred at 25°C and pH 8 for 2.5 hours. The pH of the mixture is held constant at 7.8-8 by adding 2-N sodium hydroxide using an autotitrator. The dark solution is freed from tetrahydrofuran at 40°C in vacuo. Thereafter, 25 the solution is diluted with water to a volume of 2 litres. The pH is adjusted to 2 with 2-N sulphuric acid. The 1 ncv/ 28 substance which thereby precipitates out is filtered off under suction, washed with 1 litre of water and dried at 40°C in vacuo for 2 days. For purification, the dried substance is firstly dissolved in a mixture of 100 ml of water and 300 ml of acetone. The dark solution is diluted with acetone to a volume of 2/litres. The dark material which thereby precipitates/out is filtered off and discarded. The filtrate is treated with 1 litre of ethyl / . acetate and 1 litre or solvent is evaporated off at 40 C in vacuo. The soluti!on is now diluted with 2 litres of ethyl acetate. The beige-brown substance which thereby precipitates /ut is discarded. The filtrate is extensively concentratefu at 40°C in vacuo. The acid whd^ch thereby / ' /■ crystallises out is filtered off under s^tion. For recrystallisation, the acid is firstly dissolved in 800 ml of^methanol at reflux. The solu^on is cooled down to 25°C and filtered off from a small amount of orange coloured / substance. The yellow filtrate is stirred in an ice-bath for 1.5 hours, whereby the acid crystallises. The acid is j/ filtered off under suction, washed successively with methanol and low-boiling petroleum ether and dried at 25°C in vacuo. There is thus obtained the desired starting material in the form of beige crystals. The starting material exists as a Z/E mixture (75:25) according to the nuclear magnetic ,2C D resonance spectrum. [air, = -127.9° (c = 1 in dimethyl- formamide). <vv 1 90 %\ New . - v-':3-d1 Example 3 Manufacture of methylene-(6R,7R)-7-[2-(2-amino-4--thiazolyl)-2-(Z-methoxyimino)acetamido]— 3—{_/ [2,5-dihydro--2-methyl-5-oxo-6- [ (pivaloyloxy/methoxy] -as-triazin-3-yl] --thio_/methyl}-8-oxo-5-thia-lXazabicyclo[4.2.0]oct-2-ene-2--carboxylate pivalate. 1.85 g of the cephalosporin disodium salt manufactured as described in Example 1 are suspended in/So ml of dimethy 1-formamide and treated with 1.35 g of piydloyloxymethyl 10 iodide at 0°-5°C while gassing with ifitrogen. The mixture is stirred ax 0°-5°C for 30 minutes' and thereafter poured into 500^ml of ethyl acetate. y/vcie mixture is washed three times with water, twice with sodium hydrogen carbonate solution and finally again/with water. The solution is 15 dried over sodium sulph^xe and extensively concentrated at 35°C in vacuo. The >6itle substance precipitates out in amorphous form aft^r adding ether. This substance is filtered off unfter suction, washed with ether and low--boiling petroleum ether and dried at 25°C overnight in a 20 high vacuum. The title substance is obtained in the form of a beige amorphous powder. The nuclear magnetic resonance spectrum and-the microanalysis are in agreement with the structure indicated.

The following Examples illustrate pharmaceutical preparations containing the cephalosporin derivatives provided by the present invention: ■O J*a 10 " ' u n - NCVv ■•.£□ | Example A p-,\^ 0* Manufacture of dry ampoules for intramuscular administration: /' A lyophilisate of 1 g of the disodium salt of (6R,7R) -7- [2-(2-amino-4-thiazolyl)-2-(Z-me^hoxyimino)acetamido]-3- / [ (2 ,5-dihydro-6-hydroxy-2-mei±Lyl-5-oxo-as-triazin-3-yl) -thio]methyl_/-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2--carboxylic acid is prepared^ in the usual manner and filled into an ampoule. Prior jco the administration, the 10 lyophilisate is treated^with 2.5 ml of a 2% aqueou lidocaine hydrochloride solution.

Example B Interlocking gelatin capsules ea,dh containing the following ingredients are manufactured in the usual manner: ^Methylene-<6R,7R)-7-[2-(2-amlno-4- -thiazolyl)-2-(^-methoxyinumo)-acetamido]-3-{/ [2 ,5-dih^ro-2--methyl-5-oxo-6- [ (pivalo^yloxy)-methoxy] -as-triazin-3-wl] thio_7~ 20 methyl}-8-oxo-5-thia-L-azabicyclo- [4.2.0] oct-2-ene-2-ca»rboxylate pivalate / 500 mg Luviskol (water-s'Qiuble polyvinylpyrrolidone) 20 mg Mannitol 20 . mg Talc 15 mg Magnesium stearate 2 mg . ,5.5.7, mg

Claims (6)

1. WHAT WE CLAIM IS: Compounds of the general formula h h ch3on=c—conh- -ch2 s cooh ., in which X represents the/l,2,5,6--tetrahydro-2-methyl-5,6/aioxo-as--triazin-3-yl group, Jme 2,5-dihydro-6--hydroxy-2-methyl-5^-oxo-as-triazin-3-yl group or the 1, V, 5,6-tetrahyaro-4-methy1--5,6-dioxo-as^triazin-3-yl group, as well as readily hydrolysable esters, readily"hydrolysable y y ethers and saits of these compounds and hydrates of the compounds pi formula I and of their e§^€ers, ethers and salts.
2. 2. / Compounds of formula I given in claim 1, in syn-isomeric form or mixtures irj/which the syn-isomeric form predominates.
3. 3. ; Compounds of/formula I given in claim 1, wherein X represents the 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as--triazin-3-y1 group or the 2,5-dihydro-6-hydroxy-2-methyl-~5-oxo-as-triazin-3-yl group, as well as salts of these compounds and hydrates of these compounds and salts.
4. 4. Compounds of formula I given in claim 1,. wherein X represents the 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as- 190532 NOW AMH - 32:- -triazin-3-yl group, as well as salts of these compounds and hydrates of these compounds and salts.
5. 5. 1 (6R, 7R)-7-[2-(2-Amino-4--Uiiazolyl)-2- (Z-methoxyimino)- 1 /'■' acetamido]-3-[_ [ (2 ,5-dihydro-<6-hydroxy-2-methyl-5-oxo-as--triazin-3-yl)thio]methyl_7'-8-oxo-5-thia-l-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid as well as salts °f this compound and hydrates/-of this compound and salts. / /'
6. 6. Readily hydrolysable esters of the compounds of formula I set forth in any one of claims 1 to L as well as 10 salts of these esters and hydrates of these/esters and salts. / 15

   7. ^/Readily hydrolysable ethers the compounds of formula I set forth in any one of' claims 1 to 5 as well as salts of these ethers and hyda?cites of these ethers and salts.

   8. Pivaloyloxymeth^i esters of the comoounas of formula I / 1 set forth in any one of claims 1 to 5 'as'well as salts of / .1 these esters and hydrates of these esters and salts. 20 9.' Methylene-(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z- \ . _ -methoxyimino) acetamido] -3- {/_ [2 ,5-dihydro-2-methyl-5-oxo--6-[(pivaloyloxy)methcxy]-as-triazin-3-yl]thio_7methyl}-8--oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate pivalate as well as salts of this compound and -hydrates o] this' comDQund and salts. 190532 ,NCV.' /tVr^ - 33 -

   10. ! Compounds of the general formula ch3on=c conh n RHN ch2 s x cooh 10 in which X represents the 1, 2,5,6-tetra-hydro-2-metfiyl-5,6-dioxo-as-triazin-3-yl group, tMe. 2,5-dihydro-6-hydroxy-2-methyl--5-oxo./as-triazin-3-yl group or the 1,4,5^6--te-$£ahydro-4-methyl-5,6-dioxo-as-triafzin-3- group, R represents a cleavable protecting group and the carboxy/ group can be present in protected form. II

   11. | Compounds according to^laim 10, ,wherein X represents the 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl group or the 2,5-dihydpo-6-hydroxy-2-methyl-5-oxo-as--triazin-3-yl group. 15 12. (6R,7R)-7-/ 2-[2-(2-Chloroacetamido)-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--1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. 190532 WOW AMENDED - 34 :-

   13. i Compounds as set forth in any one of /claims 1 to suitable for use as pharmaceutically active substances

   14. (6R, 7R)-7-[2-(2-Amino-4-thiazol^l)-2-(Z-mey4oxyimino)-acetamido]-3-/ [ (2,5-dihydro-6-hyd^oxy-2-methy3^5-oxo-as- 5 -triazin-3-yl) thio]methyl__/-8-oxo-5-"thia-l-a^!abicyclo- [4 . 2 .0] oct-2-ene-2-carboxylic/^acia as well/as salts of this compound and hydrates of compound amd salts suitable for use as pharmaceutically a^tiv^ substances. I

   15. Compounds as set ifbrth in any on^ of claims 1 to 9 suitable for use as 20_pharmaceutically grctive substances for the treatment and prophylaxis of yfnfectious diseases.

   16. (6RJfR)-7-[2-(2-5mu.no-4-thiazolyl)-2-(Z-methoxyimino)-acetamido]-3-/ [(2,S/dihydro-6-hydroxy-2-methyl-5-oxo-as--triaj^.n-3-yl)thiMmethyl_/-8-oxo-5-thia-l-azabicyclo-25 C4y2-0]oct-2-en^-2-carboxylic acid as well as salts of this rompound and hydrates of this compound and salts suitable for / ' use as pharmaceutically active substances for the treatment and ' phrophyla6cis of infectious diseases. &QW AMENDED 190533 _ 35 IV. i A pharmaceutical preparation which contains a compound of 'the general formula H H CH3ON=C CONH- JH' COOH , wherein X represent/ the 1,2,5,^-tetrahydro- -2-methyl-5,6-dioxq/as-triazin^T-yl group, the 2,5-dihydro-6-hyaf-oxy-2-methVL-5-oxo-as- -triazin-3-yl jgfroup or the/1, 4 , 5 ,6-tetra- hydro-4-methjfl-5 ,6-dioxq/as-triazin-3-yl group, 10 or a readily ftydrolysable/ester, readily hydrolysable ether or salt of ;such a compound or a hydrate of a compound of formula. 3/or of an eater, ether or salt thereof. 18./ A pharmaceutical preparation according to claim 17 wt>icn contains/ (6r, 7R) -7- [2- (2-amino-4-thiazolyl) -2- ( Z-Amethoxyimino)acetamido]-3-/ [ (2,5-dihydro-6-hydroxy-2--methyl-5j'oxo-as-triazin-3-yl)thio]methyl_/-8-oxo-5-thia-l--azabicyclo[4.2.O]oct-2-ene-2-carboxylie acid or a salt of this/compound or 'a hydrate of this compound or of a salt thereof. 190532 BOW AMENDED - 36 _ 19 - < A pharmaceutical preparation solely for tiae treatment and jjf ■ n prophylaxis of infectious diseases whicly contains a/compound of the general formula ch3on=c—conh- 10 h h -N-. -CH' cooh , wherein X represeiyts the 1,2,6-tetra-hyaro-2-methyl-5,6Adioxo-as-t^iazin-3-yl group, the 2,5-§4hydro-6-hydtoxy-2-methyl-5--oxo-as-triazi£-3-yl groupf or the 1,4,5,6--tetrahydro-y4-methyl-5,/-dioxo-as-triazin--3-yl gro\ or a readily h/drolysableyfester, readily hydrolysable ether or salt of sylch a compound or a hydrate of a compound of formula I dr. of an esi^r, ether or salt thereof.

   20. iy pharmaceutical preparation according to claim 19 15 which/contains (STl,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z--methoxyimino) sfcetamido]-3-/—[(2,5-dihydro-6-hydroxy-2--,methyl-5-oxcAas-triazin-3-yl) thio]methyl_7-8-oxo-5-thia-l--azabicyclo'[4. 2.0] oct-2-ene-2-carboxylic acid or a salt of this compound or a hydrate of this compound or of a salt 180533 WOW AMENDED - 37 -

   21. A process for the manufacture of the cephalosporin derivatives set forth in any one of claims 1 to 9/ which process comprises (a) cleaving off the protecting group^R (and, if 5 desired, also a carboxy protecting group Jmich may be present) in a compound .of the general formula H H ch3on=c conh n rhn ca2 s x II 10 or , wherein X has the significance given in claim 1, R ^represents aycleavable protecting group anyr the carboxy' group can be present in projected form,. este 15 carboxy1: 0 for the 2nanufacture of a readily hydrolysable or ether ox a compound of formula I, subjecting a .ic aci/a or an enol of formula I to a corresponding esterification or etherification, or [c) for the manufacture of salts or hydrates of a compound of formula I or hydrates of said salts, converting 20 ascompound of formula I into a salt or hydrate or into a hydrate of said salts. 1S053 r. *30 - 38 - HOW AMENDED 22, A process for the manufacture of a compound according to claim 1, substantially as hereinbefore described with particular reference to ajfiy one of Examples 1 to 3.

   23. Compounds as claimed in cls&m 1, w &r prepared according to the process claimetyin claim : claim 22.

   24. Compounds as claimed An any one claims 2 to 9, whenever prepared according to the proj sss claimed in claim 21 or claim 22.

   25. A pharmaceutical prepara fon according to claim 17, substantially hereinbef^ described with particular reference to eitner of Examp, res A and B. atfcu i i"..c s day Oh 19 ^2. A. J. PARK & SON PER JJ S. AGENTS FOR THE APPLICANTS tyP. 1905 j 2 - 24 - crystallises. A further 25 ml of acetone are now added portionwise ana the mixture is stored in a deep-freeze cabinet for 2 hours. Thereafter, the crystallisate is filtered off under suction, washed successively with 25 ml 5 of an ice-cold acetone/water mixture (80:20), pure acetone and low-boiling petroleum ether and dried overnight at 40°C in a high vacuum. There is obtained the disodium salt of (6R,7R)-7-/ 2-[2-(2-chloroacetamido)-4-thiazolyl]-2-(Z--methoxyimino)acetamido_/-3-/ [(2,5-dihydro-6-hydroxy-2-10 -methyl-5-oxo-as-triazin-3-yl)thio]methyl_/-8-oxo-5-thia-1--azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in the form of light yellow crystals; = "142.7° (c = 1 in water). The nuclear magnetic resonance spectrum and the microanalysis correspond to the structure indicated. 19053 ' PS> ''"'I'.D - 25 - Example 2 Manufacture of methylene-(6R, 7R)-7-[2-(2-amino-4--thiazolyl) -2- (Z-methoxyimino) acetamido]-3-{/~[2 , 5-dihydro--2-methyl-5-oxo-6- [ (pivaloyloxy)methoxy] -as-triazin-3-yl] --thio_7niethyl}-8-oxo-5-thia-l-azabicyclo [4.2.0]oct-2-ene-2--carboxylate pivalate. 1.S5 g of the cephalosporin disodium salt manufactured as described in Example 1 are suspended in 50 ml of dimethyl forrnamide and treated with 1.35 g of pivaloyloxymethyl iodide at 0°-5°C while gassing with nitrogen. The mixture is stirred at 0°-5°C for 30 minutes and thereafter poured into 500 ml of ethyl acetate. The mixture is washed three times with water, twice with 5% sodium hydrogen carbonate solution and finally again with water. The solution is dried over sodium sulphate and extensively concentrated at 35°C in vacuo. The title substance precipitates out in amorphous form after adding ether. This substance is filtered off under suction, washed with ether and low--boiling petroleum ether and dried at 25°C overnight in a high vacuum. The title substance is obtained in the form of a beige amorphous powder. The nuclear magnetic resonance spectrum and the microanalysis are in agreement with the structure indicated. The following Examples illustrate pharmaceutical preparations containing the cephalosporin derivative^' provided by the present invention: t\ & 190532 * j-* p ^ Manufacture of dry ampoules for intramuscular administration: A lyophilisate of 1 g of the disodium salt of (6R,7R)-5 -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] me thy 1_/-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2--carboxylic acid is prepared in the usual manner and rilled into an ampoule. Prior to the administration, the 10 lyophilisate is treated with 2.5 ml of a 2% aqueous lidocaine hydrochloride solution. Example B Interlocking gelatin capsules each containing the following ingredients are manufactured in the usual manner: 15 20 25 - 26 - Example A Methylene-(6R, 7R) -7- [2- (2-amino-4--thiazolyl) -2- (^-methoxyimino) -acetamido]-3-{/ [2,5-dihydro-2--methyl-5-oxo-6-[(pivaloyloxy) -methoxy]-as-triazin-3-yl]thio_7~ methyl}-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylate pivalate 500 mg Luviskol (water-soluble polyvinylpyrrolidone) 20 mg Mannitol 20 mg Talc 15 mg Magnesium stearate 2 mg 1 9053 •'LED - 27 - WHAT WE CLAIM IS: 1 . A compound of the general formula h h ch3cn=c conh HoN COOH , in which X represents the 1,2,5,6--tetrahydro-2-methyl-5,6-dioxo-as-triazin--3-yl group or the 2,5-dihydro-6-hydroxy--2-methyl-5-oxo-as-triazin-3-yl group, as well as readily hydrolysable esters / ethers and salts of this compound and hydrates of the compound of formula I and of its esters / ethers and salts.

   2. Compounds of formula I given in claim 1, in syn- isomeric form or mixtures in which the syn-isomeric form predominates. 3 . (6R,7R)-7-[2-(2-Amino-4-thiazolyl) -2- (Z-methoxyimino) - acetamido] -3-/i (2 , 5-dihydro-6-hydroxy-2-methyl-5-oxo-as--triazin-3-y 1) thio] methyl7-8-oxo-5-thia-l-azabicyclo-[ 4 . 2.0]oct-2-ene-2-carboxylic acid as well as salts of this compound and hydrates of this compound and salts. 190532 r /} "ED - 28 -

   4. Readily hydrolysable esters / ethers of the compounds of formula I set forth in any one of claims 1 to 3 as well as salts of these esters / ethers and hydrates of these esters / ethers and salts.

   5. Methylene-(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z--methoxyimino)acetamido]— 3 — {/T 2,5-dihydro-2-methyl-5-oxo--6-[(pivaloyloxy)methoxy]-as-triazin-3-yl]thio_7methyl}-8--oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate pivalate as well as salts of this compound and hydrates of this compound and salts. . 6. Compounds of the general formula , in which X represents the 1, 2 , 5,6-tetra-hydro-2-methyl-5,6-dioxo-as-triazin-3-yl group or the 2,5-dihydro-6-hydroxy-2-methyl--5-oxo-as-triazin-3-yl group, R represents a cleavable protecting group and the carboxy group can be present in protected form. 190532 - 29 -

   7. (6R,7R)-7-/2-[2- (2-Chloroacetaraido) - 4-thiazolyl] --2- (Z-methoxyimino) acetamido?-3-/T (2 ,5-dihydro-6-hydroxy--2-methyl-5-oxo-as-triazin- 3-yl) thio] methyl7-8-oxo-5-thia--1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid.

   8. Compounds as set forth in any one of claims 1 .to 5 suitable for use as pharmaceutically active substances. 9 . (6R,7R)-7-[2-(2-£mino-4-thiazolyl) -2- (Z-methoxyimino) - acetamido] — 3 —/T (2 , 5-dihydro-6-hydroxy-2-methyl-5-oxo-as--triazin-3-yl)thio]methyl7-8-oxo-5-thia-l-azabicyclo-[4.2.0] oct-2-ene-2-carboxylic acid as well as salts of this compound and hydrates of this compound and salts suitable for use as pharmaceutically active substances.

   10. Compounds as set forth in any one of claims 1 to 5 suitable for use as pharmaceutically active substances for the treatment and prophylaxis of infectious diseases. 11 • (6R,7R)-7-[2- (2-Amino-4-thiazolyl) -2- (Z-methoxyimino) - acetamido] — 3 — /T (2 , 5-dihydro-6-hydroxy-2-methyl-5-oxo-as--triazin-3-yl) thio] methyl7-8-oxo-5-thia-l-azabicyclo-[4 . 2.0] oct-2-ene-2-carboxylic acid as well as salts of this compound and hydrates of this compound and salts suitable for use as pharmaceutically active substances for the treatment and prophylaxis of infectious diseases. 1905 SAP> dr.* - ,-D 30 -

   12. A pharmaceutical preparation which contains a compound of the general formula h h ch3on=c conh COOH , wherein X represents the 1,2,5,6-tetra-hydro-2-methyl-5,6-dioxo-as-triazin-3-yl group or the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group, or a readily hydrolysable ester / ether or salt of such a compound or a hydrate of a compound of formula I or of an ester / ether or salt thereof.

   13. A pharmaceutical preparation according to claim 12 which contains (6R,7R)-7-[2- (2-amino-4-thiazolyl)-2-(Z-methoxyimino) acetamido] -3-/i (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 or a salt of this compound or a hydrate of this compound or of a salt thereof. 190532 j. i :D - 31 -

   14. A pharmaceutical preparation solely for the treatment and prophylaxis of infectious diseases which contains a compound of the general formula , wherein X represents the 1,2,5,6-tetra-hydro-2-methyl-5,6-dioxo-as-triazin-3-yl group or the 2,5-dihydro-6-hydroxy-2-methyl--5-oxo-as-triazin-3-yl group, or a readily hydrolysable ester / ether or salt of such a compound or a hydrate of a compound of formula I or of an ester / ether or salt thereof.

   15. A pharmaceutical preparation according to claim 14 which contains (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]methyl7-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid or a salt of this compound or a hydrate of this compound or of a salt thereof. 19053 '.DEI - 32 -

   16. A process for the manufacture of the cephalos porin derivatives set forth in any one of claims 1 to 5, which process comprises (a) cleaving off the protecting group R (and, if desired, also a carboxy protecting group which may be present) in a compound of the general formula H H ch30n=c conh COOH II , wherein X has the significance given in claim 1, R represents a cleavable protecting group and the carboxy group can be present in protected form, or (b) for the manufacture of a readily hydrolysable ester / ether of the compound of formula I, subjecting same to a corresponding esterification / etherification, or (c) for the manufacture of salts or hydrates of the compound of formula I or hydrates of said salts, converting the compound of formula I into a salt or hydrate or into a hydrate of said salts. 90532 ED - 33 -

   17. A process for the manufacture of a compound according to claim 1, substantially as hereinbefore described with particular reference to either of Examples 1 and 2.

   18. Compounds as claimed in claim 1, whenever prepared according to the process claimed in claim 16 or claim 17. 1-9. Compounds as claimed in any one of claims 2 to 5, whenever prepared according to the process claimed in claim 16 or claim 17.

   20. A pharmaceutical preparation according to claim 12, substantially as hereinbefore described with particular reference to either of Examples A and B. OATED THIS DAY OF ^ ^ A. J, PARXfyA SON per AGENTS FOR "THE APfllCANTS r/V & \X<