CH637399A5 - 3,7-Disubstituted 3-cephem-4-carboxylic acid compounds, and antibacterial agents containing them - Google Patents

Abstract

The invention relates to compounds of the formula: <IMAGE> their salts and pharmaceutical preparations containing them. In the above formula, R<1> denotes thiadiazolyl or isothiazolyl, R<2> denotes hydrogen or lower alkyl, R<3> denotes carboxyl or esterified carboxyl, R<4> denotes hydrogen, acyloxy, or a heterocyclic ring which is bound via a thio group, and R<5> denotes hydrogen or lower alkoxy. The compounds, and, in particular, among these the syn isomers, in which syn denotes the arrangement with regard to the acid amide group, are notable for a strong antibacterial effect. They can be used for treating infectious diseases in humans and animals.

Description

       

  
 

** WARNING ** beginning of DESC field could overlap end of CLMS **. 

 



   PATENT CLAIMS
1.    3,7-disubstituted-3-cephem-4-carboxylic acid compounds, characterized by the general formula
EMI1. 1
 in which mean:
R 'thiadiazolyl or isothiazolyl, each of which may have one or more substituents,
R2 is hydrogen or lower alkyl,
R3 carboxy or esterified carboxy,
R4 is hydrogen, acyloxy or a hetero ring bonded via a thio group, which may have one or more substituents, and
R5 is hydrogen or lower alkoxy, and their salts. 



   2nd  Compounds according to claim 1, characterized in that in the formula (I) Rl isothiazolyl or thiadiazolyl, which is optionally substituted by a lower alkyl, and R4 is hydrogen, acyloxy or a hetero ring bonded via a thio group, which is optionally substituted by lower alkyl or di ( lower) alkylamino (lower) alkyl is substituted. 



   3rd  Syn isomers of the compounds of claim 2, wherein syn is the arrangement with respect to the acid amide group. 



   4th  Compounds according to claims 1 to 3, characterized in that R3 is carboxy. 



   5.  Compounds according to claims 1 to 4, characterized in that R2 denotes lower alkyl. 



   6.  Compounds according to Claim 5, characterized in that the R1 thiadiazolyl, which is optionally substituted by a lower alkyl, and R4 is a hetero ring bonded via a thio group, which is optionally substituted by a lower alkyl or a di (lower) alkylamino (lower) alkyl, mean. 



   7.  Compounds according to Claim 6, characterized in that R4 contains an unsaturated 5-membered monocyclic hetero ring bonded via a thio group, which contains four nitrogen atoms with a lower alkyl or a di (lower) alkylamino (lower) alkyl or else one sulfur atom and two nitrogen atoms, means. 



   8th.  Compounds according to claim 7, characterized in that R4 is tetrazolylthio which is substituted by a lower alkyl or a di (lower) alkylamino (lower) alkyl, or thiadiazolylthio. 



   9.  A compound according to claim 8, characterized in that Rl is thiadiazolyl and R4 is tetrazolylthio which is substituted by a lower alkyl or a (di (lower) alkylamino (lower) alkyl). 



   10th  Antibacterial agent, characterized in that it contains as active ingredient a 3,7-disubstituted 3-cephem-4-carboxylic acid compound according to claim 1 or a pharmaceutically acceptable salt thereof. 



   The invention relates to new 3,7-disubstituted-3-cephem4-carboxylic acid compounds and their salts, in particular their pharmaceutically acceptable salts, which have antimicrobial activity, and pharmaceutical compositions containing them or 



  antibacterial agents that can be used for the therapeutic treatment of infectious diseases in humans and animals. 



   An object of the present invention is to provide new 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and their salts, especially their pharmaceutically acceptable salts, which are highly effective against a number of pathogenic microorganisms. 



   The aim of the invention is also to provide new pharmaceutical compositions which contain as active ingredient at least one of the 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and / or their pharmaceutically acceptable salts and which are used for the treatment of pathogens Bacteria can be used in humans and animals for infectious diseases. 



   Cephalosporin compounds were already known which carry an acetamido group in the 7-position, the 2-position of which is substituted by an etherified oxyimino group and a heterocyclic group (DE-OS 2 223 375) or  which are substituted in the 7-position by a 2-alkoxyimino-2- (2-aminothiazol-4-yl) acetamido group (DE-OS 2 556 736). 



   The 3,7-disubstituted-3-cephem-4-carboxylic acid compounds forming the subject of the invention are new and they can be represented by the general formula:
EMI1. 2nd
 in which mean:
R1 thiadiazolyl or isothiazolyl, each of which may have one or more substituents,
R2 is hydrogen or lower alkyl,
R3 carboxy or esterified carboxy,
R4 is hydrogen, acyloxy or a hetero ring bonded via a thio group, which may have one or more substituents, and
R5 is hydrogen or lower alkoxy. 



   The 3, 7-disubstituted-3-cephem-4-carboxylic acid compounds of formula (I) can be prepared by conventional methods as used in the field of cephalosporins, which can be represented by the following reaction scheme:



  Procedure I
EMI2. 1
 (11) or its reactive derivative on the amino group or a salt thereof (III) or its reactive derivative on the carboxy group or a salt thereof (I) or a salt thereof. Method 2
EMI2. 2nd
 (IV) (Ia) or a salt thereof or a salt thereof in which R 1, R 2, R 3, R 4 and R 5 each have the meanings given above, R 2 is hydrogen, lower alkyl or a hydroxyl protective group and R 3 is protected carboxy. 



   The starting compounds of formulas (III) and (IV) are also new and can be prepared by methods which can be represented by the following reaction scheme:
EMI2. 3rd
  
EMI3. 1
 wherein Rl has the meanings given above, R2 ,, lower alkyl, R2 is a hydroxy protecting group, R5, an amino protecting group and Z is protected carboxy. 



   The starting compound of formula (IV) can be prepared according to process 1 explained above. 



   In the present case, the following applies to the compounds of the formulas (I) and (Ia) according to the invention and to the starting compounds of the formulas (III), (IIIa) to (IIId) and (IV) and to the other compounds ( IV) ', (V), (VII), (VIII), (X) and (XI) that all these compounds also include the syn isomer, the anti isomer and a mixture thereof.  With regard to the compounds (I) and (Ia) according to the invention, among the syn isomers thereof there is a geometric isomer with the group of the formula
EMI3. 2nd
 and under the anti isomer the other geometric isomer with a group of the formula
EMI3. 3rd
 where Rl and R2 each have the meanings given above to understand. 

  Also in the starting compounds and in the other compounds, the syn and anti isomers thereof are represented by the same geometric configuration as the compound according to the invention. 



   Suitable pharmaceutically acceptable salts of the 3,7-disubstituted-3-cephem-4-carboxylic acid compounds of the formula (I) according to the invention include non-toxic salts, e.g. B.  Metal salts such as an alkali metal salt (e.g. a sodium, potassium salt and the like. ) and an alkaline earth metal salt (e.g. a calcium, magnesium salt and the like. ), an ammonium salt, an organic amine salt (e.g. B.  a trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, N, N'-dibenzylethylenediamine, diethanolamine salt and the like. ), an organic acid salt (e.g. B.  a maleate, lactate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate and the like. ), an inorganic acid salt (e.g. B.  a hydrochloride, hydrobromide, sulfate, phosphate and the like. ) or a salt with an amino acid (e.g. B. 



  Arginine, aspartic acid, lysine, glutamic acid and the like. ) and the like 



   In the above and following description and in the patent claims, the examples and explanations given for the various definitions within the scope of the invention are defined as follows:
The expression down or   low stands for a radical which, unless otherwise stated, has 1 to 6 carbon atoms. 

 

   Suitable examples of thiadiazolyl are 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and 1,3,4-thiadiazolyl. 



   The thiadiazolyl and isothiazolyl for Rl can one or more, in particular one or two, suitable substituents, such as. B.  lower alkyl, halogen, hydroxy, amino, protected amino or the like.  exhibit. 



   Suitable protected amino groups include an acylamino group and an amino group which are protected by a conventional protecting group other than the acyl group such as e.g. B. 



  Benzyl, diphenylmethyl, trityl or the like. , is protected.   



   Suitable lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. -Butyl, pentyl, hexyl and the like  and preferably those with 1 to 4 carbon atoms, especially those with 1 to 2 carbon atoms.  Suitable halogen atoms include chlorine, bromine, fluorine and iodine. 

  Examples of esterified carboxy groups are: lower alkyl esters (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, t-pentyl, hexyl, 1-cyclopropyl ethyl ester and the like . ); lower alkenyl esters (such as vinyl, allyl esters and the like. ); lower alkynyl esters (such as ethynyl, propynyl esters and the like. ); a mono (or di or tri) halogen (lower) alkyl ester (such as 2-iodoethyl ester, 2,2,2-tri-chloroethyl ester and the like. ); lower alkanoyloxy (lower) alkyl esters (such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl, pivaloyloxymethyl, 2-acetoxyethyl, 2-propionyloxyethyl and the like. );

   lower alkanesulfonyl (lower) alkyl esters (such as 2-mesyl ethyl ester and the like. ); Ar (lower) alkyl esters, preferably a mono (or di or tri) phenyl (lower) alkyl esters, which may have one or more suitable substituents (such as a benzyl, 4-methoxybenzyl, 4-nitrobenzyl, phenethyl, trityl -, Diphenylmethyl, diphenylethyl, bis (methoxyphenyl) methyl, 3,4-dimethoxybenzyl, 4-hydroxy-3,5-di-tert. -butylbenzyl ester and the like ); Aryl esters, which may have one or more suitable substituents (such as a phenyl, tolyl, tert. Butylphenyl, xylyl, mesityl, cumenyl ester and the like. ) and the like 



   In particular, preferred examples of esterified carboxy groups can be: lower alkoxycarbonyl having 2 to 7 carbon atoms (such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, 1-cyclopropylethoxy). ) and preferably one with 2 to 4 carbon atoms; or diphenyl (lower) alkoxycarbonyl having 14 to 19 carbon atoms (such as diphenylmethoxycarbonyl, diphenylethoxycarbonyl and the like. ) and preferably one with 14 to 16 carbon atoms. 



   Suitable acyl radicals in the terms acylamino and acyloxy as mentioned above include carbamoyl, in which the amino function can be protected, an aliphatic acyl group and an acyl group which contains an aromatic or heterocyclic ring.  Suitable examples of such an acyl group are lower alkanoyl (such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl and the like. ) and preferably one with 1 to 3 carbon atoms; lower alkoxycarbonyl (such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropyl-ethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl and the like. , and preferably one having 2 to 5 carbon atoms;

   lower alkanesulfonyl (such as mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl and the like. ); Arenesulfonyl (such as benzenesulfonyl, tosyl and the like. ); Aroyl (such as benzoyl, toluoyl, naphthoyl, phthaloyl, indancarbonyl and the like. ); Ar (lower) alkanoyl (such as phenylacetyl and the like. ) and the like  The acyl radical mentioned above can have one or two suitable substituents, such as. B.  Halogen (such as chlorine, bromine, iodine or fluorine), hydroxy, cyano, nitro, lower alkoxy (such as methoxy, ethoxy, propoxy, isopropoxy and the like. ), lower alkyl (such as methyl, ethyl, propyl, isopropyl, butyl and the like. ), lower alkenyl (such as vinyl, allyl and the like. ), Aryl (such as phenyl, tolyl and the like. ) or the like , exhibit. 



   Suitable examples of the acyl having one or more of these substituents are preferably halogen (lower) alkanoyl (such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl and the like. ), especially one with 2 to 3 carbon atoms and the like. 



   A suitable protecting group for amino in the above acyl group (e.g. B.  Carbamoyl) is preferably e.g. B.  Acyl such as halogen (lower) alkanoyl (e.g. chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl and the like. ) or the like 



   The hetero ring bonded via a thio group, which may have one or more suitable substituents, is to be understood as a saturated or unsaturated, monocyclic or polycyclic heterocyclic group which has at least one heteroatom, e.g. B.  an oxygen, sulfur, nitrogen atom and the like. , contains.  Particularly preferred examples of the heterocyclic group are the following heterocyclic groups: an unsaturated 3- to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, such as. B. 

  Pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (such as 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2, 3-triazolyl and the like. ), Tetrazolyl (such as 1H-tetrazolyl, 2H-tetrazolyl and the like. ) and the like ; a saturated 3- to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, such as. B.  Pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl and the like. , an unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atoms, such as. B.  Indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl and the like. ; an unsaturated 3- to 8-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as. B. 

  Oxazolyl, isoxazolyl, oxadiazolyl (such as 1,2,4 oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl and the like. ) and the like ; a saturated 3- to 8-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as. B.  Morpholinyl and the like ; an unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, e.g. B. 



  Benzoxazolyl, benzoxadiazolyl and the like; an unsaturated 3- to 8-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as. B.  Thiazolyl, thiadiazolyl (such as 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl and the like. ) and the like ; a saturated 3- to 8-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as. B.    Thiazolidinyl and the like ; an unsaturated 3- to 8-membered heteromonocyclic group containing a sulfur atom, such as. B.  Thienyl and the like ; an unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, e.g. B. 



  Benzothiazolyl, benzothiadiazolyl and the like. , and the like. ; wherein the heterocyclic group may have one or more, preferably one or two suitable substituents, such as. B.  lower alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl and the like. ), lower alkenyl (such as vinyl, allyl, butenyl and the like. ), Aryl (such as phenyl, tolyl and the like. ), Halogen (such as chlorine, bromine, iodine or fluorine), amino, (di (low) alkylamino (low) alkyl (such as dimethylaminomethyl, dimethylaminoethyl, diethylaminopropyl, diethylaminobutyl and the like. ) or the like 

 

   Suitable hydroxyl and amino protecting groups can each preferably be the acyl radical explained above. 



   Suitable lower alkoxy can include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, hexyloxy and the like. , preferably one with 1 to 4, in particular one with 1 to 2 carbon atoms. 



   Preferred embodiments of the compound of formula (I) are as follows:
A preferred embodiment of Rl is thiadiazolyl (especially 1, 2,3-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4 thiadiazolyl and the like. ), the lower alkyl (preferably methyl, ethyl and the like. ) may have, or isothiazolyl; a preferred embodiment for R2 is hydrogen or lower alkyl (preferably methyl, ethyl and the like. ); a preferred embodiment for R3 is carboxy or diphenyl (lower) alkoxycarbonyl;

   a preferred embodiment for R4 is hydrogen, acyloxy (preferably lower alkanoyloxy (such as acetoxy and the like. ) or carbamoyloxy), thiadiazolylthio (preferably 1,3,4 thiadiazolylthio), the lower alkyl (preferably methyl, ethyl and the like. ) may have, or tetrazolylthio (preferably 1H-tetrazolylthio) with lower alkyl (preferably methyl, ethyl and the like. ) or di (lower) alkylamino (lower) alkyl; and a preferred embodiment for R5 is hydrogen or lower alkoxy (preferably methoxy and the like. ). 



   The processes for the preparation of the compounds (I) and (Ia) according to the invention are explained in more detail below. 



   Procedure I
The compound (I) of the present invention can be prepared by reacting the compound (II) or its reactive derivative on the amino group or a salt thereof with the compound (III) or its reactive derivative on the carboxy group or a salt thereof, and if so Compound obtained on the hydroxy in its hydroxyimino group has a protective group, subsequent removal of the protective group from the compound thus obtained to form a compound (I) in which R2 is hydrogen. 



   Suitable reactive derivatives on the amino group of the compound (II) include imino derivatives of the Schiff base type or their tautomeric derivatives of the enamine type which are obtained by reacting the compound (II) with a carbonyl compound (such as aldehyde, ketone and the like. ) are formed, and isocyanate; a silyl derivative which is formed by reacting the compound (II) with a silyl compound (e.g. B.  Bis (trimethylsilyl) acetamide, trimethylsilylacetamide and the like. ); a derivative formed by reacting the compound (II) with phosphorus trichloride or phosgene, and the like. 



   Suitable salts of compound (II) include an acid addition salt such as. B.  an organic acid salt (such as an acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate and the like. ) or a salt of an inorganic acid (e.g. B.  a hydrochloride, hydrobromide, sulfate, phosphate and the like. ); a metal salt (e.g. B.  a sodium, potassium, calcium, magnesium salt and the like. ); an ammonium salt; an organic amine salt (e.g. B.  a triethylamine, dicyclohexylamine salt and the like. ) and the like 



   Suitable reactive derivatives on the carboxy group of the compound (III) include an acid halide, an acid anhydride, an activated amide, an activated ester and the like.  Suitable examples are an acid chloride; an acid azide; a mixed acid anhydride with an acid such as e.g. B.  substituted phosphoric acid (such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid and the like. ), Dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkyl carbonic acid, an aliphatic carboxylic acid (such as pivalic acid, pentanoic acid, isopentanoic acid, 2-ethyl butyric acid or trichloroacetic acid and the like. ) or an aromatic carboxylic acid (such as benzoic acid and the like. ); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole;

   an activated ester (e.g. B.  a cyanomethyl, methoxymethyl, dimethylaminomethyl [(CH3) 2N + = CH -] -, vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, mesylphenyl, phenylazophenyl, phenylthioester , a p-nitrophenylthioester, p-cresylthioester, carboxymethylthioester, pyranyl, pyridyl, piperidyl, 8-quinolylthioester or an ester with N, N-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide , N-hydroxyphthalimide or 1-hydroxy-6-chloro-1H-benzotriazole and the like.  These reactive derivatives can, if desired, be selected from those given above depending on the kind of the compound (III) used. 



   The salts of compound (III) can be salts with an inorganic base, e.g. B.  alkali metal salts (such as sodium or potassium salt) or an alkaline earth metal salt (e.g. B.  a calcium or magnesium salt) or a salt with an organic base such as trimethylamine, triethylamine, dicyclohexylamine or the like.  act. 



   The reaction of the compound (II) with the compound (III) is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N dimethylformamide, pyridine or any other organic solvent, which does not adversely affect the reaction.  Among these solvents, the hydrophilic solvents can be used mixed with water. 



   When the compound (III) is used in the free acid form or in the form of a salt in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as e.g. B.  a carbodiimide compound (such as N, N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N '- (4-diethylaminocyclohexyl) carbodiumid, N, NN, N'-diethylcarbodiimide, N, N'- Diisopropyl carbodiimide, N-ethyl-N '- (3-dimethylaminopropyl) carbodimide and the like. ), N, N'-carbonylbis- (2-methylimidazole), pentamethylene ketone-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, alkoxyacetylene, 1-alkoxy-1-chloroethylene, trialkylphosphite, ethylpolyphosphate, isopropylpolyphosphate, phosphoryl chloride oxychloride, phosphoryl chloride oxychloride , Triphenylphosphine,

   N-ethylbenzisoxazolium salt, N-ethyl-5-phenyi-isoxalium-3'-sulfonate, 1- (p-chlorobenzenesulfonyloxy) -6-chloro-lH-benzotriazole, of the Vilsmeier reagent (such as (chloromethylene) dimethylammonium chloride, a compound which by reacting dimethylformamide with phosphorus oxychloride and the like.  is formed) or the like.  carried out. 



   The reaction can also in the presence of an inorganic or organic base, such as. B.  an alkali metal bicarbonate, alkali metal carbonate, a tri (lower) alkylamine, pyridine, N- (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine, N, N-di (lower) alkylaniline or the like.  be performed.  If the base or condensing agent is liquid, it can also be used as a solvent.  The reaction temperature is not critical and the reaction is usually carried out under cooling or at ambient temperature. 

 

   In the reaction described, even if the compound (III) in which R2 represents a hydroxy protecting group is used as the starting compound, the compound (I) in which R2 represents hydrogen can occasionally be isolated from the reaction mixture depending on the kind of Hydroxy protecting group, the reaction conditions and the like. 



   If the compound obtained in this process has a hydroxy protecting group on the hydroxy in the hydroxyimino group, this protecting group is removed by a conventional method (e.g. B.  by hydrolysis and the like ) eliminated to form compound (I), in which R2 means hydrogen.  That is, the elimination of the protecting group is usually carried out, for example, using a method in which an acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid and the like. ) or a base, e.g. B.  an inorganic base such as an alkali metal hydroxide (such as sodium hydroxide, potassium hydroxide and the like. ), an alkali metal bicarbonate (such as sodium bicarbonate, potassium bicarbonate and the like. ) or an alkali metal carbonate (such as nitrate carbonate, potassium carbonate and the like. ), an organic base, such as. B. 

   an alkali metal alkylate (such as sodium ethylate, sodium ethylate and the like. ), a trialkylamine (such as trimethylamine, triethylamine and the like. ), Triethanolamine, N, N-dimethylaniline, N, N-dimethylbenzylamine, N-methylmorpholine or pyridine, or an elimination reaction which is carried out using silica gel, basic or acidic aluminum oxide, a basic or acidic ion exchange resin, thiourea, trifluoroacetic acid / Anisole, copper / dimethylformamide, zinc / dimethylformamide, zinc / acetic acid, zinc / formic acid, trifluoroacetic acid / zinc and the like  is carried out.  The elimination reaction is usually carried out in water, in a hydrophilic solvent or in a mixture thereof.  The reaction temperature is not critical and the reaction is preferably carried out at ambient temperature or with cooling. 



   In this process, partial or almost complete isomerization between the syn and anti geometry of compound (III) may occur during its activation process or during its reaction with compound (II) (i.e. H. 



  in acylation) occur depending on the environmental conditions, such as. B.  the reaction conditions or the like  In general, such isomerization tends to equilibrate towards the more stable anti-geometry.  With such a chemical behavior of the compound (III) in the case of the selective preparation of the syn isomer of the compound (I) according to the invention, it should be noted in good yield that it is essential to use the syn isomer of the compound (III) as the starting compound and select the reaction conditions suitable for the selective preparation of the syn isomer in good yield. 

  For example, for this purpose the acylation reaction in this process is preferably carried out in such a way that the compounds (II) and (III) in the presence of a condensing agent such as. B.  a Vilsmeier reagent and the like , and under reaction conditions, such as. B.  about neutral conditions. 



   Procedure 2
The compound (Ia) according to the invention or a salt thereof can be prepared by eliminating the carboxy protective group from the compound (IV) or a salt thereof.  With regard to suitable salts of the compound (IV), reference is made to the exemplary acid addition salts given above for the compound (II).  In the aforementioned elimination reaction, all conventional methods that can be used to eliminate the carboxy protecting group, such as e.g. B.  hydrolysis, reduction and the like.  If the carboxy protecting group is an ester, it can be eliminated by hydrolysis.  The hydrolysis is preferably carried out in the presence of a base or an acid.  Suitable bases include inorganic bases and organic bases as set forth in Process 1 above. 



   Suitable acids include an organic acid (such as formic acid, acetic acid, trifluoroacetic acid, propionic acid and the like. ) and an inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like. ).  Trifluoroacetic acid can be used in the presence of anisole. 



   The hydrolysis is usually carried out in an organic solvent, in water or in a mixture thereof.  The reaction temperature is not critical and can be selected appropriately depending on the type of carboxy protecting group and the elimination process used. 



   The reduction is carried out similarly to the method (D) mentioned below in the part of the preparation of the starting compound (III). 



   Some processes for the preparation of the starting compound (III) are explained below. 



   Method (A): (1V) "(V) and (X) + (XI)
Compounds (V) and (XI) can each be prepared by alkylating compounds (IV) 'and (X). 



   The alkylating agent that can be used in these alkylation reactions can include: (di (lower) alkyl sulfate (such as dimethyl sulfate, diethyl sulfate, and the like. ), Diazo (low) alkane (such as diazomethane, diazoethane and the like. ), Lower alkyl halide (such as methyl iodide, ethyl iodide and the like. ), Lower alkyl sulfonate (such as methyl p-toluenesulfonate and the like. ) and the like 



   The reaction in which di (lower) alkyl sulfate, lower alkyl halide or lower alkyl sulfonate is used is typically carried out in a solvent such as water, acetone, ethanol, ether, ethyl acetate, dimethylformamide or in any other solvent which does not adversely affect the reaction. carried out and it is preferably in the presence of a base, such as. B.  one of the above-mentioned inorganic or organic bases.  The reaction temperature is not critical and the reaction is usually carried out with cooling to about the boiling point of the solvent.  When using diazoalkane, the reaction is usually carried out in a solvent such as ether, tetrahydrofuran or the like. , carried out. 

  The reaction temperature is not critical and the reaction is usually carried out under cooling or at ambient temperature. 



     Method (B): (V) + (V) (V1i)
The compound (VII) can be prepared by reacting the compound (V) with the compound (VI). 



   The reaction is usually carried out in a solvent such as. B.  an alcohol (such as methanol, ethanol and the like. ), Chloroform, water or in any other solvent which does not adversely affect the reaction.  The reaction temperature is not critical and the reaction is usually carried out at ambient temperature or with heating. 



  Method (C): (VII) (VIII)
The compound (VIII) can be prepared by reacting the compound (VII) with a sulfurizing agent. 



   Suitable sulfurizing agents include conventional sulfurizing agents that can sulfurize an active methylene group, such as. B.  Sulfur, ammonium sulfide, sulfur dihalide (such as sulfur dichloride, sulfur dibromide and the like. ), Thionyl halide (such as thionyl chloride, thionyl bromide and the like. ) or the like  The reaction can be carried out with or without a solvent and, for example, benzene, methylene chloride or any other solvent which does not adversely affect the reaction can be used as the solvent. 

 

  The reaction temperature is not critical and the reaction is usually carried out at ambient temperature, with heating or with heating. 



  Method (D): (Vlll) + (llla), (Xl) + (lll) b) and (Xll) ¯ (XIII)
Compounds (purple), (IIIb) and (XIII) can be prepared by removing their carboxy protecting group from compounds (VIII), (XI) and (XII), respectively.  In this elimination reaction, all conventional methods, such as. B.  hydrolysis, reduction and the like. , be applied. 



   If the protected carboxy group is an ester, the protecting group can preferably be eliminated by hydrolysis.  The hydrolysis is preferably carried out in the presence of a base or an acid.  Suitable bases include inorganic bases and organic bases, such as. B.  an alkali metal (such as sodium, potassium and the like. ), an alkaline earth metal (such as magnesium, calcium and the like. ), a hydroxide or a carbonate or a bicarbonate thereof, a trialkylamine (such as trimethylamine, triethylamine and the like. ), Picoline, 1,5-diazabicyclo [4th 3rd 0] -non-5-ene, 1,4-diazabicyclo [2nd 2nd 2] octane, 1,8-diazabicyclo [S. 4th 0] -undecen-7 or the like. 

  Suitable acids include an inorganic acid (such as formic acid, acetic acid, propionic acid, trifluoroacetic acid and the like. ) and an inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like. ). 



   The reaction is usually carried out in a solvent such as water, an alcohol (such as methanol, ethanol and the like. ), a mixture thereof or in any other solvent which does not adversely affect the reaction. 



  A liquid base or a liquid acid can also be used as the solvent.  The reaction temperature is not critical and the reaction is usually carried out with cooling to heating. 



   The reduction can preferably be used to eliminate protective groups such as e.g. B.  2-iodoethyl, 2,2,2 trichloroethyl or the like.  The reduction method applicable to the elimination reaction can be, for example, the reduction using a combination of a metal (such as zinc, zinc amalgam and the like). ) or a salt of a chromium compound (such as chromium (II) chloride, chromium (II) acetate and the like. ) and an organic or inorganic acid (such as acetic acid, propinic acid, hydrochloric acid and the like. ) or conventional catalytic reduction in the presence of a conventional metal catalyst. 



   Method (E): (IX) - (X)
Compound (X) can be prepared by nitrosating compound (IX). 



   The nitrosating agent to be used in the reaction is a conventional nitrosating agent which can react with an active methylene compound to form a C-nitroso compound and includes e.g. B. 



  Nitrous acid or a salt thereof, e.g. B.  an alkali metal nitrite (such as sodium nitrite and the like. ) or an ester thereof, such as. B. 



  a lower alkyl nitrite (such as tert. Butyl nitrite, isopentyl nitrite and the like. ) and the like 



   If a nitrous acid salt is used as the nitrosating agent, the reaction is usually carried out in the presence of an inorganic or organic acid, such as hydrochloric acid, sulfuric acid, acetic acid or the like. , carried out. 



  Conversely, if an ester of nitrous acid is used as the nitrosating agent, the reaction is preferably carried out in the presence of a fairly strong base such as e.g. B.  an alkali metal alkylate (such as sodium methylate, sodium ethylate, potassium tert. -butylate and the like ) and the like , carried out. 



   This reaction is usually carried out in a solvent such as water, acetic acid, in an alcohol (such as ethanol, methanol and the like. ), in ether, tetrahydrofuran or any other solvent which does not adversely affect the reaction.  The reaction temperature is not critical and the reaction is usually carried out under cooling or at ambient temperature. 



   Procedure (F): (IX) <(XII)
The compound (XII) can be prepared by oxidizing the compound (IX) with an oxidizing agent.



   Suitable oxidizing agents are the conventional oxidizing agents which can oxidize an active methylene group to a carbonyl group and include e.g. Selenium dioxide, manganese (II) acetate and potassium permanganate or the like



  The reaction is usually carried out in a solvent which does not adversely affect the reaction, e.g. in water, dioxane, pyridine, tetrahydrofuran and the like. The reaction temperature is not critical and the reaction is preferably carried out with heating to heating.



   Method (G): (X) + (XIII)
The compound (XIII) can be prepared by hydrolysis of the compound (X).



   The hydrolysis is carried out in a conventional manner, e.g. in the presence of an alkali metal bisulfite (such as sodium bisulfite and the like), titanium trichloride, a hydrohalic acid (such as hydrochloric acid, hydrobromic acid and the like), formic acid, nitric acid or the like, and preferably a hydrochloric acid in the presence of an aldehyde such as formaldehyde and the like. be applied.



   The reaction is usually carried out in an aqueous solvent such as water, in an aqueous alcohol (such as methanol, ethanol and the like), in aqueous acetic acid or in any other aqueous solvent which does not adversely affect the reaction. The reaction temperature is not critical and the reaction is carried out at ambient temperature, with heating or heating.



  Method (H): (Xlll) + (XIV) <(111Z,)
The compound (111b) can be prepared by reacting the compound (XIII) with the compound (XIV) or a salt thereof.



   Suitable salts of the compound (XIV) include inorganic acid salts (such as a hydrochloride, hydrobromide, sulfate and the like), organic acid salts (such as an acetate, maleate, p-toluenesulfonate and the like) and the like. The reaction is usually carried out in a solvent, e.g. in water, in an alcohol (such as methanol, ethanol and the like), in a mixture thereof or in any other solvent which does not adversely affect the reaction. The reaction is preferably carried out in the presence of a base, e.g. an inorganic base such as an alkali metal (e.g. sodium, potassium and the like), an alkaline earth metal (e.g. magnesium, calcium and the like), a hydroxide or carbonate or bicarbonate thereof or the like, and in the presence of an organic base such as an alkali metal alkylate (e.g.

  Sodium methylate, sodium ethylate and the like), a trialkylamine (such as trimethylamine, triethylamine and the like), N, N-dialkylamine (such as N, N-dimethylaniline and the like), N, N-dialkylbenzylamine (such as N, N-dimethylbenzylamine and Like.), Pyridine or the like. The reaction temperature is not critical and the reaction is usually carried out with cooling to heating.

 

   In this process, a mixture of syn and anti isomers of the compound (IIIb) can occasionally be obtained depending on the reaction conditions used and the like. The syn and anti isomers can be separated and isolated from such a mixture using conventional separation - and isolation procedures, e.g. by esterification of the mixture, by separation of the esters into the syn and anti isomers, for example by chromatographic fractionation and subsequent recovery of each of the corresponding carboxylic acids from each of the separated syn and anti isomer esters by hydrolysis of the respective ester functions.



  Method (1): (XIII) + (1113 + (Illd)
The compound (IIIC) can be prepared by reacting the compound (XIII) with hydroxylamine or a salt thereof.



   With regard to suitable hydroxylamine salts, reference is made to the examples given above for the compound (XIV). The reaction is preferably carried out essentially in a similar manner to that in process (H): (XIII) + (XIX) <(IIIb) has been specified.  The reaction may preferably be carried out in the presence of an alkaline earth metal hydroxide (such as magnesium hydroxide, calcium hydroxide and the like. ) be performed. 



   Procedure (J): (III)
The compound (IIId) can be produced by introducing a protective group for hydroxy into the compound (IIIc). 



   Suitable introducing agents include an acylating agent which comprises an aliphatic, aromatic or heterocyclic carboxylic acid and the corresponding sulfonic acid, formic acid ester, isocyanic acid ester and carbamic acid and the corresponding thioic acid thereof and the reactive derivatives of the acids given above.  Suitable reactive derivatives of the above acids include the same ones as those given in the explanation of the reactive derivative on the carboxy group of the compound (III). 



   Examples of the protecting group (e.g. B.  the acyl group) which can be introduced into the hydroxyimino group in the compound (IIIC) are the same (e.g. B.  Acyl groups), as described above in the explanation of the protective group residue (e.g. B.  of the acyl radical) have been given for the expression acylamino. 



   The reaction is carried out in substantially the same manner as explained in the reaction of the compound (11) or its reactive derivative on the amino group or a salt thereof with the compound (III) or its reactive derivative on the carboxy group. 



   In the above-mentioned reactions and / or in the aftertreatment of the reactions according to the invention, the above-mentioned syn or anti isomer can occasionally be converted into the other geometric isomer. 



   If the compound (I) according to the invention is obtained in the form of the free acid in the 4-position and / or if the compound (I) according to the invention has a free amino group, it can be pharmaceutically acceptable in its salt, preferably in its salt, using a conventional method ches salt, as indicated above. 



   The compound (I) according to the invention has a high antimicrobial activity and it inhibits the growth of a number of microorganisms, such as. B.  of pathogenic gram-positive and gram-negative bacteria.  It should also be pointed out that among the compounds according to the invention in particular the syn isomer is characterized by an even higher antimicrobial activity. 



   For therapeutic administration, the cephalosporin compounds according to the invention are used in the form of a pharmaceutical preparation which contains the compound (s), optionally in a mixture with pharmaceutically acceptable carriers, such as, for. B.  an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration.  The pharmaceutical preparations can be in solid form, e.g. B.  in the form of capsules, tablets, dragees, ointments or suppositories, or in liquid form, e.g. B.  in the form of solutions, suspensions or emulsions.  If desired, the above-mentioned preparations can also contain auxiliary substances, stabilizers, wetting or emulsifying agents, buffers and other customarily used additives. 



   Although the dosage of the compounds may vary and may also depend on the age and condition of the patient, an average single dose of approximately 50 mg, 100 mg, 250 mg and 500 mg of the compounds according to the invention has been found to be effective for the treatment of infectious diseases caused by a number of pathogenic bacteria.  In general, amounts between about 1 and about 1000 mg or more can be administered per day. 



   Some test data relating to the antimicrobial activity of some representative compounds are given below in order to show the usefulness of the compounds (I) according to the invention. 



  Test connections 1.  7- [2-Methoxyimino-2- (1, 2,3-thiadiazol-4-yl) acetamido] - 3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn- Isomeres) 2.  7- [2-Methoxyimino-2- (1, 2,3-thiadiazol-4-yl) acetamido] - 3- (1-methyl-1H-tetrazol-S-yl) thiomethyl-3-cephcm-4-carboxylic acid ( anti-isomer) 3.  7- [2-Hydroxyimino-2- (1,2,5-thiadiazol-3-yl) acetamido] - 3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid ( syn-isomer) 4.  7- [2-Hydroxyimino-2- (isothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



  Test procedure
In vitro antibacterial activity was determined using the dual agar plate dilution procedure described below. 



   An eyelet fill of an overpowered culture of each test strain in a trypticase soy broth (108 viable cells per ml) was streaked onto a cardiac infusion agar (HI agar) containing graded concentrations of antibiotics, and after 20 hours incubation at 37 C, the minimum Inhibitory concentration (MIC) expressed in µg / ml was determined. 



  Test results test bacteria MI C (g / ml)
Test compounds (1) (2) (3) (4) Staph. aureus209PJC-1 3. 13 12. 5 0. 78 0. 39 E.  coli NIHJ JC-2 0. 78 25 3. 13 1. 56 Sh.  flexneri 2a 1. 56 12. 5 0. 39 0. 39 Sal.  enteritidis 0. 2 6. 25 1. 56 0. 78
The invention is explained in more detail by the following examples, but without being restricted thereto. 

 

   Example 1 a) Preparation of the starting compound
1.  160 g of powdered potassium carbonate was added to a solution of 152 g of ethyl 2-hydroxyiminoacetoacetate (a mixture of the syn and anti isomers) in 500 ml of acetone.  With stirring, 130 g of dimethyl sulfate were added dropwise at 45 to 50 ° C. over a period of 1 hour and the mixture was stirred for 2 hours.  An insoluble material was filtered off and the filtrate became a few under reduced pressure.      



  tight.  The insoluble matter filtered off was dissolved in 500 ml of water and this solution was added to the residue.  The mixture was extracted twice with 300 ml of ethyl acetate.  The extract was washed twice with 200 ml of water and with 200 ml of a saturated aqueous sodium chloride solution and dried over magnesium sulfate.  The solvent was distilled off under reduced pressure and the residue was distilled under reduced pressure to give 145.3 g of a colorless oil of ethyl 2-methoxyiminoacetoacetate (a mixture of the syn and anti isomers), bp.  55 to 64 "C / 0.5 mm Hg. 



  IR spectrum (film): 1745, 1695, 1600 cm 'N. M. R. Spectrum (CDCl3, o) ppm 4. 33 (4H, q, J = 8Hz)
4th 08 (3H, s)
3rd 95 (3H, s)
2nd 40 (3H, s)
1. 63 (3H, s)
1. 33 (6H, t, J = 8Hz)
2nd  A solution of 34.6 ethyl 2-methoxyiminoacetoacetate (a mixture of the syn and anti isomers) and 26.4 g t-butoxycarbonylhydrazine in 200 ml ethanol was stirred at ambient temperature for 7.5 hours and allowed to stand overnight Crystals failed.  The crystals were collected by filtration, washed with ethanol and dried to give 41.7 g of ethyl 2-methoxyimino-3-t-butoxycarbonylhydrazonobutyrate (a mixture of the syn and anti isomers), F. 



  144 to 145 "C.    



  I. R. -Spectrum (Nujol) 3200, 1750, 1705, 1600, 1520 cm- N. M. R. Spectrum (CDCl3, o) ppm 8. 52 (1H, broad s)
4th 35 (2H, q, J = 7Hz)
4th 10 (3H, s)
2nd 00 (3H, s)
1. 50 (9H, s)
1. 33 (3H, t, J = 7Hz)
3rd  A mixture of 28.7 g of ethyl 2-methoxyimino-3-tbutoxycarbonylhydrazonobutyrate (a mixture of the syn and anti isomers) and 30 ml of thionyl chloride was heated to 50 ° C. with stirring on a water bath for 3 minutes and then for 5 minutes stirred at ambient temperature to give a black solution.  To the reaction mixture, 200 ml of ethyl acetate was added, and the mixture was poured into 300 ml of ice water. 

  The ethyl acetate layer was separated, washed successively with water, with a saturated aqueous sodium bicarbonate solution and with a saturated aqueous sodium chloride solution.  After drying over magnesium sulfate, the ethyl acetate solution was treated with activated carbon and concentrated to give a black oil.  The oil was purified by column chromatography on silica gel using a benzene / ethyl acetate (19/1) mixture as the eluent to give 4 g of ethyl 2-methoxyimino-2- (1, 2,3-thiadiazol-4-yl) acetate (anti Isomeres) received. 



  I. R. -Spectrum (film) 1730.1590 cm- l N. M. R. Spectrum (CDCl3, o) ppm 9. 38 (1H, s)
4th 47 (2H, q, J = 7Hz)
4th 20 (3H, s)
1. 40 (3H, t, J = 7Hz) 4.  15.9 ml of sulfur dichloride was added with stirring at ambient temperature to a solution of 14.36 g of ethyl 2-methoxyimino-3-t-butoxycarbonylhydrazonobutyrate (a mixture of the syn and anti isomers) in 150 ml of methylene chloride and the mixture became 1 Stirred for one hour at ambient temperature.  300 ml of ice water was added to the reaction mixture, and the methylene chloride layer was washed with water, with a saturated aqueous sodium bicarbonate solution and with a saturated aqueous sodium chloride solution, and dried over magnesium sulfate.  The solvent was distilled off to obtain an oil. 

  The oil was purified by column chromatography on silica gel using a benzene / n-hexane (19/1) mixture as the eluent, starting with 1.8 g of ethyl 2-methoxyimino 2- (1,2,3-thiadiazol-4 -yl) acetate (syn-isomer), F.  77 to 79 "C.    



  I. R. -Spectrum (Nujol) 1720.1595 cm- 1 N. M. R. Spectrum (CDCl3, b) ppm 8. 92 (1H, s)
4th 46 (2H, q, J = 7Hz)
4th 06 (3H, s)
1. 38 (3H, t, J = 7Hz)
From the following fractions, 0.7 g of ethyl 2-methoxyimino-2 (1, 2,3-thiadiazol-4-yl) acetate (anti-isomer) was obtained in the form of an oil. 



  I. R. -Spectrum (film) 1730, 1590 cm- 'N. M. R. Spectrum (CDCl3, o) ppm 9. 38 (1H, s)
4th 47 (2H, q, J = 7Hz)
4th 20 (3H, s)
1. 40 (3H, t, J = 7Hz)
5.  A solution of 0.47 g of sodium hydroxide in 10 ml of water became a solution of 2.1 g of ethyl-2-methoxyimino-2 (1,2,3-thiadiazol-4-yl) acetate (anti-isomer) in 20 ml Methanol was added and the resulting mixture was stirred at ambient temperature for 6 hours.  The methanol was removed from the reaction mixture and water was added to the residue.  The resulting mixture was washed with ether, adjusted to pH 1 with 10% hydrochloric acid and extracted twice with 50 ml of ether.  The extract was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. 

  The solvent was distilled off to obtain 1.3 g of an oil of 2 methoxyimino-2- (1,2,3-thiadiazol-4-yl) acetic acid (anti-isomer).  IR spectrum (film): 2700-2200, 1715, 1600 cm-l.    



  b) Preparation of the compound according to the invention
A mixture of 0.56 g of dimethylformamide and 1.17 g of phosphorus oxychloride was heated to 40 ° C. for 1 hour. 



  After cooling, 10 ml of methylene chloride were added and distilled off.  The residue was suspended in 10 ml of dry ethyl acetate.  A solution of 1.3 g of 2-methoxyimino-2- (1, 2,3-thiadiazol-4-yl) acetic acid (anti-isomer) in 10 ml of dry ethyl acetate was added to the suspension with stirring and under ice cooling, and the resultant resulting mixture was stirred at the same temperature for 30 minutes.  On the other hand, 2.3 g of 7-amino-3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid was dissolved in a solution of 5.9 g of trimethylsilylacetamide in 40 ml of dry ethyl acetate.  

  To the solution was added the ethyl acetate solution obtained above with stirring at -20 "C and the mixture was stirred at -10 to -20" C for 1.5 hours.  After 60 ml of water was added to the reaction mixture at -20 ° C, the precipitates which had precipitated out were collected by filtration and washed with acetone.  The filtrate and the washings were combined and the organic layer was separated.  The aqueous layer was extracted with ethyl acetate.  The extract was combined with the organic layer obtained above and the mixture was treated with activated carbon. 

  The activated carbon was filtered off and the filtrate was adjusted to pH 7 with an aqueous sodium bicarbonate solution after the addition of 100 ml of water. 



  The aqueous layer was separated and 100 ml of ethyl acetate was added.  The mixture was adjusted to pH 2 with 10% hydrochloric acid and extracted with ethyl acetate.  The aqueous layer was further extracted with 50 ml of ethyl acetate.  The ethyl acetate extracts were combined, washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate.  After the solvent was distilled off, ether was added to the residue to obtain a powder.  The powder was collected by filtration and dried, yielding 0.6 g of 7- [2-methoxyimino-2- (1,2,3-thiadiazol-4-yl) acetamido] -3 - (1,3, 4-thiadiazole -2-yl) thiomethyl-3-cephem-4-carboxylic acid (anti-isomer) was obtained. 



  I. R. -Spectrum (Nujol) 3150.1760.1705.1660.1590.1530 cm- N. M. R. Spectrum (d6-DMSO, o) ppm 9. 68 (iH, s)
9. 58 (1H, d, J = 8Hz)
9. 51 (1H, s)
5. 84 (1H, dd, J = 5.8Hz)
5. 20 (1H, d, J = 5Hz)
4th 45 (2H, ABq, J = 13Hz)
4th 07 (3H, s)
3rd 72 (2H, ABq, J = 17Hz)
Example 2 a) Preparation of the starting compound
1.  A solution of 226.6 g of ethyl 2-methoxyiminoacetoacetate (a mixture of the syn and anti isomers) and 78.5 g of acetohydrazide in 500 ml of ethanol was stirred at ambient temperature for 1.5 hours. 

  The precipitates were collected by filtration, washed with ethanol and ether and dried to give 155.7 g of ethyl 2-methoxyimino-3-acetylhydrazonobutyrate (a mixture of the syn and anti isomers), F.  190 to 191.5 C.    



  I. R. -Spectrum (Nujol) 3150.1725.1660.1600.1585 cm¯ N. M. R. Spectrum (CDCl3, o) ppm 9. 82 (1H, s)
4th 32 (2H, q, J = 7Hz)
3rd 97 (3H, s)
2nd 20 (3H, s)
2nd 10 (3H, s)
1. 35 (3H, t, J = 7Hz)
2nd  A mixture of 22.9 g of ethyl 2-methoxyimino-3-acetylhydrazonobutyrate (a mixture of the syn and anti isomers) and 51 g of thionyl chloride was heated to 65 ° C. for 10 minutes with stirring on a water bath.  1200 ml of ethyl acetate was added to the reaction mixture, and the resulting mixture was poured into 300 ml of ice water.  The ethyl acetate layer was separated, washed successively with water, with a saturated aqueous sodium bicarbonate solution and with a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. 

  After
After treatment with activated carbon, the solvent was distilled off to obtain a black oil.  The oil was through
Column chromatography on silica gel using
Purified benzene as the eluent, 2 g of ethyl-2-methoxyimino-2- (1, 2,3-thiadiazol-4-yl) acetate (syn isomer) first being obtained, F.  77 to 79 "C.    



  I. R. -Spectrum (Nujol) 1720.1595 cm- N. M. R. Spectrum (CDCl3, o) ppm 8. 92 (1H, s)
4th 46 (2H, q, J = 7Hz)
4th 06 (3H, s)
1. 38 (3H, t, J = 7Hz)
6.4 g of ethyl 2-methoxyimino-2- (1, 2,3-thiadiazol-4-yl) acetate (anti-isomer) were obtained from the subsequent fractions in the form of a t) l.    



  I. R. -Spectrum (film) 1730.1590cm- 'N. M. R. Spectrum (CDCl3, o) ppm 9. 38 (1H, s)
4th 47 (2H, q, J = 7Hz)
4th 20 (3H, s)
1. 40 (3H, t, J = 7Hz)
3rd  6.7 ml of a 1 N aqueous sodium hydroxide solution were added to a solution of 1.2 g of ethyl 2-methoxyimino-2- (1,2,3thiadiazol-4-yl) acetate (syn isomer) in 10 ml of methanol and the Mixture was stirred at ambient temperature for 1.5 hours.  The methanol was distilled off from the reaction mixture and water was added to the residue.  The mixture was washed with ether, adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate.  The extract was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. 

  The solvent was distilled off to give 0.7 g of prisms of 2-methoxyimino-2- (1,2,3-thiazid-4-yl) acetic acid (syn-isomer), F.  110 to 113 "C.    



  I. R. -Spectrum (Nujol) 2750-2150, 1730, 1595 cm- 'N. M. R. Spectrum (d6-DMSO, o) ppm 9. 47 (1H, s)
4th 01 (3H, s) b) Preparation of the compound according to the invention
0.6 g of 2-methoxyimino-2- (1, 2,3-thiadiazol-4-yl) acetic acid (syn isomer) and 1.1 g of 7-amino-3- (1,3,4-thiadiazol-2 -yl) thiomethyl-3-cephem-4-carboxylic acid were reacted with one another in a similar manner to that indicated in Examples 12 and 15, giving 0.7 g of 7- [2-methoxyimino-2- (1,2,3-thiadia - zol-4-yl) acetamido] -3- (1,3, 4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), F.  90 to 98 "C (dec. ). 



  I. R. -Spectrum (Nujol) 3250.1780.1725.1680.1530 cm- 1 N. M. R. Spectrum (d6-DMSO, o) ppm 9. 82 (1H, d, J = 8Hz)
9. 51 (1H, s)
9. 37 (1H, s)
5. 88 (1H, dd, J = 5.8Hz)
5. 20 (1H, d, J = SHz)
4th 44 (2H, ABq, J = 13Hz)
3rd 99 (3H, s)
3rd 72 (2H, ABq, J = 17Hz)
Example 3 a) Preparation of the starting compound
1.  A sodium ethylate solution was prepared from 230 mg sodium and 5 ml absolute ethanol and this was at 0 to 5 "C to a solution of 1.86 g of ethyl 2- (5-methyl 1,3,4-thiadiazol-2-yl ) acetate and 3 ml of isopentyl nitrite in 25 ml of absolute ethanol were added dropwise.  The resulting mixture was stirred at the same temperature for 3 hours and at ambient temperature for 1 hour. 

  The reaction mixture was acidified with 10% hydrochloric acid, whereby crystals precipitated.  After the ethanol was distilled off under reduced pressure at 30 ° C, 30 ml of water was added to the residue, after which the mixture was extracted three times with 30 ml of ethyl acetate.  The extracts were washed with water and dried over sodium sulfate.  The solvent was distilled off under reduced pressure, whereby 1.50 g of crystals of ethyl 2-hydroxyimino-2- (5-methyl 1,3,4-thiadiazol-2-yl) acetate (a mixture of syn and anti Isomers) was obtained.  The crystals were recrystallized from ethyl acetate to give pure crystals, F.  181 to 184 C (dec. ). 



  I. R. -Spectrum (Nujol) 3120.2800-2100, 1742 cm M. R. Spectrum (d6-DMSO, o) ppm 4. 37 (2H, q, J = 7Hz)
2nd 80 (3H, s)
1. 30 (3H, t, J = 7Hz)
2nd 2.85 g of potassium carbonate and 2.2 g of dimethyl sulfate were added to a suspension of 3.7 g of ethyl 2-hydroxyimino-2- (5-methyl-1,3,4-thiadiazol-2-yl) acetate (a mixture of the syn and anti isomers) in 60 ml of ethyl acetate and the resulting mixture was stirred at 40 to 45 C for 6 hours.  The reaction mixture was washed with 50 ml of water and dried over magnesium sulfate.  The solvent was distilled off to obtain 2.5 g of an oil. 

  The oil was purified by column chromatography on silica gel using a benzene / ethyl acetate (9/1) mixture as the eluent, first by 0.3 g of ethyl 2-methoxyimino2- (5-methyl-1,3,4-thiadiazole) 2-yl) acetate (syn-isomer), F.  104 to 106 C.    



  I. R. -Spectrum (Nujol) 1735.1590 cm-l N. M. R. Spectrum (CDCl3, o) ppm 4. 42 (2H, q, J = 7Hz)
4th 03 (3H, s) 2. 77 (3H, s)
1. 37 (3H, t, J = 7Hz)
The following fractions gave 1.3 g of ethyl 2-methoxyimino-2- (5-methyl-1,3, 4-thiadiazol-2-yl) acetate (anti-isomer), F.  79 to 81 C. 



  I. R. - Spectrum (Nujol) 1735, 1700, 1600 cm-1 N. M. R. - spectrum (CDCl3, b) ppm 4.42 (2H, q, J = 7Hz)
4th 17 (3H, s)
2nd 82 (3H, s)
1. 37 (3H, t, J = 7Hz)
3.04 g of ethyl 2-methoxyimino-2- (5-methyl-1,3,4-thiadiazol-2-yl) acetate (syn isomer) and 2.1 ml of a 1N aqueous solution of sodium hydroxide were prepared in a similar manner to in Example 1 (A) (5) to give 0.25 g of 2-methoxyimino-2 (5-methyl-1,3,4-thiadiazol-2-yl) acetic acid (syn isomer), F.  168 to 171 C (dec. ). 



  I. R. -Spectrum (Nujol) 2750-2150, 1725, 1600 cm-1 N. M. R. Spectrum (d6-DMSO, o) ppm 4. 00 (3H, s)
2nd 74 (3H, s) Preparation of the compound according to the invention
0.21 g of 2-methoxyimino-2- (5-methyl-1,3, 4-thiadiazol-2-yl) acetic acid (syn isomer) and 0.41 g of 7-amino-3- (1,3,4 -thia diazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid were reacted with one another in a similar manner as in Examples 12 and 15, 0.23 g of 7- [2-methoxyimino-2- (5-methyl - 1,3,4-thiazol-2-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), F.  175 to 178 C (dec. ). 



  I. R. -Spectrum (Nujol) 3250, 1785, 1700, 1665, 1620, 1590.1550 cm- l N. M. R. Spectrum (d6-DMSO, o) ppm 9.83 (1H, d, J = 8Hz)
9. 57 (1H, s)
5. 87 (1H, dd, J = 5.8Hz)
5. 18 (1H, d, J = SHz) 4. 43 (2H, ABq, J = 13Hz)
4th 00 (3H, s) 3. 70 (2H, ABq, J = 17Hz)
2nd 77 (3H, s)
Example 4 a) Preparation of the starting compound
1.2 g of ethyl 2-methoxyimino-2- (5-methyl-1,3,4-thiadiazol-2-yl) acetate (anti-isomer) and 10.5 ml of a 1N aqueous solution of sodium hydroxide were prepared in a similar manner treated as in Example 1 (a) (5) to give 1.06 g of 2-methoxyimino-2- (5methyl-1,3,4-thiadiazol-2-yl) acetic acid (anti-isomer), F.  173 to 174 C (dec. ). 



  I. R. -Spectrum (Nujol) 2700-2150, 1660, 1540 cm-1 N. M. R. Spectrum (d6-DMSO, o) ppm 4. 12 (3H, s)
2.79 (3H, s) b) Preparation of the compound according to the invention
0.99 g of 2-methoxyimino-2- (5-methyl-1,3,4-thiadiazol-2-yl) acetic acid (anti-isomer) and 1.62 g of 7-amino-3- (1,3,4thiadiazole -2-yl) -thiomethyl-3-cephem-4-carboxylic acid were reacted with one another in a manner similar to that in Example 1 (b), giving 1.25 g of 7- [2-methoxyimino-2- (5-methyl-1 , 3,4-thia diazol-2-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3cephem-4-carboxylic acid (anit-isomer), F.  110 to 115 C (dec. ).    

 

  I. R. - Spectrum (Nujol) 3200, 1780, 1730, 1680, 1630, 1530 cm N. M. R. Spectrum (d6-DMSO, o) ppm 9.74 (1H, d, J = 8Hz)
9. 52 (1H, s)
5. 86 (1H, dd, J = 5.8Hz)
5. 20 (1H, d, J = SHz) 4. 45 (2H, ABq, J = 13Hz)
4th 16 (3H, s) 3. 72 (2H, ABq, J = 17Hz)
2nd 90 (3H, s)
Example S a) Preparation of the output connection
1.  9.5 g of ethyl 2- (1,2,5-thiadiazol-3-yl) acetate and 10 ml of isopentyl nitrite were reacted with each other in a similar manner to that in Example 3 (a) (1), whereby 10.5 g of ethyl -2-hydr oxyimino-2- (1,2,5-thiadiazol-3-yl) acetate (a mixture of the syn and anti isomers), F.  60 to 66 C.    



  I. R. -Spectrum (Nujol) 3150.1710 cm- l N. M. R. Spectrum (d6-DMSO, o) ppm 9. 27 (111, s)
4th 33 (2H, q, J = 7Hz)
1. 30 (3H, t, J = 7Hz) 2.  10.4 g of ethyl-2-hydroxyimino-2- (1,2,5-thiadiazol-3-yl) acetate (a mixture of the syn and anti isomers) and 6.5 g of dimethyl sulfate were prepared in a similar manner to that in Example 3 (a) (2) were reacted with one another and the oil obtained was purified by column chromatography on silica gel using benzene as the eluent, firstly 0.5 g of an oil of ethyl 2-methoxyimino-2- (1, 2, 5-thiadiazol-3-yl) acetate (syn-isomer) was obtained. 



  I. R. -Spectrum (film)
1735, 1592 cm-l N. M. R. Spectrum (CDCl3, o) ppm 8. 96 (111, s)
4th 50 (2H, q, J = 7Hz)
4th 13 (3H, s)
1. 42 (3H, t, J = 7Hz)
6.4 g of ethyl 2-methoxyimino-2- (1, 2,5-thiadiazol-3-yl) acetate (anti-isomer) was obtained in the form of an oil from the following fractions. 



  I. R. -Spectrum (film) 1730.1585 cm- l N. M. R. Spectrum (CDCl3, 6) ppm 9. 05 (111, s)
4th 43 (2H, q, J = 7Hz)
4th 20 (3H, s) 1. 40 (3H, t, J = 7Hz) 3.  3rd 0 g of ethyl 2-methoxyimino-2- (1, 2,5-thiadiazol-3-yl) acetate (anti-isomer) was treated with 16.8 ml of a 1N aqueous sodium hydroxide solution in a similar manner as in Example 1 (a) (5) treated to give 2.46 g of 2-methoxyimino-2- (1,2,5 thiadiazol-3-yl) acetic acid (anti-isomer), F.  110 to 111 C.    



  I. R. -Spectrum (Nujol) 2700-2100, 1700, 1560 cm- N. M. R. Spectrum (d6-DMSO, 6) ppm 9. 27 (1H, s)
4th 07 (3H, s) b) Preparation of the compound according to the invention
1.87 g of 2-methoxyimino-2- (1,2,5-thiadiazol-3-yl) acetic acid (anti-isomer) and 3.3 g of 7-amino-3- (1,3,4-thiadiazol-2 -yl) - thiomethyl-3-cephem-4-carboxylic acid were reacted with one another in a similar manner as in Example 1 (b), 3.0 g of a powder of 7- [2-methoxyimino-2- (1, 2, 5-thiadiazol-3-yl) acetamido] -3- (1, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (anti-isomer), F.  115 to 120 "C (dec. ). 



  I. R. -Spectrum (Nujol) 3300.1770.1700.1675, 1625.1585 cm- N. M. R. Spectrum (d6-DMSO, 6) ppm 9. 6 (111, s)
9. 55 (1H, d, J = 8Hz)
9. 30 (1H, s)
5. 82 (1H, dd, J = 5.8Hz) 5. 18 (1H, d, J = 5Hz)
4th 42 (2H, ABq, J = 13Hz)
4th 10 (3H, s)
3rd 73 (2H, broad s)
Example 6 a) Preparation of the starting compound
1.  A solution of 1.01 g sodium in 10 ml absolute methanol was added over a period of 15 minutes
Stir and, while cooling with ice, added dropwise to a solution of 6.30 g of methyl 2- (isothiazol-4-yl) acetate and 10.6 g of isopentyl nitrite in 63 ml of absolute methanol.  The mixture was at the same temperature for 30 minutes and at for 3 hours
Ambient temperature stirred. 

  The reaction mixture was concentrated and the residue was poured into a mixture of 50 ml of ethyl acetate and 50 ml of water.  The aqueous layer was separated and the ethyl acetate layer was extracted twice with 20 ml and 10 ml of a 1N aqueous solution of sodium hydroxide.  The extracts and the aqueous layer separated off above were combined, adjusted to pH 1 with 10% hydrochloric acid and twice with 70 ml and
50 ml of ethyl acetate extracted.  The extracts were made with a
5% aqueous sodium bicarbonate solution and washed with a saturated aqueous sodium chloride solution and over
Magnesium sulfate dried.  The solvent was distilled off under reduced pressure, 4.55 g of methyl 2-hydroxyimino-2- (isothiazol-4-yl) acetate (anti-isomer), F.  110 to 112 "C. 



   IR spectrum (Nujol): 3230, 1730 com 1
2nd  A mixture of 3.41 g of methyl 2-hydroxyimino-2 (isothiazol-4-yl) acetate (anti-isomer), 24 ml of a 36% aqueous formaldehyde solution, 12 ml of concentrated hydrochloric acid and 24 ml of water was used for 7 hours long at 90 to
100 "C stirred.  The reaction mixture was left overnight in a refrigerator, whereby crystals precipitated. 



   The crystals were collected by filtration, washed with a small amount of ice water, and then dried to obtain 2.09 g of 2- (isothiazol-4-yl) glyoxylic acid.  The mother liquor was extracted with ethyl acetate to give 0.34 g of the same compound, F.  145 to 148 "C.    



   IR spectrum (Nujol): 1720, 1675 cm
3rd  A suspension of 240 mg of 2- (isothiazol-4-yl) glyoxylic acid, 290 mg of magnesium hydroxide and 140 mg of hydroxylamine hydrochloride in a mixture of 2 ml of ethanol and 10 ml
Water was stirred at ambient temperature for 2 hours and left at ambient temperature overnight.  The ethanol was distilled off and ethyl acetate was added to the residue.  The mixture was adjusted to pH 1 with 10% hydrochloric acid and the ethyl acetate layer was washed with water and dried over magnesium sulfate.  The solvent was distilled off under reduced pressure, giving 0.20 g of 2-hydroxyimino-2- (isothiazol-4-yl) acetic acid (syn-isomer), F. 



   159 to 161 "C (dec. ). 



   IR spectrum (Nujol): 3250.3200, 1690 cm
4th 3.58 g of dichloroacetyl chloride was added with stirring and with ice cooling to a suspension of 1.50 g of 2-hydroxy imino-2- (isothiazol-4-yl) acetic acid (syn isomer) in 40 ml of dry methylene chloride and the mixture was
Stirred for 2 hours at the same temperature.  The reaction mixture was concentrated to a volume of 10 ml.  50 ml of petroleum ether were added to the residue and the
Mixture was cooled in a dry ice-acetone bath.  The
Precipitates were collected by filtration and washed with petroleum ether, giving 1.20 g of 2-dichloroacetoxyimino
2- (isothiazol-4-yl) acetic acid (syn-isomer) was obtained. 

 

   b) Preparation of the compound according to the invention
770 mg of thionyl chloride was added to 330 mg of dimethylformamide and the resulting mixture turned 30
Stirred at 40 "C for minutes.  The mixture was concentrated to dryness and the residue was suspended in 40 ml of methylene chloride.  At - 10 to - 15 "C, 1.20 g of 2-dichloroacetoxyimino-2- (isothiazol-4-yl) acetic acid (syn isomer) was added and the mixture was stirred at the same temperature for 30 minutes.  On the other hand, a suspension of 1.32 g of 7-amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid and 3.2 g of bis (trimethylsilyl) acetamide in 40 ml Dry methylene chloride was stirred at ambient temperature for 30 minutes to give a clear solution. 

  This solution was added all at once at -40 "C to the methylene chloride solution obtained above and the mixture was stirred at -40 to -20" C for 1 hour and at 0 to 5 "C for 1 hour.  The reaction mixture was concentrated and the residue which was 7- [2-dichloroacetoxyimino-2- (isothiazol-4-yl) acetamido] -3 - (1-methyl-1H-tetrazol-5-yl) thio-methyl- 3-cephem-4-carboxylic acid (syn isomer) contained, 100 ml of ethyl acetate and 50 ml of 5% hydrochloric acid were added.  The ethyl acetate layer was separated, washed with water and dried over magnesium sulfate. 

  The solvent was distilled off, 860 mg of 7- [2-hydroxyimino-2- (isothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn isomer) received.  This compound was dissolved in 20 ml of acetone and the solution was chromatographed on activated carbon using acetone as the eluent.  Acetone was distilled off from the eluate and the residue was pulverized with ether to give 400 mg of the pure desired compound, F.  113 to 116 "C (dec. ). 



  I. R. -Spectrum (Nujol) 3250, 1790, 1700, 1660 cm- 'N. M. R. Spectrum (d6-acetone + D2O, o) ppm 9. 16 (111, s)
8th. 78 (1H, s)
6. 00 (1H, d, J = SHz)
5. 25 (1 d, J = SHz)
4th 43 (2H, s)
4th 00 (3H, s)
3rd 80 (2H, s)
Example 7 a) Preparation of the starting compound
1.  A mixture of 25.0 g of methyl 2- (1,2,5-thiadiazol-3-yl) acetate and 52.6 g of selenium dioxide in a mixture of 15.8 ml of water and 158 ml of dioxane was added for 45 minutes 120 "C stirred and the precipitates were filtered off.  The filtrate was concentrated under reduced pressure to give crude methyl 2- (1,2,5-thiadiazol-3-yl) glyoxyate. 

  500 ml of methanol and 99 ml of a 2N aqueous sodium hydroxide solution were added to this compound.  The mixture was stirred for 2.5 hours.  The methanol was distilled off and ethyl acetate and concentrated hydrochloric acid were added to acidify the whole.  The resulting mixture was extracted with ethyl acetate.  The extract was washed, dried and concentrated.  The residue (14.5 g) was added to a solution of 920 ml of ethanol and 92 ml of a 1N aqueous potassium hydroxide solution.  The resulting mixture was stirred for 30 minutes and the precipitates were collected by filtration and washed with ethanol to obtain potassium 2- (1, 2,5-thiadiazol-3-yl) glyoxylate. 

  This compound was added to a mixture of 10 ml of concentrated hydrochloric acid, 30 ml of water and 100 ml of ethyl acetate and extracted with the ethyl acetate.  After salting out, the aqueous layer was further extracted with ethyl acetate.  Both extracts were combined and an insoluble material was filtered off.  The filtrate was dried over magnesium sulfate and concentrated to give 12 g of 2- (1,2,5-thiadiazol-3-yl) glyoxylic acid. 



  IR spectrum (Nujol) 1700 cm¯ NMR spectrum (D2O + KOH, o) ppm 8.7 (1H, s)
2nd  7.4 g of 2- (1,2,5-thiadiazol-3-yl) glyoxylic acid and 3.1 g of hydroxylamine hydrochloride were mixed together in the presence of 4.7 g of magnesium hydroxide according to a procedure similar to that in Example 6 (a) (3) implemented to obtain 7.5 g of 2-hydr oxyimino-2- (1, 2,5-thiadiazol-3 yl) acetic acid (syn isomer). 



  IR spectrum (Nujol) 1700 cm 'NMR spectrum (d6-acetone, o) ppm 9.08 (111, s)
3rd 4.8 g of 2-hydroxyimino-2- (l, 2,5-thiadiazol3-yl) acetic acid (syn isomer) and 9.2 g of dichloroacetyl chloride were mixed with one another in a similar manner to that in Example 6 (a) (4) implemented to obtain 3.7 g of crystals of 2-dichloroacetoxyimino-2- (1,2,5thiadiazol-3-yl) acetic acid (syn isomer). 



  IR spectrum (Nujol): 1780, 1755 cm 1 b) Preparation of the compound according to the invention
2.5 g of phosphorus pentachloride were added with stirring and with ice cooling to a suspension of 3.7 g of 2-dichloroacetoxyimino-2- (1,2,5-thiadiazol-3-yl) acetic acid (syn isomer) in 100 ml of dry methylene chloride and the mixture was stirred at ambient temperature for 1 hour.  The resulting mixture was concentrated and benzene was added and distilled off (repeated twice).  The residue was dissolved in dry methylene chloride.  The solution was stirred and cooled with ice to a solution of 3.9 g of 7-amino-3 - (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid and 12 ml of bis- ( trimethylsilyl) acetamide added dropwise in 200 ml of dry methylene chloride. 

  The resulting mixture was stirred at the same temperature for 1 hour and at ambient temperature for 1 hour.  The methylene chloride was distilled off, and ethyl acetate and water were added to the residue.  After an insoluble material was filtered off, the ethyl acetate layer in the filtrate was washed three times with water, with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. 



  The solvent was distilled off to obtain a residue (4.5 g).  The residue containing the 7 - dichloroacetoxyirnino-2- (1, 2,5-thiadiazol-3-yl) acetamido} -3- (1-methyl 1H-tetrazol-5-yl) thiomethyl-3-cephem- 4-carboxylic acid (syn isomeres) was dissolved in a mixture of water and acetone and the solution was stirred at ambient temperature for 2 hours and extracted with ethyl acetate.  The extract was washed with water and with a saturated aqueous sodium chloride solution and dried over magnesium sulfate.  The solvent was distilled off and the residue was dissolved in ethyl acetate.  The solution was chromatographed on 5 g of silica gel and the eluate was concentrated. 



  The residue was reprecipitated from a mixture of ethyl acetate and ether and the precipitates were collected by filtration, washed with ether and dried (3 g).  The powder was dissolved in distilled acetone and the solution was treated with 3 g of activated carbon in a column and then concentrated.  The residue was reprecipitated from an acetone / ether mixture.  The precipitates were collected by filtration, washed with ether and dried, giving 2.5 g of 7- [2-hydroxyimino-2- (1, 2,5-thiadiazol-3-yl) acetamido] -3- (1- methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), F.  155 to 160 "C (dec. ). 

 

  N. M. R. Spectrum (d6-acetone + D2O, o) ppm 9. 00 (111, s)
5. 30 (1H, d, J = 4. 5Hz)
5. 07 (1H, d, J = 4. 5Hz)
4th 43 (2H, s)
4th 03 (3H, s)
3rd 87 (2H, s)
Example 8
0.43 g of dimethylformamide was added to 2 ml of dry ethyl acetate and with stirring were below
10 C 0.9 g of phosphorus oxychloride added.  10 ml of dry ethyl acetate and 1 g of 2-methoxyimino were added to the mixture
2- (1, 2,3-Thiadiazol-4-yl) acetic acid (anti-isomer) was added at 0 ° C., after which the mixture obtained was stirred at the same temperature for 30 minutes. 

  On the other hand
6 g of trimethylsilylacetamide to a suspension of 1.58 g
7-Aminocephalosporanic acid in 30 ml of dry ethyl acetate was added and the resulting mixture was stirred at 40 ° C for 1 hour to give a clear solution.  The ethyl acetate solution obtained above was added dropwise to this solution at −20 ° C., after which the mixture was stirred at the same temperature for 1 hour.  20 ml of water was added and the ethyl acetate layer was separated after shaking the mixture.  The ethyl acetate layer was with
Washed water and 30 ml of water was added.  The
Mixture was adjusted to pH 7.5 with sodium bicarbonate and extracted.  The aqueous layer was separated and 50 ml of ethyl acetate was added. 

  The resulting mixture was adjusted to pH 2 with dilute hydrochloric acid and extracted with ethyl acetate.  The extract was washed with water and with a saturated aqueous sodium chloride solution and dried over magnesium sulfate.  The solution was treated with activated carbon and concentrated under reduced pressure.  The residue was pulverized with ether and the powder was collected by filtration and dried to give 0.8 g of a pale yellow powder of 7- [2-methoxyimino-2- (1, 2,3-thiadiazol-4-yl) acetamido ] - cephalosporanic acid (anti-isomer). 



   I. R. -Spectrum (Nujol) 3300.1780.1730.1680.1640 cm-
N. M. R. Spectrum (d6-DMSO, o) ppm 9. 72 (1H, s) 9. 60 (1H, d, J = 8Hz)
5. 88 (1H, dd, J = 5.8Hz)
5. 23 (1H, d, J = 5Hz)
4th 87 (2H, ABq, J = 13Hz)
4th 07 (3H, s)
3rd 60 (2H, ABq, J = 17Hz)
2nd 04 (3H, s)
Example 9
1.0 g of 2-methoxyimino-2- (1, 2,3-thiadiazol-4-yl) acetic acid (anti-isomer) and 2.16 g of 7-amino-3- (5-methyl-1,3,4 -thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid were reacted with one another in a similar manner as in Examples 1 (b) and 8, 1.68 g of a pale yellow powder of 7-methoxyimino-2- (1, 2,3-thiadiazol-4-yl) acetamidoj-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (anti-isomer), F. 

   104 to 115 C (dec. ). 



  I. R. -Spectrum (Nujol) 3350, 1785.1730 cm- l N. M. R. Spectrum (d6-DMSO, o) ppm 9. 72 (1H, s)
9. 61 (1H, d, J = 8Hz)
5. 85 (1H, dd, J = 5.8Hz)
5. 15 (1H, d, J = SHz) 4. 38 (2H, ABq, J = 13Hz)
4th 07 (3H, s)
3rd 70 (2H, broad s)
2nd 67 (3H, s)
Example 10
1 g of 2-methoxyimino-2- (1, 2,3-thiadiazol-4-yl) acetic acid (anti-isomer) and 1.9 g of 7-amino-3- (1-methyl-1H-tetrazol-5-yl ) -thiomethyl-3-cephem-4-carboxylic acid were reacted with one another in a similar manner as in Examples 1 (b) and 8,

   1.5 g of a pale yellow powder of 7- [2-methoxyimino-2- (1,2,3-thiadiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazole-5 -yl) thiomethyl-3-cephem-4-carboxylic acid (anti-isomer) was obtained. 



  I. R. -Spectrum (Nujol) 3300.1790.1730.1690.1630 cm- N. M. R. Spectrum (d6-DMSO, o) ppm 9. 78 (1H, s)
9. 66 (1H, d, J = 8Hz)
5. 83 (1H, dd, J = 5.8Hz)
5. 17 (1H, d, J = SHz)
4th 33 (2H, broad s)
4th 10 (3H, s)
3rd 93 (3H, s)
3rd 69 (2H, broad s)
Example 11 a) Preparation of the starting compound
1.  A mixture of 6.0 g of ethyl 2-hydroxyimino-2 (1,2,5-thiadiazol-3-yl) acetate (a mixture of the syn and anti isomers), 40 ml of a 36% aqueous formaldehyde solution, 20 ml Concentrated hydrochloric acid and 40 ml of water were treated in a similar manner as in Example 6 (a) (2) to give 1.6 g of crystals of 2- (1,2,5-thiadiazol-3-yl) glyoxylic acid, F.  130 to 133 "C.    



   2nd  (i) 3 drops of phenolphthalein indicator were added to a solution of 0.95 g of O-methylhydroxylamine hydrochloride in 10 ml of dry methanol.  11 ml of a 1N methanol solution of sodium methylate was added dropwise to the solution with stirring at ambient temperature until the color of the solution turned purple.  O-Methylhydroxylamine hydrochloride was added in small portions until the solution became colorless.  The mixture was stirred at ambient temperature for 30 minutes.  After the precipitated sodium chloride was filtered off, 1.5 g of 2- (1,2,5-thiadiazol-3-yl) glyoxylic acid was added to the filtrate and the mixture was stirred at ambient temperature for 50 minutes.  After the methanol was distilled off at a low temperature, water was added to the residue. 

  The mixture was adjusted to pH 7.5 with an aqueous sodium bicarbonate solution and washed with ether.  The aqueous layer was adjusted to pH 1.5 with 10% hydrochloric acid, salted out and extracted with ether.  The extract was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate.  The ether was distilled off at low temperature, giving 1.5 g of 2-methoxyimino-2- (1,2,5thiadiazol-3-yl) acetic acid (a mixture of the syn and anti isomers). 



   (ii) This material was dissolved in 15 ml of ether and a solution of diazomethane in ether was carefully added with ice cooling until the color of the mixture turned yellow. 

 

  Immediately thereafter, acetic acid was added and the mixture was washed with an aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and dried over magnesium sulfate.  The ether was distilled off to obtain an oily residue.  The oily residue was chromatographed on silica gel using benzene as the eluent.  First, the eluate containing syn isomers was eluted, and the eluate was collected and concentrated to give 0.9 g of oily methyl 2-methoxyimino-2- (1,2,5-thiadiazol-3-yl) acetate (syn isomer) received. 



  I. R. -Spectrum (film) 1740.1590 cm-l N. M. R. Spectrum (CDCl3, b) ppm 8. 92 (111, s)
4th 09 (3H, s)
3rd 96 (3H, s)
After the eluate containing the syn isomer was eluted, the eluate containing the anti isomer was eluted.  The eluate was collected and concentrated to give 0.5 g of oily methyl 2-methoxyimino-2- (1, 2,5-thiadiazol-3-yl) acetate (anti-isomer). 



  IR spectrum (film): 1740, 1590 cm (iii) 5.4 ml of an aqueous 1N sodium hydroxide solution were added to a solution of 0.9 g of methyl-2-methoxyimino-2- (1, 2.5 -thiadiazol-3-yl) acetate (syn-isomer) in 10 ml of methanol was added and the mixture was stirred at ambient temperature for 1 hour.  The methanol was distilled off and water was added to the residue, after which the mixture was washed with ether.  The aqueous layer was adjusted to pH 1.5 with 10% hydrochloric acid, salted out and extracted with ether.  The extract was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate.  The ether was distilled off. 

  Benzene was added to the residue and, after removal, 0.67 g of crystals of 2-methoxyimino-2- (1,2,5-thiadiazol-3-yl) acetic acid (syn-isomer), F.  99 to 100 C.    



  I. R. -Spectrum (Nujol) 2650-2150, 1735, 1690, 1600 cm- N. M. R. Spectrum (d6-DMSO, o) ppm 9. 15 (111, s)
4th 05 (3H, s) b) Preparation of the compound according to the invention
0.6 g of 2-methoxyimino-2- (1, 2,5-thiodiazol-3-yl) acetic acid (syn isomer) and 1.16 g of 7-amino-3- (1,3,4-thiadiazol-2 -yl) thiomethyl-3-cephem-4-carboxylic acid were reacted with one another in a similar manner as in Examples 12 and 15, 1.10 g of 7- [2-methoxyimino-2- (1,2,5-thiadiazole- 3-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), F.  111 to 120 C.    



  I. R. - Spectrum (Nujol) 3300, 1770, 1725, 1670, 1620, 1550 cm-1 N. M. R. Spectrum (d6-DMSO, o) ppm 9. 77 (1H, d, J = 8Hz)
9. 58 (1H, s)
9. 13 (1H, s)
5. 85 (1H, dd, J = 5.8Hz)
5. 18 (1H, d, J = 5Hz) 4. 43 (2H, ABq, J = 13Hz) 4. 02 (3H, s)
3rd 68 (2H, broad s)
Example 12
0.34 g of dimethylformamide was added to 1 ml of dry ethyl acetate and then 0.72 g of phosphorus oxychloride was added below 10 ° C.  The mixture was stirred at -5 C to solidify it.  10 ml of dry ethyl acetate was added, and 0.8 g of 2-methoxyimino-2- (1,2,3-thiadiazol-4-yl) acetic acid (syn isomer) was added to the mixture at 0 C, after which the obtained was Mixture stirred at the same temperature for 30 minutes. 

  On the other hand, 4.9 g of trimethylsilylacetamide were added to a suspension of 1.28 g of 7-amino-cephalosporanic acid
30 ml of dry ethyl acetate was added and the mixture was stirred at 40 ° C for 1 hour to give a clear solution.  The ethyl acetate solution obtained above was added dropwise to this solution at −20 ° C. and the mixture was stirred at the same temperature for 1 hour.  To the
Reaction mixture was added 20 ml of water and the resulting mixture was shaken sufficiently.  The ethyl acetate layer was separated, washed with water, and 30 ml of water was added to the ethyl acetate solution.  The mixture was adjusted to pH 7.5 with sodium bicarbonate and washed with ethyl acetate.  The aqueous layer was adjusted to pH 2 with dilute hydrochloric acid with stirring after the addition of 50 ml of ethyl acetate. 

  The ethyl acetate layer was washed with water and with a saturated aqueous sodium chloride solution and dried over magnesium sulfate.  After the treatment with activated carbon, the solvent was distilled off under reduced pressure.  The residue was pulverized with ether to give 1.2 g of a pale yellow powder of 7- [2-methoxyimino-2- (1,2,3-thiadiazol-4-yl) acetamido] cephalosporanic acid (syn isomer) . 



  I. R. -Spectrum (Nujol) 3300, 1790, 1735, 1680 cm- N. M. R. Spectrum (d6-DMSO, o) 9. 83 (1H, d, J = 8Hz) 9. 40 (1H, s) 5. 86 (1H, dd, J = 5.8Hz) 5. 18 (1H, d, J = SHz) 4. 83 (2H, ABq, J = 1411z) 3. 97 (3H, s) 3rd 55 (2H, broad s) 2. 00 (3H, s)
Example 13
3.47 g of 2-methoxyimino-2- (1,2,3-thiadiazol-4-yl) acetic acid (syn isomer) and 4.3 g of 7-amino-3-methyl-3-cephem-4-carboxylic acid were similar Reacted as in Examples 12 and 15 with each other, 5.0 g of 7- [2-meth oxyimino-2- (1,2,3-thiadiazol-4-yl) acetamido] -3-methyl-3-ce - received phem-4-carboxylic acid (syn isomer), F.  111 to 116 C (dec. ). 



  I. R. - Spectrum (Nujol) 3300, 1785, 1660, 1600, 1548 cm-1 N. M. R. Spectrum (d6-DMSO), o) 9. 77 (1H, d, J = 8Hz) 9. 37 (1H, s) 5. 78 (1H, dd, J = 5.8Hz) 55. 11 (1H, d, J = 5Hz) 3. 97 (3H, s) 3rd 45 (2H, ABq, J = 17Hz) 2. 00 (3H, s)
Example 14
0.65 g of 2-methoxyimino-2- (1,2,3-thiadiazol-4-yl) acetic acid (syn isomer) and 0.96 g of 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid were added reacted with one another in a manner similar to Examples 12 and 15, 0.7 g of 7- [2-methoxyimino-2- (1,2,3-thiadiazol-4-yl) acetamido] -3 carbamoyloxymethyl-3-cephem -4-carboxylic acid (syn isomer) was obtained. 

 

  I. R. -Spectrum (Nujol) 3250.1780.1720.1670 cm- l N. M. R. Spectrum (d6-DMSO, o) 9. 77 (1H, d, J = 9Hz) 9. 36 (1H, s) 6. 54 (2H, s) 5. 87 (1H, dd, J = 5.9 Hz)
5. 16 (1H, d, J = 5Hz) 4. 74 (2H, ABq, J = 13Hz)
3rd 96 (3H, s) 3. 51 (2H, broad s)
Example 15
0.34 g of dimethylformamide was added to 1 ml of dry ethyl acetate and then 0.72 g became below 10C
Phosphorus oxychloride added.  The mixture was stirred at -5 ° C to solidify it. 

  10 ml of dry ethyl acetate were added, and 0.8 g of 2-methoxyimino-2- (1,2,3-thiadiazol-4yl) acetic acid (syn isomer) were added to the mixture at 0 C, after which the resulting mixture became 30 Stirred at the same temperature for minutes.  On the other hand, 4.9 g of trimethylsilylacetamide were added to a suspension of 1.54 g of 7-amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid in 30 ml of dry ethyl acetate was added and the mixture was stirred at 40 ° C for 1 hour to give a clear solution. 



  To this solution, the ethyl acetate solution obtained above was added dropwise at -20 ° C., and the mixture was stirred at the same temperature for 1 hour.  The reaction mixture was post-treated in a manner similar to that in Example 12, 0.9 g of a pale yellow powder of 7-f2-methoxyimino-2- (1,2,3-thiadiazol-3-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



  I. R. -Spectrum (Nujol) 3300.1780.1730.1680.1630 cm- N. M. R. Spectrum (d6-DMSO, o) ppm 9.89 (1H, d, J = 8Hz)
9. 40 (1H, s)
5. 88 (1H, dd, J = 5.8Hz)
5. 20 (1H, d, J = 5Hz)
4th 33 (2H, broad s) 4. 01 (311, s)
3rd 93 (3H, s)
3rd 73 (2H, broad s)
Example 16
350 mg of 2-methoxyimino-2- (1,2,3-thiadiazol-4-yl) acetic acid (syn isomer) and 600 mg of 7-amino-3- [1- (2-dimethylaminoethyl) - 111-tetrazol-5 -yl] thiomethyl-3-cephem-4-carboxylic acid were reacted with one another in a manner similar to Examples 12 and 15, giving 230 mg of 7- [2-methoxyimino-2- (1,2,3-thiadiazol-4- yl) acetamido] -3- [1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl] thiomethyl-3-cephem-4-carboxylic acid (syn-isomer). 



     I. R. -Spectrum (Nujol) 1775, 1670.1605 cm¯ l N. M. R. Spectrum (d6-DMSO, o) ppm 9.85 (1H, d, J = 8Hz)
9. 43 (1H, s)
5. 83 (1H, dd, J = 5.8Hz)
5. 15 (1H, d, J = SHz)
4th 37 (2H, t, J = SHz)
4th 30 (2H, broad s)
3rd 98 (3H, s)
3rd 65 (2H, broad s)
3rd 05 (2H, t, J = SHz)
2nd 38 (6H, s)
Example 17
0.99 g of dicyclohexylcarbodiimide became a solution of 2.1 g of diphenylmethyl-7-amino-7-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate at ambient temperature in 20 ml of dry tetrahydrofuran and then 0.9 g of 2 methoxyimino-2- (1, 2,3-thiadiazol-4-yl) acetic acid (syn isomer) were added at ambient temperature to give white precipitates. 



  After stirring for 2 days at ambient temperature, the precipitates were filtered off and the filtrate was concentrated under reduced pressure to give a brown oil.  The oil was subjected to silica gel column chromatography, eluted with a chloroform / ethyl acetate mixture, and the eluate was concentrated under reduced pressure to give 1.78 g of diphenylmethyl-7- [2-methoxyimino-2- (1,2,3- thiadi azol-4-yl) acetamidoj-7-methoxy-3 - (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate (syn-isomer). 



  I. R. -Spectrum (Nujol) 3300, 1780.1720.1690 cm- N. M. R. Spectrum (d6-DMSO, o) ppm 10.24 (1H, s)
9. 37 (1H, s)
7. 06 - 7. 72 (1OH, m)
6. 82 (1H, s) 5. 19 (1H, s)
4th 22 (2H, broad s)
3rd 94 (3H, s)
3.79 (3H, s) 3rd 64 (2H, broad s)
3rd 48 (3H, s)
Example 18
0.86 ml of anisole was added to a solution of 0.86 g of diphenylmethyl-7- [2-methoxyimino-2 (1,2,3-thiadiazol-4-yl) acetamido] -7-methoxy-3- (1 -inethyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylate (syn isomer) in 10 ml of dry 1,2-dichloroethane and then 1.68 g of trifluoroacetic acid were added dropwise with ice-cooling. 



  The resulting mixture was stirred under ice-cooling for 2 hours, and the reaction mixture was concentrated under reduced pressure.  20 ml of ethyl acetate and 20 ml of water were added to the residue.  After the mixture was shaken, the ethyl acetate layer was separated.  The remaining aqueous layer was further extracted with 10 ml and 5 ml of ethyl acetate.  The ethyl acetate layers were combined and 20 ml of a 10% aqueous dipotassium hydrogen phosphate solution was added.  The mixture was shaken and the aqueous layer was separated. 



  The ethyl acetate layer was further extracted with 10 ml and 5 ml of a 10% aqueous dipotassium hydrogen phosphate solution.  The aqueous layers were combined and washed successively with 10 ml and 5 ml of ethyl acetate and 10 ml of ether.  The residual solvent in the aqueous layer was removed by passing nitrogen gas through it.  The aqueous layer obtained was adjusted to pH 2 with 10% hydrochloric acid with ice cooling. 



  The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure, giving 0.21 g of 7- [2-methoxyimi no-2- (1,2,3-thiadiazol-4-yl) acetamido] - 7-methoxy-3- (1methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained. 



  I. R. - Spectrum (Nujol) 3250, 1780, 1730, 1690 cm-1 N. M. R. Spectrum (d6-DMSO, o) ppm 10. 22 (1H, s)
9. 27 (1H, s)
5. 17 (1H, s)
4th 22, 4. 4 (2H, ABq, J = 13Hz) 4. 01 (3H, s)
3rd 94 (3H, s)
3rd 90 (2H, s)
3rd 52 (3H, s)
Example 19
The following compounds were obtained in a similar manner to that in Example 18:
1) 7- [Methoxyimino-2- (1,2,3-thiadiazol-4-yl) acetamido] 3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cepnem-4-carboxylic acid (anti -Isomeres). 



  I. R. -Spectrum (Nujol) 3150.1760.1705.1660.1590.1530 cm- N. M. R. Spectrum (d6-DMSO, o) ppm 9. 68 (1H, s)
9. 58 (1H, d, J = 8Hz) 9. 51 (111, s)
5. 84 (1H, dd, J = 5.8Hz)
5. 20 (1H, d, J = 5Hz) 4. 45 (2H, ABq, J = 13Hz)
4th 07 (3H, s) 3rd 72 (2H, ABq, J = 17Hz) 7- [2-methoxyimido-2- (1,2,3-thiadiazol-4-yl) acetamido] -3 (1,3,4-thiadiazol-2-yl) thiomethyl -3-cephem-4-carboxylic acid (syn isomer), F.  90-98 C (dec. ). 



  I. R. - Spectrum (Nujol) 3250.1780.1725.1680, 1530 cm¯ N. M. R. Spectrum (d6-DMSO, o) ppm 9. 82 (1H, d, J = 8Hz)
9. 51 (1H, s)
9. 37 (1H, s)
5. 88 (1H, dd, J = 5, 8Hz)
5. 20 (1H, d, J = 5Hz)
4th 44 (2H, ABq, J = 13Hz)
3rd 99 (3H, s)
3rd 72 (2H, ABq, J = 17Hz)
3) 7- [2-methoxyimino-2- (5-methyl-1,3,4-thiadiazol-2-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3- cephem-4carboxylic acid (syn isomer), F.  175-178 C (dec. ). 



  I. R. - Spectrum (Nujol) 3250, 1785, 1700, 1665, 1620, 1590, 1550 cm-1 N. M. R. Spectrum (d6-DMSO, o) ppm 9.83 (1H, d, J = 8Hz)
9. 57 (1H, s)
5. 87 (1H, dd, J = 5.8Hz)
5. 18 (1H, d, J = 5Hz)
4th 43 (2H, ABq, J = 13Hz)
4th 00 (3H, s) 3. 70 (2H, ABq, J = 17Hz)
2nd 77 (3H, s)
4) 7- [2-methoxyimino-2- (5-methyl-1,3,4-thiadiazol-2-yl) acetamido] -3- (1,3,4-thidiazol-2-yl) thiomethyl-3- cephem-4carboxylic acid (anti-isomer), F. 110-115 C (dec. ). 



  I. R. - Spectrum (Nujol) 3200, 1780, 1730, 1680, 1630, 1530 cm-1 N. M. R. Spectrum (d6-DMSO, o) ppm 9. 74 (1H, d, J = 8Hz)
9. 52 (1H, s)
5. 86 (1H, dd, J = 5.8Hz)
5. 20 (1H, d, J = 5Hz)
4th 45 (2H, ABq, J = 13Hz)
4th 16 (3H, s) 3. 72 (2H, ABq, J = 17Hz)
2nd 90 (3H, s)
5) 7- [2-methoxyimino-2- (1,2,5-thiadiazol-3-yl) acetami do] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem- 4-carboxylic acid (anti-isomer), F.  115-120 C (dec. ). 



  I. R. - Spectrum (Nujol) 3300, 1770, 1700, 1675, 1625, 1585 cm-1 N. M. R. Spectrum (d6-DMSO, o) ppm 9. 6 (1H, s)
9. 55 (1H, d, J = 8Hz)
9. 30 (1H, s)
5. 82 (1H, dd, J = 5.8Hz)
5.18 (1H, d, J = 5Hz) 4. 42 (2H, ABq, J = 13Hz)
4th 10 (3H, s)
3rd 73 (2H, broad s)
6) 7- [2-Hydroxyimino-2- (isothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) . 



  I. R. -Spectrum (Nujol) 3250, 1790, 1700, 1660 cm- 'N. M. R. Spectrum (d6-acetone + D2O, o) ppm 9. 16 (1H, s)
8th. 78 (1H, s)
6. 00 (1H, d, J = 5Hz)
5. 25 (1H, d, J = SHz)
4th 43 (2H, s) 4. 00 (3H, s)
3rd 80 (2H, s)
7) 7- [2-Hydroxyimino-2- (1,2,5-thiadiazol-3-yl) acetamido] 3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn .  Isomeres), F.  155-160 C (dec. ). 



  N. M. R. Spectrum (d6-acetone + D2O, o) ppm 9. 00 (1H, s)
5. 30 (1H, d, J = 4.5Hz)
5. 07 (111, d, J = 4.5Hz)
4th 43 (2H, s)
4th 03 (3H, s)
3rd 87 (2H, s)
8) 7- [Methoxyimino-2- (1,2,3-thiadiazol-4-yl) acetamido] cephalosporanoic acid (anti-isomer). 



  I. R. - Spectrum (Nujol) 3300, 1780, 1730, 1680, 1640 cm-1 N. M. R. Spectrum (d6-DMSO, o) ppm 9. 72 (1H, s)
9. 60 (1H, d, J = 8Hz)
5. 88 (1H, dd, J = 5.8Hz)
5. 23 (1H, d, J = 5Hz)
4th 87 (2H, ABq, J = 13Hz)
4.07 (3H, s)
3rd 60 (2H, ABq, J = 17Hz)
2nd 04 (3H, s)
9) 7- [2-Methoxyimino-2- (1,2,3-thiadiazol-4-yl) acetamido] 3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem -4-carboxylic acid (anti-isomer), F.  104-115 C (dec. ). 

 

  I. R. - Spectrum (Nujol) 3350, 1785, 1730 cm-1 N. M. R. Spectrum (d6-DMSO, o) ppm 9. 72 (1H, s) 9. 61 (111, d, J = 8Hz)
5. 84 (1H, dd, J = 5.8Hz)
5. 15 (1H, d, J = 5Hz) 4. 38 (211, ABq, J = 13Hz)
4th 07 (3H, s)
3rd 70 (2H, broad s)
2nd 67 (3H, s)
10) 7- [2-methoxyimino-2- (1,2,3-thiadiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid ( anti-isomer). 



  I. R. - Spectrum (Nujol) 3300, 1790, 1730, 1690, 1630 cm-1 N. M. R. Spectrum (d6-DMSO, o) ppm 9. 78 (1H, s)
9. 66 (1H, d, J = 8Hz)
5. 83 (1H, dd, J = 5.8Hz)
5. 17 (1H, d, J = 5Hz)
4th 33 (2H, broad s)
3rd 93 (3H, s)
3rd 69 (2H, broad s)
11) 7- [2-Methoxyimino-2- (1,2,5-thidiazol-3-yl) acetamido] -3- (1,3,4-thidiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomeres), F.  111-120 C. 



  I. R. - Spectrum (Nujol) 3300, 1770, 1725, 1670, 1620, 1550 cm-1 N. M. R. Spectrum (d6-DMSO, o) ppm 9. 77 (1H, d, J = 8Hz)
9. 58 (1H, s)
9. 13 (1H, s)
5. 85 (1H, dd, J = 5.8Hz)
5. 18 (1H, d, J = 5Hz)
4th 43 (2H, ABq, J = 13Hz)
4th 02 (3H, s)
3rd 68 (2H, broad s)
12) 7- [2-methoxyimino-2- (1,2,3-thiadiazol-4-yl) acetamido] cephalosporanic acid (syn isomer). 



  I. R. - Spectrum (Nujol) 3300, 1790, 1735, 1680 cm-1 N. M. R. Spectrum (d6-DMSO, 8) 9. 83 (1H, d, J = 8Hz) 9. 40 (1H, s) 5. 86 (1H, dd, J = 5.8Hz) 5. 18 (1H, d, J = SHz) 4.83 (2H, ABq, J = 14Hz) 3. 97 (3H, s) 3rd 55 (2H, broad s) 2. 00 (3H, s)
13) 7- [2-Methoxyimino-2- (1,2,3-thiadiazol-4-yl) acetami do] -3-methyl-3-cephem-4-carboxylic acid (syn isomer).  F.  111116 C (dec. ). 



  I. R. - Spectrum (Nujol) 3300, 1785, 1720, 1660, 1600, 1548 cm-1 N. M. R. Spectrum (d6-DMSO, o) 9. 77 (1H, d, J = 8Hz) 9. 37 (1H, s) 5. 78 (1H, dd, J = 5.8Hz) 5. 11 (1H, d, J = 5Hz) 3. 97 (3H, s) 3rd 45 (2H, ABq, J = 17Hz) 2. 00 (3H, s)
14) 7- [2-methoxyimino-2- (1,2,3-thiadiazol-4-yl) acetami do] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, (syn-isomer). 



   I. R. Spectrum (Nujol)
3250, 1780, 1720, 1670 cm-1
N. M. R. Spectrum (d6-DMSO, o)
9. 77 (1H, d, J = 9Hz)
9. 36 (1H, s)
6. 54 (2H, s)
5. 87 (1H, dd, J = 5.9 Hz) 5. 16 (1H, d, J = SHz)
4th 74 (2H, ABq, J = 13Hz)
3rd 96 (3H, s)
3rd 51 (2H, broad s)
15) 7- [2-Methoxyimino-2- (1,2,3-thidiazol-4-yl) acetami do] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4 - carboxylic acid (syn isomer),
I. R. Spectrum (Nujol)
3300, 1780, 1730, 1680, 1630 cm-1
N. M. R. Spectrum (d6-DMSO, o) ppm 9. 89 (1H, d, J = 8Hz)
9. 40 (1H, s)
5. 88 (1H, dd, J = 5.8Hz)
5.20 (1H, d, J = 5Hz)
4th 33 (2H, broad s)
4th 01 (3H, s)
3rd 93 (3H, s)
3rd 73 (2H, broad s)
16) 7- [2-Methoxyimino-2- (1,2,3-thiadiazol-4-yl) acetami do] -3- (2-dimethylaminoethyl) 1H-tetrazol-5-yl] thio methyl-3-cephem -4-carboxylic acid (syn isomer). 

 

   I. R. Spectrum (Nujol)
1775, 1670, 1605 cm-1
N. M. R. Spectrum (d6-DMSO, o) ppm 9.85 (1H, d, J = 8Hz)
9. 43 (1H, s)
5. 83 (1H, dd, J = 5.8Hz)
5. 15 (1H, d, J = 5Hz)
4th 37 (2H, t, J = 5Hz)
4th 30 (2H, broad s)
3rd 98 (3H, s)
3rd 65 (2H, broad s)
3rd 05 (2H, t, J = 5Hz)
2nd 38 (6H, s)


    

Claims (10)

 PATENT CLAIMS 1. 3,7-disubstituted-3-cephem-4-carboxylic acid compounds, characterized by the general formula EMI1.1  in which mean: R 'thiadiazolyl or isothiazolyl, each of which may have one or more substituents, R2 is hydrogen or lower alkyl, R3 carboxy or esterified carboxy, R4 is hydrogen, acyloxy or a hetero ring bonded via a thio group, which may have one or more substituents, and R5 is hydrogen or lower alkoxy, and their salts.  2. Compounds according to claim 1, characterized in that in the formula (I) Rl isothiazolyl or thiadiazolyl, which is optionally substituted by a lower alkyl, and R4 is hydrogen, acyloxy or a hetero ring bonded via a thio group, which is optionally by lower alkyl or Di (lower) alkylamino (lower) alkyl is substituted.  3. Syn isomers of the compounds of claim 2, wherein syn means the arrangement with respect to the acid amide group.  4. Compounds according to claims 1 to 3, characterized in that R3 is carboxy.  5. Compounds according to claims 1 to 4, characterized in that R2 means lower alkyl.  6. Compounds according to claim 5, characterized in that the Rl thiadiazolyl, which is optionally substituted by a lower alkyl, and R4 a hetero bonded via a thio group, which is optionally substituted by a lower alkyl or a di (lower) alkylamino (lower) alkyl is mean.  7. Compounds according to claim 6, characterized in that R4 is an unsaturated 5-membered monocyclic hetero ring bonded via a thio group, the four nitrogen atoms with a lower alkyl or a di (lower) alkylamino (lower) alkyl or a sulfur atom and two nitrogen atoms contains means.  8. Compounds according to claim 7, characterized in that R4 is tetrazolylthio which is substituted by a lower alkyl or a di (lower) alkylamino (lower) alkyl, or thiadiazolylthio.  9. A compound according to claim 8, characterized in that Rl is thiadiazolyl and R4 is tetrazolylthio which is substituted by a lower alkyl or a (di (lower) alkylamino (lower) alkyl).  10. Antibacterial agent, characterized in that it contains as active ingredient a 3,7-disubstituted 3-cephem-4-carboxylic acid compound according to claim 1 or a pharmaceutically acceptable salt thereof.  The invention relates to new 3,7-disubstituted-3-cephem4-carboxylic acid compounds and their salts, in particular their pharmaceutically acceptable salts, which have antimicrobial activity, and pharmaceutical compositions containing them or antibacterial agents that can be used for the therapeutic treatment of infectious diseases in humans and animals.  An object of the present invention is to provide new 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and their salts, especially their pharmaceutically acceptable salts, which are highly effective against a number of pathogenic microorganisms.  The aim of the invention is also to provide new pharmaceutical compositions which contain at least one of the 3, 7-disubstituted-3-cephem-4-carboxylic acid compounds and / or their pharmaceutically acceptable salts as active ingredient and which are used for the treatment of pathogenic by Bacteria can be used in humans and animals for infectious diseases.  Cephalosporin compounds were already known which carry an acetamido group in the 7-position, the 2-position of which is substituted by an etherified oxyimino group and a heterocyclic group (DE-OS 2 223 375) or which in the 7-position is a 2-alkoxyimino-2 - (2-aminothiazol-4-yl) acetamido group are substituted (DE-OS 2 556 736).  The 3,7-disubstituted-3-cephem-4-carboxylic acid compounds forming the subject of the invention are new and they can be represented by the general formula: EMI1.2  in which mean: R1 thiadiazolyl or isothiazolyl, each of which may have one or more substituents, R2 is hydrogen or lower alkyl, R3 carboxy or esterified carboxy, R4 is hydrogen, acyloxy or a hetero ring bonded via a thio group, which may have one or more substituents, and R5 is hydrogen or lower alkoxy.    The 3, 7-disubstituted-3-cephem-4-carboxylic acid compounds of formula (I) can be prepared by conventional methods as used in the field of cephalosporins, which can be represented by the following reaction scheme: ** WARNING ** End of CLMS field could overlap beginning of DESC **.