NO810767L - PROCEDURE FOR THE PREPARATION OF MICROBIALLY ACTIVE CEPHALOSPORINE DERIVATIVES. - Google Patents

Description

The present invention relates to the production of new cefem compounds and pharmaceutically acceptable salts thereof. More particularly, the invention relates to the production of new cefem-

compounds and pharmaceutically acceptable salts thereof which have antimicrobial activities, and further a method for

conversion of these compounds and salts therapeutically by treat-

ling of infectious diseases in humans and animals.

Accordingly, it is an object of the invention to provide

novel cefem compounds and pharmaceutically acceptable salts thereof,

which are active against a number of pathogenic microorganisms.

Another purpose of the invention is to provide

pathways for the production of new cefem compounds and pharma-

cosmetically acceptable salts thereof.

A further object of the invention is to provide pharmaceutical preparations which comprise, as active ingredients,

the said novel cefem compounds and pharmaceutically acceptable salts thereof.

Another object of the invention is to provide a method for the treatment of infectious diseases caused by pathogenic bacteria in humans and animals.

The new cefem compounds can be represented by the following

general formula (I):

where

R is amino or a protected amino group;

2

R is hydrogen, lower alkyl which may be substituted with a

or more suitable substituents, lower alkenyl, lower alkynyl, cyclo(lower)alkyl, cyclo(lower)alkenyl, or O-containing 5-membered heterocyclic group substituted with a

or more oxo groups;

R 3 is a group with the formula:

X is hydrogen or carbamoyl; and

where

R is _C00~; . or

R 3 is 2-lower alkyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazinyl-

ten; and

4

R is carboxy or protected carboxy.

According to the invention, the compound of formula (I) can be prepared by the following methods:

Procedure 2

Method 3 ' Method 4

12 3 4

where R , R , R , and R are each as defined above;

R a is a group which may be substituted with a group of

3 3

formula: R where R is as defined above;

R^<k>is a compound with formula:

where

X is as defined above and

R^<a>is carboxy; or

3b 3c 3c

R is one. compound of formula: R -H where R is 2-lower alkyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazinylthio and R is carboxy or protected carboxy;

R a is protected carboxy(lower)alkyl;

2 Id

R is carboxy(lower)alkyl; and

2c

R is a protecting group of hydroxy.

Among the starting compounds used in the invention, some of the compounds with formula (Ia) are new and can be prepared by the following methods.

1.

in. ^1 ^2 2a 2b n ..r.

where R , R , R and R are each as defined above,

R"^ is lower alkanoyl(lower)alkanoyloxy and R is carboxy or protected carboxy.

Furthermore, some of the compounds (II) can be prepared by

the following methods:

3rd

where X is as defined above and R is a group which may be

substituted with a group of formula:

Among these compounds, compound (XI) is new.

With regard to the compounds produced according to the invention, with formulas (I), (Ib), (Ic), (Id) and (le) and the starting compounds (III), (VI), (VII), (VIII ) and (XIII), shall

that. are understood to include tautomeric isomers. This means that in the event that the group of formula:

(R"<*>" is as defined above) is contained in

the molecules in the aforementioned compounds that produce

is set according to the invention and the output connections, so . the aforementioned group with the indicated formula can also alternatively be represented by its tautomeric formula:

(R is imino or a protected imino group.) This means that both of the mentioned groups are in equilibrium with each other, and such a tautomerism can be represented by the following equilibrium statement:

1 1'

where R and R .each are as defined above.

These types of tautomerism between the amino compound and the corresponding imino compound as stated above have been well known in the literature, and it is obvious to a person skilled in the art that both tautomeric isomers can be easily converted reciprocally and belong to the same category of the compound as like that.

Accordingly, both the tautomeric forms of the compounds produced according to the invention and the starting compounds discussed above are clearly included within the scope of the invention. In the present description and claims, the different types of compounds including the group of such tautomeric isomers are represented by using one of the designations for them, i.e. the following formula:

Furthermore, with regard to the compounds (I), (I ), (Ib), (Ic), (Id) and (le) and the starting compounds (III), (VI), (VII), (VIII) and ( XIII) it is understood that both types of compounds include syn-isomer, anti-isomer and a mixture thereof. For example, with regard to the compound of formula (I), syn isomer means one geometric isomer which has the partial structure represented by the following formula:

(where R ■ 1 and R 2 are as defined above) and anti-isomer means it

other geometric isomer having the partial structure represented by the following formula

(where R 1 and R 2 are each as defined above).

With respect to the other compounds of both categories mentioned above, the syn isomer and the anti isomer may also be referred to as the same geometric isomers as illustrated for the compound of formula (I).

Suitable pharmaceutically acceptable salts of the compounds of formula (I) are conventional non-toxic salts and include such a metal salt as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc. ), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,H'-dibenzylethylenediamine salt, etc.), an organic acid salt (e.g. acetate, maleate , tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt (e.g., hydrochloride, hydrobromide, hydroiodide, thiocyanate, sulfate, phosphate, etc.), or a salt with an amino acid (e.g. e.g. arginine, α-paragic acid, glutamic acid, etc.) and the like.

In the above and subsequent mentions in the present description, suitable examples and illustrations of the various definitions which the present invention includes within its scope are explained in detail below.

The term "lower" or "low-<*>" shall mean 1-|6 carbon atoms, unless otherwise indicated.

Suitable "protected amino" for R 1 may include an acyl-amino or an amino group substituted with a conventional protecting group, e.g. ar(lower)alkyl which may have at least one suitable substituent (eg benzyl or trityl) or the like.

Appropriate acyl moiety 1 term "acylataino" may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring. Furthermore, suitable examples of said acyl can be lower-alkanoyl (e.g.* formyl, acetyl-, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.) j lower-alkoxycarbonyl (e.g. methoxy— carbonyl, ethoxycarbonyl, propoxycarbonyl., 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.); lower alkanesulfonyl (eg, mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.);

arenesulfonyl (eg, benzenesulfonyl, tosyl, etc.);

aroyl (eg, benzoyl, toluoyl, syloyl, naphthoyl, phthaloyl, indacarbonyl, etc.);

ar(lower)alkanoyl (eg, phenylacetyl, phenylpropionyl, etc.); are (lower) alkoxycarbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, etc.) and the like*

The Aeyl moiety as indicated above may require at least one suitable substitute, e.g. halogen (chlorine, bromine, fluorine and iodine), lower alkanoyl as indicated above, or the like.

Suitable lower alkyl for R 2 is one having 1-6 carbon atoms and may include methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, pentyl, tert-pentyl , hekayl et al., and preferably one having 1-4 carbon atoms.

Appropriately, the<a>lower-alkyl'* substituent on 1,2,4-triazinylthio for R and lower alkyl^moieties in the terms "protected carboxy (lower) alkyl" and "carboxy(lower) alkyl<a>may refer to them as exemplified above" **Lower alkyln father R 2 may be substituted with 1-3 suitable substituents, eg halogen (eg chloro>bromo, fluorine or iodine); carboxy; protected carboxy as mentioned below; low -alkylthio (e.g. methylthio, ethylthio, propylthio, butylthio, etc.); aryl (e.g. phenyl, tolyl, xylyl, mesityl, cumenyl, etc.); etc.

Suitably, lower alkenyl may include vinyl, allyl, iso-propenyl, 1-propenyl, 2-butenyl, 3-psntenyl and the like, preferably one having 2-4 carbon atoms.

Suitably lower alkynyl may include a group having 2-6 carbon atoms* e.g. ethynyl, 2-propynyl; 2-butynyl, 3-pentynyl, 3-hexynyl or the like, preferably one having 2-4 carbon atoms.

Suitably, cyclo(lower)alkyl may include a group which

has 3-6 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like, preferably one having 4-6 carbon atoms.

Appropriately, cyclo(lower)alkenyl may include a group having 3-6 carbon atoms, e.g. cyclopentenyl, cyclohexenyl or the like, preferably one having 5 or 6 carbon atoms.

Suitably, a G-containing 5-membered heterocyclic group may include saturated or unsaturated groups, e.g. dihydrofuryl, tetrahydrofuryl or the like, which is substituted with 1 or 2 oxo groups.

Appropriately, protected carboxy and protected carboxy moiety in the term "protected carboxy(lower)alkyl" may include esterified carboxy where the ester may: be, for example, lower alkyl ester (e.g. methyl ether* ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester , t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, i-cyclopropyl ethyl ester, etc.), where the lower alkyl portion may preferably be one having 1-4 carbon atoms; lower alkenyl esters (eg, vinyl esters, allyl esters, etc.); lower alkynyl esters (eg, ethynyl esters, propynyl esters, etc.); mono (or di or tri )-halogen(lower) alkyl esters (eg, 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower alkanoyloxy (lower) alkyl ester (e.g., acetoxymethyl ester, propionyloxymethyl ester, 1-acetoxypropyl ester, valeryloxyethyl ester, pivalyloxymethylester, -hexanoyloxymethylester, 1-acetoxyethylester, 2-propionyloxyethylester, 1-isobutyryloxyethylester, etc.);

lower alkanesulfonyl (lower) alkyl esters (eg, raesyl methyl ester, 2-mesyl ethyl ester, etc.);

ar(lower) alkyl ester, e.g. phenyl (lower) alkyl ester which may be substituted with one or more suitable substituents (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester., phenethyl ester, trityl ester, diphenyl methyl ester, bis(methoxyphenyl) methyl ester, 3, 4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert.-butyl benzyl ester, etc.);

lower alkoxycarbonyloxy(lower)alkyl esters (eg methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, ethoxycarbonyloxyethyl ester, etc.) which may be substituted with azido;

a heterocyclic ester preferably benzotetrahydrofuryl ester which may be substituted with an oxo group, more preferably phthalidyl ester;

aroyloxy(lower)alkyl ester (eg, benzoyloxyethyl ester, benzoyloxyethyl ester, toluoyloxyethyl ester, etc.);

aryl esters sora can have one or more suitable substituents (e.g. phenyl ester, tolyl ester, tert-butyl phenyl ester, xylyl ester, inesity ester, cumenyl ester, etc.) etc.

Preferred examples of protected carboxy may be lower carboxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, etc.) having 2-7 carbon atoms, preferably a group having 2-5 carbon atoms, and phenyl(lower)-alkoxycarbdnyl which may be substituted with nitro (e.g. 4-nitrobenzyloxycarbonyl, benzyloxycarbonyl, 4-nitrophenethyloxycarbonyl, etc.).

Preferred examples of R 3 a and R 3 e may include acyloxy, halogen, azido and the like, where the acyl part in the term "acyloxy" and halogen may refer to those exemplified earlier.

A suitable protecting group for hydroxy may include aryl acyl, ar (lower) alkyl (eg, benzyl, trityl, etc.) and the like.

Suitably, lower alkarioyl(lower)alkanoyloxy may include acetoacetoxy, propionylacetoxy, acetopropionyloxy and the like.

In the following, preferred compounds of formula (I) shall be indicated.

R* is preferably amine©;

R is hydrogen, lower-^alkyl, ar(lower)alkyl I or triphenyl(lower)-alkyl], lower-alkylthio(lower)alkyl, halo(lower)alkylIor tri-halo(lower)alkyl1, carboxy(lower)alkyl , esterified carboxy(lower) alkyl [or lower alkoxycarbonyl(lower) alkyl or phenyl(lower) alkoxycarbonyl(lower) alkylJ, lower alkenyl, lower alkynyl, cyclo(lower) alkyl, cyclo(lower) alkenyl, or tetrahydrofuryl substituted with

oxo group;

R is a group with the formula?

where X is hydrogen

or carbamoyl and R<4> is -C00=* or

3

R is 2-lower alkyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazinyl-thio and R 4 is carboxy.

The methods according to the invention will be explained in detail in the following.

Procedure 1

The compound of formula (I) can be prepared by reacting the compound of formula (IX) or its reactive derivative at the amino group or a salt thereof with the compound of formula (III) or its reactive derivative at the carboxy group or a salt thereof.

Suitable reactive derivatives at the amino group of compound (II) may include conventional reactive derivatives used in amidation, for example imino-type Schiff's base or its tautomeric enamine-type isomer formed by reacting compound (II) with a carbonyl compound; a silyl derivative formed by reacting compound (II) with a silyl compound, e.g. bis(trimethylsilyl)acetamide, trimethylsilylacetamide or the like; a derivative formed by reaction of compound (II) with phosphorus trichloride or phosgene, and the like.

Suitably, a salt of compound (II) may include an acid addition salt such as e.g. an organic acid salt (eg, acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate, etc.) or an inorganic acid salt (eg, hydrochloride, hydrobromide, sulfate, phosphate, etc*);

a metal salt (eg, sodium salt, potassium salt, calcium salt, magnesium salt, etc.); ammonium aalt; an organic amine salt (eg, triethylamine salt, dicyclohexylamine salt, etc.), and the like.

Suitably, a reactive derivative at the carboxy group of compound (III) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like. A suitable example would be an acid chloride; an acid azide^ a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphoric acid., sulfuric acidTl thiosulfuric acid, sulfuric acid, alkylcarboxylic acid, aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, acetic acid or trichloroacetic acid, etc.) or aromatic carboxylic acid (eg, benzoic acid, etc.); a symmetrical acid anhydride; an activated amide with iridazole, dimethylpyrazole, triazole or tetrazole; or an activated ester (e.g. cyano-methyl ester, methoxy methyl ester, dimethyliminomethyl f(CH3)2N ~CH-1 ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-di-nitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, raesyl phenyl ester , phenylazophenyl ester, phenylthioester, p-nitrophenylthioester*p-cresylthioester, carboxymethylthioester, pyranyl ester, pyridylester, piperidylester, 8-quinolylthioester, or an ester with N,N-dimethylhydroxylamine, l-hydroxy-2-(lH)-pyridone, N -hydroxysuccinimide, N-hydroxyphthalimide, or 1-hydroxy-6-chloro-1H-benzoetriazole, etc. These reactive derivatives can optionally be selected from among those among the type of compound (III) to be used.

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

The reaction is usually carried out in a conventional solvent, e.g. water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent that does not adversely affect the reaction. Among these solvents, hydrophilic solvents can be used in mixture with water.

If compound (III) is used in free acid form or its salt form in the reaction, then the reaction is preferably carried out in the presence of a conventional condensing agent, e.g. N,N-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N 1 -(4-diethylaminocyclohexyl)carbodiimide; N,N-diethylcarbodiimide; N,N-diisopropylcarbodiimide; N-ethyl-N1-(3-dimethylaminopropyl)carbodiimide; N,N-carbonylbis(2-methylimidazole); pentamethylene-ketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; ethyl polyphos barrel; isopropyl polyphos barrels; diethylphos forchloridite; phos oxychloride; phos for trichloride; phos forpentachloride; thionyl chloride; oxalyl chloride; triphenylphosphine; N-ethyl-7-hydroxybenzisoxazolium fluoroborate; N-ethyl-5-phenyl-isoxazolium-3'-sulfonate; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzoetriazole; so-called Vilsmeier reagent, for example (chloromethylene)dimethylammonium chloride produced by reacting dimethylformamide with thionyl chloride or phosgene, a compound produced by reacting dimethylformamide with phosphorus oxychloride, etc.

The reaction can also be carried out in the presence of an inorganic or organic base, e.g. an alkali metal hydroxide, an alkali metal bicarbonate, alkali metal carbonate, alkali metal acetate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholih, N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline as exemplified below , etc. If the base or condensing agent is liquid, it (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 above-mentioned reaction, a syn-isomer of the compound of formula (I) can be obtained preferably by carrying out the reaction of compound (II) with a syn-isomer of the starting compound (III).

Procedure 2

The compound of formula (I) or a salt thereof can be prepared by reacting compound (XIII) or a salt thereof with compound (IV) or its reactive derivative.

Suitable salts of compound (XIII) can be mentioned such as

is exemplified for compound (II).

A suitable reactive derivative of compound (IV) may include a metal salt such as an alkali metal salt (eg, sodium salt, potassium salt, etc.) or the like.

The reaction described here can be carried out in a solvent such as e.g. water, phosphate buffer, acetone, chloroform, nitrobenzene, methylene chloride, ethylene chloride, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethylsulfoxide or any other organic solvent that does not adversely affect the reaction, preferably those with strong polarities. Among the solvents, hydrophilic solvents can be used in mixture with water. The reaction is preferably carried out in an approximately neutral environment. If compound (XIII) or compound (IV) is used in free form, the reaction is preferably carried out in the presence of a base, for example an inorganic base, e.g. alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, an organic base, e.g. trialkylamine and the like. The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, possibly under slight heating.

The reaction discussed here includes within its scope the case that a protected carboxy group is converted into a free carboxy group during the course of the reaction.

Procedure 3

The compound of formula (Ic) or a salt thereof can be prepared by subjecting compound (Ib) or a salt thereof

for elimination reaction of the protecting group of carboxy.

Suitable salts of compound (Ib) are, for example, those which are

exemplified for the compound (II)..

The reaction discussed here is carried out in accordance with a conventional method such as e.g. hydrolysis, reduction etc.

If the protecting group is an ester, the protecting group can be removed by hydrolysis. Hydrolysis is preferably carried out in the presence of a base or an acid. A suitable base may include an inorganic base and an organic base, e.g. an alkali metal (eg sodium, potassium, etc.), an alkaline earth metal

(e.g. magnesium, calcium, etc.), the hydroxide, or carbonate or bicarbonate thereof, trialkylamine (e.g. trimethylamine, triethylamine, etc.), picoline, 1,5-diazabicycloI4,3,0Jnon-5-ene, 1,4-diazabicycloI2,2,2Joctane, 1,8-dia2abicycloI5,4,0]undecene-7 or the like. A suitable acid may be an organic acid (eg formic acid, acetic acid, propionic acid, trifluoroacetic acid, etc.) and an inorganic acid (eg hydrochloric acid, hydrobromic acid, sulfuric acid, etc.).

The reaction is usually carried out in a solvent such as water, an alcohol (eg, methanol, ethanol, etc.), a mixture thereof, or any other solvent that does not adversely influence the reaction. A liquid base or acid can also be used as a solvent. The reaction temperature is not critical, and the reaction is usually carried out during cooling or heating.

Reduction can preferably be used to remove it

. protecting group, for example 4-nitrobanzyl, 2-iodoethyl, 2,2,2-trichloroethyl or the like. The reduction method applicable to the elimination reaction may include, for example, reduction using a combination of a metal (e.g. zinc, zinc amalgam, etc.) or a salt of a chromium compound (e.g. chromium(II) chloride, chromium (II)acetate, etc.) and an organic or inorganic acid (eg acetic acid, propionic acid, hydrochloric acid);

and conventional catalytic reduction in the presence of a conventional metal catalyst (eg, palladium-carbon).

Procedure 4

The compound of formula (Ie) or a salt thereof can be prepared by subjecting compound (Id) or a salt thereof to the elimination reaction of the protecting group of hydroxy.

A suitable salt of compound (Id) may be such as are

exemplified for compound (II).

The elimination reaction mentioned here can be carried out in essentially the same way as with the acid hydrolysis in method 3.

The production of output connections will now be explained in detail.

Production 1

Compound (VI) or a salt thereof can be prepared by reacting compound (III) or its reactive derivative at the carboxy group or a salt thereof with compound (V) or its reactive derivative at the amino group or a salt thereof.

A suitable reactive derivative and salt for compound (V)

is, for example, as exemplified for compound (II).

The reaction mentioned here can be carried out in essentially the same way as stated for method 1.

. Manufacturing 2

Compound (VIII) or a salt thereof can be prepared by subjecting compound (VII) or a salt thereof to the elimination reaction of the protecting group of carboxy.

As suitable salts of compound (VII) can be mentioned those which

is exemplified for compound (II).

The reaction mentioned here can be carried out in essentially the same way as stated for method 3.

Manufacturing 3

Compound (XI) or a salt thereof can be prepared by

react compound (IX) or a salt thereof with compound (X).

As suitable salts of compound (IX) can be mentioned those which

is exemplified for compound (II).

The turnover can be carried out in essentially the same way as described for method 2.

Manufacturing 4

Compound (XII) or a salt thereof can be prepared by subjecting compound (XI) or a salt thereof to the elimination reaction of the protecting group of amino at the 7-position.

The aforementioned elimination reaction is carried out by a method by reacting compound (XI) or a salt thereof with an iminohalogenating agent and then with an iminophoretic agent and, if necessary, hydrolysis of the resulting compound.

The reaction is carried out according to a conventional method.

In the previously mentioned reactions and/or post-processing of the reactions according to the present invention, the previously mentioned geometric isomer and/or tautomeric isomer can occasionally be converted into the other geometric isomer and/or tautomeric isomer, and such cases shall also be included within the scope of the invention frame.

If the compound of formula (I) has a free carboxy group and/or a free amino group, it can be converted into its pharmaceutically acceptable salt, as mentioned earlier, by a conventional method.

The compound of formula (I) produced according to the invention exhibits high antimicrobial activity and inhibits the growth of a number of microorganisms including pathogenic gram-positive and gram-negative bacteria.

For therapeutic administration, the cephalosporin compounds produced according to the invention* are used in the form of a pharmaceutical preparation containing the aforementioned compounds in admixture with pharmaceutically acceptable carriers, e.g. an organic or inorganic, solid or liquid excipient suitable for oral, parenteral or extemal administration. The pharmaceutical preparations can be in solid form*, e.g. as capsules, tablets, dragees, ointment or suppositories, or in liquid form, e.g. in solution, suspension or emulsion. If desired, excipients, stabilizers, wetting or emulsifying agents, puffers and other commonly used additives can be included in the above-mentioned preparations.

Although the dosage of the compounds may vary and also depend on the age and condition of the patient, an average single dose of approx. 50 mg, 100 mg, 250 mg and 500 mg of the compounds produced according to the invention have been shown to be effective for the treatment of infectious diseases caused by a number of pathogenic bacteria. In general, a daily dose of between 1 mg/body weight and approx. 1000 mg/body weight or even more is administered.

In order to show the usefulness of the compounds of formula (I), test data regarding antimicrobial activity for representative compounds produced according to the invention will now be given.

Test method

A loop filled with an overnight culture of each test strain in Trypticase soy broth (10 viable cells per ml) was plated on heart infection agar (HI agar) containing graded concentrations of antibiotics, and the least inhibitory concentration -tion (MIC) was expressed as µg/ml after incubation at 37°C for 20 hours.

Test connection

(1) 7-C2-ethoxyimino-2-(5-amino-1,2,4-thiadlazol-3-yl)-acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (2) 7-12-allyloxyimino~2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-eephen-4- carboxylate (syn isomer) (3) 7-12-(2-propynyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3 -cephem-4-carboxylate

(syn isomer)

(4) 7-{2-Cyclopentyloxy imino-2-(5-amino-1,2,4-thiadiazol-3-yl)-

aeetamido]-3-(1-pyridiniomethyl)-3-ceph em-4-carboxylate

(syn isomer)

(5) 7-t 2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3- cephem-4-carboxylate (syn-isomer) (6) 7-12-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamidol-3-(1-pyridiniomethyl)-3- cefera-4-carboxylate (syn isomer) (7) 7-[2-isopropoxyamino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-(2-methyl- 5-oxo-6-hydroxy-2,5-dihydro-1,2,4-tri-azin~3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (8) 7-[2- ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer).

With regard to the nomenclature for the compounds produced according to the invention (3-pyridinium methyl compound, etc.), there are different types. For example, the following compound (A) is designated as 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4 -carboxylate (syn isomer) or N-[7-(2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido)-3-cephem-3-ylmethyl]pyridinium- 4-carboxylate (syn isomer). Furthermore, the hydrochloric acid salt of compound (B) is designated 1-t(7-amino-4-carboxy-3-cephem-3-yl)-methyl]pyridinium chloride or N-[7-amino-3-cephem-3-ylmethyl]-pyridinium -4-carboxylate hydrochloride.

The other compounds disclosed herein in the specification and claims are similarly designated, and they are all included

within the scope of the invention.

The following manufacturing descriptions and examples are given for the purpose of illustrating the present invention.

Production 1

Preparation of methyl 5-amino-1,2,4-thiadiazole-3-carboxylate.

To a solution of 16.6 g of 1-ethoxycarbonylformamidine hydrobromide in 84 ml of absolute methanol was added a solution of 1.93 g of sodium in 42 ml of absolute methanol at 0°C. To the mixture was alternately added 12.8 g of bromine and a solution of 1.93 g of sodium in 42 ml of absolute methanol at 0°C, and then 8.1 g of potassium thiocyanate in 100 ml of absolute methanol was added to the suspension. The reaction mixture was stirred for one hour at 0°C and for a further 6 hours at ambient temperature. The mixture was filtered through cellulose powder, and the filtrate was evaporated

dryness. The evaporation residue was dissolved in a mixture of ethyl acetate and water, and then the ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was triturated with diethyl ether to give the title compound (9.0 g), m.p. 202-205°C.

I.R. (Bujol)s 3400, 3250, 3100, 1710, 1610, 1540 cm"<1>

N.M.R. (cL-DHSG)

3.85 (3H, s)* 8.25 (2H, s)

Produce, ing 2

Preparation of methyl 5-formamido 1,2,4-thiadiazole-3-carboxylate.

To a mixture of 33 g of formic acid and 22 g of acetic anhydride was added 6.2 g of methyl-5-amino~1,2,4-thiadiazole-*3-carboxylate,

and then the mixture was stirred for 2 days at ambient temperature.

The reaction mixture was concentrated under reduced pressure, and

the residue was triturated with a mixture of diethyl ether and n-hexane to give the title compound (7.2 g), sra.p. 210-215°C.

I.R. (Nujol): 3100, 1720, 1680 cm"<1>

N.M.R. (d6-DMS0)

6: 3.90 (3H, s) , 8.85 (1H, s)

Manufacturing 3

Preparation of 5-forraamido-3-(2-methylthio-2-methylsulfinyl-acetyl)-1,2,4-thiadiazole.

7.1 g of 50% sodium hydride while cooling in an ice bath." The mixture was stirred for one hour at ambient temperature and for an additional hour at 40°C. After cooling to ambient temperature, 300 ral of methylene chloride was added to the reaction mixture, and the resulting precipitates were collected by filtration and washed with methylene chloride. The precipitates were added to a stirred mixture of 14.7 mL hydrochloric acid, 200 mL ice water, and 200 mL methylene chloride. An insoluble material was filtered off, and the methylene chloride layer was separated from the filtrate. The solution was dried over anhydrous magnesium sulfate, evaporated and the evaporation residue triturated with diethyl ether to obtain the title compound (4.5 g),

sm.p. 130-132°C.

I.R. (Nujol): 3100, 1680, 1670 cm"<1>

N.M.R. (dg-DMSO)

Manufacturing 4

Preparation of S-methyl(5-formamido-1,2,4-thiadiazol-3-yl)-thioglyoxylate.

A mixture of 0.85 g of 5-formamido-3-(2-methylthio-2~methyl-aulfinylacetyl)-1,2,4-thiadiazole and 6.2 g of sodium periodate in 10 ml of glacial acetic acid was stirred for 45 minutes at 70° c. The reaction mixture was evaporated and the evaporation residue was dissolved in a mixture of ethyl acetate and water. The mixture was adjusted to pH 7 with an aqueous solution of sodium bicarbonate and treated with an aqueous solution of sodium thiosulfate. The organic layer was separated, dried over anhydrous magnesium sulfate and evaporated to dryness. The evaporation residue was triturated with a mixture of diethyl ether and petroleum ether to give the title compound (280 mg)^ m.p. 186-187°C.

I.R. (Nujols 3lOO, 1680, 1660 cm"1

N.M.R. (d6~DMS0)

5in 2.55 (3H, s), 8.95 (1H, s)

Manufacturing 5

Preparation of 2-methoxyamino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid {syn isomer).

A mixture of 231 mg of S-raethyl (5-formamido-1,2,4-thiadiazol-3-yl)thioglyoxylate in 2 ml of methanol and 3.5 mg of 1N aqueous solution of potassium hydroxide was stirred for one hour at ambient temperature. The mixture was adjusted to pH 7.6 with 1N hydrochloric acid, followed by the addition of 90 mg of O-methylhydroxylamine hydrochloride and stirring for 30 minutes at ambient temperature. The reaction mixture was neutralized with an aqueous solution of sodium bicarbonate and concentrated to remove methanol. The concentrated aqueous solution was adjusted to pH 4 with hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH 1 with hydrochloric acid, saturated with sodium chloride and extracted with ethyl acetate. The extract was evaporated to dryness and the evaporation residue triturated with diethyl ether, collected by filtration and. then dried to give the title compound (80 mg), m.p. 185-186°C.

I.R. (Nujol): 3150, 1720, 1690 cm"1

N.M.R. (dg-DMSO)

<5S 3.98 (3H, s), 8.84 <1H, >)

Manufacturing 6

Preparation of 2-methoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer).

A mixture of 3.2 g of 5-formamido-3-(2-methylthio-2-imethyl-sulfinylacetyl)-1,2,4-thiadiazole and 0.8 g of sodium periodate in 32 ml of glacial acetic acid was stirred for 45 minutes at 70° C. The resulting mixture was evaporated and the residue washed with n-hexane, and then 20 ml of methanol and 40 ml of a 1% aqueous solution of potassium hydroxide were added. The solution was stirred for one hour at ambient temperature. The reaction mixture was adjusted to pH 8 with 1N hydrochloric acid, followed by the addition of 0.96 g of O-methylhydroxylamine hydrochloride and stirring for one hour at ambient temperature. The reaction mixture was neutralized with an aqueous solution of sodium bicarbonate and concentrated to remove methanol. The resulting aqueous solution was washed with ethyl acetate, adjusted to pH 1 with 1056 hydrochloric acid, saturated with sodium chloride and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, evaporated and the evaporation residue triturated with diisopropyl ether to give the title compound (1.02 g), m.p. 185-186°C.

Manufacturing 7

Preparation of 2-rethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer).

A solution of 1.4 g of 2-metoxyimino-2-{5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) in 19.1 ml of a 1N aqueous solution of sodium hydroxide was heated at 50° to 55°C for one hour. 1.9 ml conc. was added to the solution. hydrochloric acid while cooling in an ice bath. The mixture was saturated with sodium chloride and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated to dryness. The evaporation residue was triturated with diethyl ether to give the title compound (0.9 g), m.p. 180-182 °C (decomposition).

I.R. (Nujol): 3450, 3250, 3100, 1715, 1610, 1530 caf<1>N.M.R. (d6-DMS0)

5: 3.90 (3H, s), 8.1© (3H, wide s)

Presentation 8

A mixture of 10 g of 5-formamido-3-(2-methylthio-2-methyl-sulfinylacetyl)-1,2,4-thiadiazole and 2.0 g of sodium periodate in 50 ml of glacial acetic acid was stirred for 50 minutes at 70°C. The solvent was evaporated and the residue washed with n-hexane. To the residue was added 160 ml of a 1N aqueous solution of sodium hydroxide, and the mixture was stirred for one hour at ambient temperature. 3.5 g of O-ethylhydroxylamine hydrochloride was added to the reaction mixture, and the solution was adjusted to pH 3-4 with 1096 hydrochloric acid and then stirred for one hour at ambient temperature. After an insoluble material was filtered off, the filtrate was washed with ethyl acetate, adjusted to pH 1 with 1036 hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated to dryness. The evaporation residue was triturated with a mixture of diethyl ether and diisopropyl ether to give 2-ethoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)-acetic acid (syn isomer), (4.5 g ), sm.p. 165-168°C (decomposition).

I.R. (Nujol): 3450, 3170, 3050, 1730, 1690, 1595, 1565 cm"<1>N.M.R. (d,-DMS0)

O: 1.30 (3H, t, J=7Hz), 4.30 (2a, q,J~7Hz),

8.87 (1H, s)

Production 9

The following compounds were obtained in a similar manner to Preparation 8: (1) 2-propoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer), m.p. 168-170°C (decomposition). I.R. (Nujol): 3250, 3140, 1720, 1690, 1590, 1530 cm"<1>N.M.R. (d6-DMS0) 6: 0.90 (3H, t, J»6Hz), 1.4-1.9 (2H, m) , 4.17 {2H, t, J«=6Hz), 8.85 (1H, s) (2) 2-isopropoxyamino-2-(5-formamido-1,2,4-thiadiazol-3-yl)-acetic acid (syn isomer), m.p. 180-182°c (decomposition).

I.R. (Nujol) t 3230, 1720, 1690, 1590, 1530 cm""<1>

N.M.R. (dg-DMSO)

6S 1.25 (6H, d, J=6Hz), 4.2-4.7 (1H, m),

8.85 (1H, a)

Production lp

A mixture of 4.4 g of 2-ethoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) and 54 ml of a 1N dilute solution of sodium hydroxide was stirred for 2 hours at 50-55°C. The mixture was cooled in an ice bath, acidified with 5.4 ml of hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated to dryness., the evaporation residue was triturated with diethyl ether to give 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn-isomer) ( 2.92 g),

sm.p. 168-170°C (decomposition).

I.R. (Hujol)t 3450, 3370, 325G, 3150, 1665, 1610, 1530 cm"<1>N.M.R. (dg-DMSO)

6: 1.22 (3H,J*7Hz), 4.17 (2H,q,J*=7Hz),

8.17 (2H, wide s)

Production 11

The following compounds were obtained in a similar manner as indicated for the preparation of 10s

( 2) 2-propoxyimino^2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer), m.p. 100-103°G (decomposition). I.R. (Nujol): 3620, 3520, 3350, 3120, 2600,

2500, 1720, 1620, 1550 cm"<1>

N.M.R. (d6-DMS0)

6: 1.00 (3H, t, J»6Ez), 1.3-2.0 (2H, m),

4.13 (2H, t, J^eHz), 8.17 (2a, wide s)

(2) 2-isopropoxyamino-2-(5,-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer)., m.p. 152-155°C (decomposition).

I.R. (Nujol): 3450, 3300, 3200, 1730, 1620, 1530 cm"1 N.M.R. (d6-DMS0)

6: 1.22 (6H, d, J=6Hz), 4.1-4.6 (1H, m),

8.20 (2H, wide s)

Production 12

(1) A mixture of 8.15 g of N-hydroxyphthalimide, 5.05 g of triethylamine, 60 ml of N,N-dimethylformamide and 8.05 g of 1-bromo-2-cyclohexene was stirred for 3.5 hours at room temperature . The reaction mixture was poured into 300 ml of water. The precipitated crystals were collected by filtration, washed successively with water and n-hexane and then dried to give N-(2-cyclohexen-1-yloxy)phthalimide (9.8 g), m.p. 87°C.

X.YAY. (Nujol): 1770, 1720, 1610cm"<1>

N".M7R. (d6-DMSO, <5)j 1.50-2.17 (6H, m), 4.60-4.77 (1H, m),

5.73-6.27 (2H, m), 7.90 {4H, s)

(2) A mixture of 58.2 g of N-hydroxyphthalimide, 36.9 g of 1-chloro-2-cyclopentene, 53.9 g of triethylamine in 370 ml of acetonitrile was treated in a similar manner as described for the preparation of 12-(1) as follows that N-(2-cyclopenten-1-yloxy)phthalimide (56.5 g) was obtained

I.R. (Nujol)s 1780, 1730, 1610 cm"<1>

N.M.R. (d6-DMSO, fi): 7.92 (4H, s), 6.28 (1H, m),

6.00 (1H, ra), 5.42 (1H, m), 2.9-1.98 (4H, m)

Production 13

(1) A mixture of 22.9 g of :N-(2-cyclopenten~1-yloxy) phthalimide

and 4.75 g of hydrazine hydrate in 115 ml of ethanol was refluxed for 5 minutes. The reaction mixture was filtered. The filtrate containing 2-cyclopenten-1-yl)oxyamine was added to a solution of 22.4 g of sodium 2-(5-formamido-1,2,4-thiadiazol-3-yl)-glyoxylate in water. The mixture was adjusted to pH 2 with 10 6 hydrochloric acid, stirred for 2 hours and then concentrated. The concentrate was adjusted to pH 1 with 10% hydrochloric acid. The precipitates were collected by filtration and dried to give 2-(2-cyclopenten-1-yl)oxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)-acetic acid (syn isomer) (20.0 g), m.p. 150°C (decomposition).

I.R. (Nujol): 3400, 3100, 1720, 1690, 1540 cm"<1>

N.M.R. (dg-DMSO, <5)s 1.80-2.50 (4H, m), 5.30-5.50 (1H, m),

5.83-6.30 (2H, m), 8.90 (1H, s)

(2) A mixture of 7.29 g of N-{2-cyclohexen-i-yloxy)-phthalimide, 1.5 g of hydrazine hydrate in 40 ml of ethanol was refluxed

for 5 minutes. The reaction mixture was cooled and filtered so that the filtrate containing (2-cyclohexen-1-yl)-oxyamine (filtrate A) was obtained. On the other hand, a mixture of S-methyl-2-(5-forraamido-1,2,4-thiadiazol-3-yl)thioglyoxylate (6.93 g) in 90 ml of a 1N aqueous solution of sodium hydroxide was stirred in 30 minutes at room temperature. The reaction mixture containing sodium 2-(5-formamido-1,2,4-diazol-3-yl)glyoxylate was adjusted to pH 7 with 1056 hydrochloric acid, and to the mixture was added filtrate A, and then the pH was adjusted to 3 with 1036 hydrochloric acid.

The mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated, and ethyl acetate was added to the concentrate. The mixture was adjusted to pH 1 with 109% hydrochloric acid. The precipitates were collected by filtration to give 2-(2-cyclohexen-1-yl)oxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (3-yne isomer) (2, 5 g)*On the other hand, the ethyl acetate layer was separated from the filtrate and evaporated. The evaporation residue was triturated with diethyl ether to give the same compound (1.5 g). Total yield: 4.0 g.,

sm.p. 190-192°C (decomposition).

I.R. (Nujol): 3550, 3400, 3200, 2500, 1690, 1590, 1540 cm"<1>N.M.R. (d6-DMS0, 6)s 1.5-2.3 (6H, m), 4.73-5, 0 (lH, m), 5.76-6.23 (2H, m), 8.97 (1H, s), 13.60 (lH, broad s) (3) To a solution of 11.2 g of sodium hydroxide 27 g of s-methyl-2-(5-formamido-1,2,4-thiadiazol-3-yl)-thioglyoxylate were added to 140 ral of water at 10°C, and the mixture was stirred for 30 minutes at 20°C The reaction mixture containing sodium 2-(5-formamido-1,2,4-thiadiazol-3-yl)glyoxylate was cooled, adjusted to pH 7 with 10% hydrochloric acid, and to this was added a solution of 15.3 g of cyclopentyloxyamine in 150 ml of ethanol. The mixture was adjusted to pH 3 with 1096 hydrochloric acid and stirred for 1.5 hours. The reaction mixture was adjusted to pH 7 with an aqueous solution of sodium bicarbonate and then evaporated to remove ethanol. The evaporation residue was washed with ethyl acetate. To the aqueous layer, ethyl acetate was added, and the mixture was adjusted to pH 1 with 10% hydrochloric acid. The precipitation products were collected by filtration to give 2-cyclo Pentyloxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (3.99 g). The filtrate was extracted with ethyl acetate, and the extract was dried over magnesium sulfate and then concentrated, the precipitates were collected by filtration and washed with diethyl ether to give the same compound (8.1 g). Total yield: 12.09 g, m.p. 180—185°C (decomposition). I.R. (Nujol): 3130, 3040, 2680, 2610, 2520, 1720, 1690,

1660, 1600, 1550 cm"<1>

N.M.R. (dg-DMSO) , 1.33-2.10 (8H, m), 4.67-5.0 (1H, m) ,

8.88 (1H, s), 13.50 (1H, s)

Production 14

A mixture of 20.0 g of 2-(2-cyclopenten-1-yl)oxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) and

200 ml of a 1N aqueous solution of sodium hydroxide was stirred for one hour at 50-55°C. The reaction mixture was cooled, adjusted to pH 7 with 10% hydrochloric acid and ethyl acetate added. The mixture was adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated. ,2,4-thiadiazol-3-yl)-acetic acid (syn isomer), m.p. 150°C (decomposition).

I.R. (Nujol)s 33O0, 3150, 1710, 1620, 1520 cm"<1>

N.M.R. (d 6 -DMSO, 6)t 1.80-2.50 (4H, m), 5.30-5.50 (1H, ra),

5.83-6.30 (2H, m), 8.20 (2H, s)

Production 15

The following compounds were obtained in a similar manner as described for preparation 14. (1) 2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid ( syn isomer), m.p. 173°C. I.R. (Nujol): 3400, 3300, 3200, 1720, 1620, 1600, 1520 cm"1 N.M.R. (d6-DMS0, A): 1.50-2.17 (6H, ra), 4.53-4.83 ( 1H, m), 5.57-6.13 (2H, m), 8.18 (2H, s) (2) 2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazole-3- yl)-acetic acid (syn isomer), m.p. 160-165 C (decomposition). IR (Nujol): 3470, 3290, 3200, 2400, 1715, 1615,

1600, 1520 cm"<1>

N.M.R. (d6-DMSØ, <5): 1.17-2.10 (8H, m), 4.60-4.97 (1H, m).

8.22 (2H, s)

Production 16

A mixture of 10 g of 5-formarido-3-(2-methylthio-2-methyl-sulfinylacetyl)-1,2,4-thiadiazole and 2.0 g of sodium periodate in 50 ml of glacial acetic acid was stirred for 50 minutes at 70°C. The solvent was evaporated and the residue washed with n-hexane. , To the residue was added 160 ml of a 1N aqueous solution of sodium hydroxide, and the mixture was stirred for one hour at ambient temperature. 4.31 g of O-allylhydroxylamine hydrochloride was added to the reaction mixture, and the solution was adjusted to pH 3-4 with 1036 hydrochloric acid and then stirred for one hour at ambient temperature. After an insoluble material was filtered off, the filtrate was washed with ethyl acetate, adjusted to pB 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated to dryness. The evaporation residue was triturated with a mixture of diethyl ether and diisopropyl ether to give 2-allyloxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (5.6 g), sm.p. 16?-172°c (decomposition).

I.R. (Nujol): 3130, 2500, 1720, 1690, 1590, 1550 cm-1 N.M.R. (dg-DMSO)

di 4.79 (2H, d, J«6Hz) , 5.1-5.6 (2H, m) , 5.8-6.4

(1H, m), 8.88 (1H>s)

Production 17

The following compounds were obtained in a similar manner as described for Preparation 16: (1) 2-(2-propynyloxyimino)-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) , sm.p. 150-155°C (decomposition). I.R. (Nujol): 3570, 3360, 3260, 3120, 1720, 1670,

1550, 1530cm"<1>

N.M.R. (dg-DMSO)

6 : 3.55 (lH, t, J«2Hz) , 4.88 (2H, d, J=2Hz),

8.85 (1H, s) (2) 2-hydroxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer), m.p. 240-241 C (decomposition).

I.R. (Nujol): 3550, 3460, 1665, 1635, 1560 cm"1

Production 18

A solution of 6.64 g of S-methyl (5-formamido-1,2,4-thiadiazol-3-yl)thioglyoxylate in 80 ml of an aqueous solution of sodium hydroxide was adjusted to pH 8.5 with 10% hydrochloric acid and stirred for 30 minutes at ambient temperature. Furthermore, a mixture of 8.78 g of N-(2,2,2-trifluoroethoxy)phthalimide and 1.7 g of hydrazine hydrate in 40 ral of ethanol was refluxed for 5 minutes and then cooled in an ice bath. The resulting precipitates were filtered off and washed with ethanol. The filtrate and wash water were combined, and the combined solution containing O-(2,2,2-trifluoroethyl)hydroxylamine was added to the above aqueous solution. The mixture was adjusted to pH 3-4 with 10% hydrochloric acid and stirred for 1.5 hours at ambient temperature. The solution was neutralized with an aqueous solution of sodium bicarbonate, concentrated to half the volume in vacuo and washed with ethyl acetate. The aqueous solution was acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate, evaporated to dryness and the evaporation residue triturated with diisopropyl ether to give 2-(2,2,2-trifluoroethoxyimino)-2-<5-formamido-<1>,2,4-thiadiazole-3 -yl)acetic acid (syn isomer) (2.46 g), m.p. lSO-lSS^C (cleavage).

N.M.R. (dg-DMSO)

6: 4.80 and 5.07 (2H., ABq, J=9Hz), 8.85 (lH, s)

Production 19

The following compound was obtained in a similar manner to preparation 18: 2-methylthiomethoxyimino-2-(5-fdramido~1,2,4-thiadiazol-3-yl)-acetic acid (syn isomer), m.p. 146-148 C (decomposition). I.R. (Nujol): 3300, 2600, 2550, 1730, 1705, 1680, 1600,

1530 cm"*1

N.M.R. (d6-DMS0)

6: 2.23 (3H, s), 5.40 (2K, s), 8.87 (1H, s)

{ Production 20]

A mixture of 6 g of S-methyl (5-formamido-1,2,4-thiadiazol-3-yl)thioglyoxylate and 50 ml of an aqueous solution of 4.2 g of sodium hydroxide was stirred for one hour at 50-55° C. The mixture was cooled to ambient temperature and adjusted to pH 7 with 10% hydrochloric acid. Furthermore, a mixture of 12.9 g of N-(ethoxycarbonyl-methoxy)phthalimide and 2.08 g of hydrazidehydrate in 60 ml of ethanol was refluxed for 5 minutes and cooled in an ice bath. The resulting precipitate was filtered off and washed with ethanol, the filtrate and the wash water were combined, and the combined solution containing O-(monohydroxycarbpnyylmethyl)hydroxylamine added to the above aqueous solution. The mixture was adjusted to pH 3 to 4 with 10% hydrochloric acid and stirred for 1.5 hours at ambient temperature. The solution was neutralized with an aqueous solution of sodium bicarbonate, concentrated to half volume in vacuo and washed with ethyl acetate. The aqueous solution was acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate, evaporated to dryness and the evaporation residue triturated with diisopropyl ether so that 2- ethoxycarbon<y>imethoxy<y>imino-2-(5-amino-1,2,4 -thiadiazol-3-yl)— acetic acid (syn isomer) (1.8 g), m.p. 135-140°c (decomposition). I.R. (Nujol); 350O, 3330, 3210, 2670, 2550, 1740,

1610, 1540cia"<1>

N.M.R. (d6-DMS0)

6: 1.24 (3H, t, J«7Ez), 4.14 (2H, q, J«7Hz) ,

4/80 (2H, s), 8.15 (2H, wide s)

Production 21

The following compound was obtained in a similar manner to preparation 20: 2-(1-ethoxycarbonyl-1-methylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) , sm.p. 165-168 C (decomposition).

I.R. (Nujol) : 3450, 3350, 3240, 1750, 1730, 1630, 1530 cm"<*1>N.M.R. (d6-DM30)

6: 1.18 (3H, t, J=7Hz), 1.50 (6H, s) , 4.15

(2H, q, J"7Hz), 8.23 (2H, wide s)

Production 22

The following compounds were obtained in a similar manner as described for preparation 14. (1) 2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer), sra.p * 93-95 C (decomposition).

I.R. (Nujol): 3430, 3100, 1710, 1615, 1525 cm""<1>

N.M.R. (dg-DMSO)

ate 4, 72 (2H, d, J=6Hz), 5.1-5.5 (2H, m),

5.7-6.3 (IK, m) > 8.17 (1H, wide s)

(2) 2-(2-propynyloxyimino)-2-(5-amino-*1,2,4-thiadiazol-3-yl)-acetic acid (syn isomer), m.p. 155-157 oC (decomposition). I.R. (Nujol): 3500, 33lO, 3160, 2600, 2480,

1745, 1610, 1535 cm"*1

N.M.R. (dg-DMSO)

6: 3.53 (1H, t, J=2Hz), 4.87 (2H, d, J=*2Hz),

8.23 (2H, wide s)

(3) 2-{2,2,2-trifluorooxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer), m.p. 140-143°C (decomposition). I.R. (Nujol)* 3450, 3350, 3260, 1745, 1670, 1645,

1615, 1515 cm"<1>

N.M.R. (dg-DMSO)

6* t 4.72 and 4.95 (2H, ABq, J=9Hz), 8.25 (2H, wide s)

(4) 2-methylthiomethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetic acid (syn isomer), m.p. 140-143°C (decomposition). I.R. (Nujol): 3500, 3300, 3150, 2670, 2580, 1740, 1615, 1605, 1530 cm' —' N.M.R. (d6-DMS0) 6: 2.22 (3H, s), 5.33 (2H, s), 8.20 (2H, broad s) (5) 2-trityloxyimino-2-(5-amino-1,2,4-thiadiazole) -3-yl)acetic acid (syn isomer), m.p* 173—174 c (decomposition).

I.R. (Nujol): 3450, 1735., 1620, 1540 cm"<1>

N.M.R. (d&-DMSO)

6 in 7.35 (15H, s), 8.22 (2H, s)

Production 23

To a mixture of 9.5 g of 2-hydroxyamino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) and 80 ml of dimethylformamide was added, with stirring at ambient temperature, 22.8 g of trityl chloride and 4.1 g of triethylamine were gradually added after 3 minutes of stirring. The resulting mixture was stirred for 10 minutes and 200 ml of ethyl acetate was added. The mixture was washed three times with water and with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. To the residue was added 50 ml of an aqueous solution of sodium bicarbonate and 100 ml of diisopropyl ether. The precipitation products were collected by filtration, and the water layer in the filtrate was separated from. The collected precipitation products were suspended in the separated water layer, and ethyl acetate was added thereto. The mixture was adjusted to pH 2 with 10% hydrochloric acid and extracted. with ethyl acetate. The extract was dried over magnesium sulfate and concentrated in vacuo. The residue was washed with bexane to give 2-trityloxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)-acetic acid (syn isomer) (17.1 g), m.p. 175—176°C (decomposition).

I.R. (Nujol)s 3180, 3070, 1700, 1600, 1540 cm"1

N.M.R. (d6-DMS0)

6: 7.35 (15H, s), 8.83 (1H, s), 13.52 (lH, wide s)

Production 24

The following compounds were obtained in a similar manner as described for preparation 12-(1).

(1)N~(1-t-butoxycarbonylethoxy)phthalimide, m.p. 80~S2°C

N.M.R. (dc-DHSO, 6); 1.42 (9B, s), 1.48 (3H, d, J«7Hz),

4.72 (1H, q, J=7Hz), 7.86 (4H, s)

(2) N-{1-t-bTatoxycarbonyl-1-iraethylethoxy)phthalimide,

sm.p. 96-100°C.

N.M.R. (dg-DMSO, 6): 1.42 (9H, s), 1.48 {6H, s),

7.87 (4H, s)

(3) N~(1-benz<y>lox<y>carbon<y>letox<y>)f thalimide, m.p. 65-68°C

I.R. (Nujol)! 1790, 1740, 1450,, 1210, 1190*1110, 1080, 980, 880, 735, 700 cm"1 (4) N-(2-oxo-3-tetranydrofuryloxy)phthalimide, m.p. 140-142°C. I.R. (Nujol) in 1785, 1760, 1720, 1605, 1215, 1185,

870, 695 cm"<1>

Production 25

The following compounds were obtained in a similar manner as described for preparation 20. (1) 2-(t-butoxycarbonylmethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer), sm.p. 150-155 oC (decomposition). I.R. (Nujol) s 3420, 3230, 3100, 1725, 1610, 1530cm"<*1>N.M.R. (DMSO)-dg, 6)s 1.45 (9H, s), 4.70 (2H, s),

8.12 (2H, wide s)

(2) 2-{1-t-butoxycarbonyloxyimino)-2-(5->amino-1,2,4-thiadiazol-3-*yl)acetic acid (syn isomer), m.p. 155-156 oC (decomposition). I.R. (Nujol): 3400, 3300, 3200, 1720, 1710, 1620, 1520 cm<*>"<1>N.M.R. (d6-DMSO, <S): 1.2-1.7 (12H, m), 4, 72 (lH, q,

J«7Hs), 8.2 (2H, wide s)

(3) 2-(1-t-butoxycarbonyl-1-methylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer), m.p. 180-181 c (split.).

I.R. (Nujol): 3400, 3300, 3200, 1745, 1715, 1630, 1530 cm"<1>

N.M.R. (d6-DMS0>, 6): 1.38 (9H, s), 1.43 (6H, s), 8.15

(2H, wide s)

(4) 2-(1-benzyloxycarbonylethoxyimino)-2-(5-arain o-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer), m.p. 129-133 C (dec.).

I.R. (Nujol): 3300, 32O0, 1720, 1620, 1530 em""1

N.M.R. (DMSO-dg, 6): 1.45 (3Hr d, J=6Hz) , 4.97 (1H, q,

J*6Hz), 5.18 (2H, s), 7.31 (5H, s), 8.17 (2H, wide a)

Production 26

S-methyl (5-formamido-1,2,4-thiadiazoi-3-yl)thioglyoxylate (64.8 g) and 1-carboxy-3-hydroxypropoxyamine, which was prepared by refluxing a mixture of 65.0 g of N -(2-oxo-3-tetrahydrofuryloxy)phthalimide, 50 ml conc. hydrochloric acid and 200 ml of water for 1 hour, was treated in a similar manner as described for preparation 20, so that 2-(1-carboxy-3-hydroxy-propoxyimino)-2-(5-amino-1,2,4 -thiadiazol-3-yl)acetic acid (syn isomer) (33.2 g), m.p. 186-188°C (decomposition). I.R. (Nujol): 3400, 3250, 3100, 1710, 1620, 1540 cm"<1>N.M.R. (BMSO-d^, <5)t 1.73-2.10 (2H, m) , 3.50 (2H, t,

J<=6Hz), 4.73 (1H, t, J=6Hz), 8.13 (2H, s)

Presentation 27

To a solution of 33.0 g of 2-(1-carboxy-3-hydroxypropoxy-imino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer)

120 g of anhydrous magnesium sulfate and 60 g of acetic anhydride were added to 2.8 1 methanol. The mixture was stirred at ambient temperature for 30 minutes, filtered and the filtrate evaporated to dryness. The evaporation residue was triturated in 200 ml of acetone, and 1 1 of ethyl acetate was added. The mixture was stirred at ambient temperature for 1 hour and the precipitates were collected by filtration and washed with ethyl acetate.

The precipitation products were dissolved in 200 ml of water, and then 500 ml of ethyl acetate, 200 ml of acetone and 40 ml of 6N hydrochloric acid were added. An organic layer was separated from and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate and evaporated to dryness. The evaporation residue was triturated in diethyl ether, filtered and washed with diisopropyl ether to obtain 2-(2-oxo-3-tetra-hydrofuryloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid ( syn—isomer) (26.5 g), saup. 185-187 C (decomposition). I.R. (Nujol): 3400, 3300, 3200, 1775, 1730, 1640,

1605, 1535 cm"<*1>

N.M.R. (d 6 -DMSO( 6 ): 2.27-2.70 (2H, m), 4.17-4.50

(2H, m), 5.27 (lH, t, J=8Hz), 8.22 (2H, s)

Production 28

The following compound was prepared in a similar manner to that described for preparation 20: 2-methoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer), m.p. 190-193°C (decomposition). I.R. (Nujol): 3380, 3280, 3180, 1750, 1710, 1610, 1510,

1260, 1230 cm"<1>

N.M.R. (DMSO-d 6 , 5 ): 3.73 (3H, s), 4.87 (2H, s), 8.2

(2H, bs)

Production 29

The following compound was obtained in a similar manner to that described for preparation 30: 7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanic acid (syn isomer), m.p. p. 140-145°C (decomposition). I.R. (Nujol): 3480, 3370, 3250, 1785,

1730, 1680, 1630, 1530 cm"<1>

N.M.R. (d6~DMS0, (5): 1.33-2.17 (8H, m) , 2.03 (3H, s),

3.57 (2H, wide s), 4.60-4.90 (lH, m), 4.73 and 4.97 (2H, ABq, J=13Hz), 5.15 (lH, d, J= 5Hz), 5.80 (lH,

dd, J=5 and 8Hz), 8.10 (2H, wide s), 9.47 (lH, d, J=8Hz)

Production 30

To a cold solution of 10.4 g of phosphorus pentachloride in 250 ml of methylene chloride was added 12.8 g of 2-cyclopentyloxyimino-2-(5-amino-1,2,4Tthiadiazol-3-yl)acetic acid (syn isomer) at -18°C, and the mixture was stirred for 15 minutes at -13 to -10°C.

Furthermore, a mixture of 15.7 g of 7-amino-3-acetoacetoxymethyl-3-cephem-4-carboxylic acid and 50 g of trimethylsilylacetamide in 250 ml of methylene chloride was heated so that it became a clear solution, and

this was cooled to -10°C. The cold solution was added to the above activated mixture and the mixture was stirred for 25 minutes at -10°C. The reaction mixture was poured into 500 ml of an aqueous solution of 29.5 g of sodium bicarbonate and stirred for 15 minutes at room temperature. The water layer was separated

from, adjusted to pH 2 with 6N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The evaporation residue was triturated with diethyl ether to give a powder of 7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl~3-cephem-4 -carboxylic acid (syn isomer)

(13.5 g), m.p. 130-135°C (decomposition).

I.R. (Nujol): 3300, 1780, 1720, 1680, 1620, 1525 cm<**1>N.M.R. (DMSO-dg, 6)s 1.3-2.0 (8H, m), 2.15 (3H, s), 3.52

(2H, bs), 3.60 (2BV s), 4.5-4.7 (lH, m), 4.77, 5.00 (2H, ABq, J»14Hz), 5.13 (lH, d, J=4Hz), 5.80 (lH, 2d,J«=4 and 8Hz), 8.10 (2H, s), 9.50 (lH, d, J»8Hz)

Production 31

To one solution of 5.16 g of 7-<*>2-(1-t-butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl -3-cephem-4-carboxylic acid (syn isomer) in 50 ml of raauric acid, 1.7 ml conc. hydrochloric acid, and the mixture was stirred for 30 minutes at room temperature. The solvent was distilled off under reduced pressure, and the distillation residue was pulverized with diethyl ether and collected by filtration to give a brownish powder. The powder was dissolved in a mixture of ethyl acetate and water and adjusted to pH 7 with a saturated aqueous solution of sodium bicarbonate while stirring. The aqueous layer was separated and ethyl acetate was added. The mixture was adjusted to pH 1 with 6N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated to dryness. The evaporation residue was pulverized with diethyl ether, collected by filtration, washed with the same solvent and dried over anhydrous phosphorus pentoxide to give a brownish powder of 7-[2-(1-carboxyethoxyimino)-2-(5-amino-1, 2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer) (3.7 g), m.p. 95-100°C (decomposition). I.R. (Nujol) f 3450, 3350, 3230, 1780, 1720, 1630, 1525 cm<*>"<1>N.M.R. (DMS0-d6, 6) : 1.45 (3H, d, J«7Hz), 2.20 (3H, s),

3.58 (2H, wide s), 3.67 (2H, s), 4.65-5.30 (3H, m),

5.22 (1H, d, J=5Hz), 5.77-6.10 (lH, m), 8.23

(2H, wide s), 9.40-9.68 (lH, m)

Production 32

The following compounds were obtained in a similar manner as described for Preparations 30 and 31s

(1) 7-t 2-(2-Cyclopenten-1-yloxyamino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoaGetoxymethyl-3-cephem-4- carb-^ oxylic acid (syn isomer), m.p. 135-140°C (decomposition). I.R. (Nujol)s 3400, 3300, 3200, 1775, 1735, 1710, 1675, 1620, 1525 cm""<1>N.M.R. (DMSO-d66): 1.93-2.47 (4H, m), 2.18 (3H, a), 3.55 (2H, bs), 3.65 (2H, fl), 4.80, 5.07 (2H, ABq, J«13Hz), 5.13 (1H, d, J=5Hz), 5.23-5.53 (lH, m), 5.70-6.23 (3H, m ), 8.12 (2H, bs), 9.50 (1H, d, J=8Hz) (2) 7-[2-carboxymethoxyimino-i-2-(5-amino-1,2,4-thiadiazole- 3-yl)-acetamido]-3-acetoacetoxymethyl-3-cephem-14-carboxylic acid (syn isomer), m.p. 95-100 C (decomposition). I.R. (Nujol): 3400, 3290, 3190, 1770, 1720, 1615, 1520 cm"<1>N.M.R. (BMSO-d^, 6): 2.17 (3H, s), 3.53 (2H, bs), 3.63 (2H, s), 4.67 (2H, s), 4.80, 5.07 (2H, ABq, J=13Hz), 5.15 (1H, d, J«5Hzj, 5.87 (1H, 2d, J=5 and 8Hz), 8.15 (2H, bs), 9.53 (1H, d, J=8Hz) (3) 7-[2-t-butoxycarbonylmethoxyimino-2-(5- amino-1,2,4-thiadiazol-3-yl)acetamido]-3-aceethoacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer), m.p. 105-110 c (decomposition). I.R. (Nujol) : 3350, 3250, 1780, 1720, 1620, 1525 cm"<1>N.M.R. (BMS0-d6, 6): 1.43 (9H, s), 2.17 (3H, s), 3.53 (2H, bs), 3.63 (2H, s), 4.63 (2H, s), 4.82, 5.05 (2H, ABq, J*13Hz), 5 .15 (1H, d, J<*> 5Hz), 5.85 (1H, 2d, J»5 and 8Hz), 8*15 (2H, bs), 9.53 (lH, d,J«8H<z>) (4) 7-!2- (1-t~butoxycarbonyloxyimino)-2-(5-araino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoaeethoxyethyl-3-cephem-4-carboxylic acid (syn isomer), brownish powder, sm. p. 110-115°C (decomposition). I.R. (Nujol): 3400, 3300, 3200, 1780, 1720, 1620, 1525 cm"<1>N.M.R. (DMS0-d6, <"<>>): 1.40 (3H, d, J«7Hz), 1.42 (9H, s), 2.17 ( 3H, s), 3.57 (2H, bs), 3.63 (2H, s), 4.58-5.22 (3H, m), 5.17 (1H, d, J»5Hz), 5773 -5.97 (1H, m), 8.10 (2H, bs), 9.33-9.57 (1H, m) (5) 7-12-(1-methyl-1-carboxyethoxyimino)-2- {5-amino-1,,2,4-thiadiaool-α-yiJacetamidol-S-aqetoacQtoxymethyl-α-cephem^-carboxyic acid (syn isomer), m.p. 180-185°C (decomposition).

I.R. (Nujol): 3350, 3250, 1780, 1720, 1625, 1525 cm"<1>N.M.R.. (DMS0-d6, 6)j 1.47 (6H, s), 2.17 (3H, s), 3, 55

(2H, bs), 3.62 (2H, s) , 4.80, 5.03 ( 2H, ABq, J=14Hz), 5.17 (1H, d, J=4Hz), 5.87 (lH , [2djj««4 and 8Hz),

8.13 (2H, s), 9.47 (lH, d, J=8Hz)

(6) 7-12-(1-methyl-1-t-butoxycarbonyloxyimino)-2-(5-amino-1,2,4-tladiazol-3^yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4 -carboxylic acid (syn isomer), sra.p. 140-145 C (decomposition). I.R. (Nujol): 3350, 3250, 1785, 1720, 1620, 1530 cia"<1>N.M.R. (DMS0-d6, <S) s 1.47 (6H, s), 1.50 (9H, s), 2, 17 (3H, s), 3.57 (2H, bs), 3.63 (2H, s), 4.80, 5.07 (2H, ABq, J=14Hz), 5.17 (1H, d) , J=4Hz), 5.86 (lH, 2d, J=4 and 8Hz), 8.13 (2H, s), 9.43 (lH, d, J=8Hz) (7) Sodium-7-[ 2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylate (syn isomer), m.p. 175- 180°C (decomposition). IR (Nujol)s 3450, 3300, 3100, 1790, 1720, 1670, 1640,

1610, 1550 cm<*>"<1>

N.M.R. (D20, 6)r 1.38 (3H, t, J«6Hz), 2.34 (3H, s), 3.44,

3.66 (2H, ABq, J=18Hz), 4.40 (2H, q, J=6Hz), 5.05, 5.86 (2H, ABq, J«12Hz), 5.26 (1H, d , J»4Hz), 5.90

(1H, d, J=4Hz)

(8) 7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer), sm .p. 120-125°C (decomposition). I.R. (Nujol) : 3350, 3250, 1780, 17l0, 1680, 1630, 1530 cm""<1>N.M.R. (D 2 O-fNaHCO 3 , 6): 2.32 (3H, s), 3.40, 3.62 (1H, ABq,

J=»18Hz), 4.10 (3H, s), 4.84, 5.04 (2H, ABq,

J=»14Hz), 5.22 (lH, d, J«=4Hz) , 5.86 (lH, d, J=4Hz)

(9) 7-[2-propoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer), sm.p. 125-130°C (decomposition).

I.R. (Nujol): 3350 , 3250, 1780, 1710, 1680, 1620, 1530 cm<*>"<1>

N.M.R. (DgO+NaHCO^6)s 0.94 (3H, t, J«6Hz), 1.5-1>9

(2H, m), 2.30 (3H, s), 3i40, 3.62 (2H, ABq, J»18Hz), 4.26 (2H, t, J=6Hz), 4.84, 5.04 (2H, ABq, J=0L2Hz), 5.22 (1H, d, J=4Hz), 5.86 (1H, d, J»4Hz) 10) 7-{2~isopropoxyimino-2-(5-amino -1,2,4-thiadiazol-3-yl)acetamido]-3-acetoaeethoxymethyl^3-cephem-4-carboxylic acid (syn isomer), m.p. 95-100°C (decomposition). I.R. (Nujol)s 3400, 3300, 3200, 1775, 1740, 1710,

1670, 1620, 1525 cm"<1>

N.M.R. (DMSO-do,. 6)s 1.28 (6H, d, J*6Hz), 2.18 (3H, s),

3.48, 3.60 (2H, ABq, J=18Hz), 3.62 (2H, s), 4.24-4.54 (1H, m), 4.78, 5.02 (2H, ABq , J«13Hz), 5.14 (lH, d, J°5Hz) , 5.80 (lH, dd, J=5 and 8Hz),

8.06 (2H, wide s) , 9.44 (lH, d, J=»8Hz)

11) Sodium 7-£ 2-allyloxyimino-2-{5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoae ethoxymethyl-3-cephem-4-carboxylate (syn isomer ), sm.p. 160-170 C (decomposition). I.R. (Nujol) s 3450, 3300, 3100, 1790, 1720, 1670, 1550 cm"<1>N.M.R. (D20, 6) » 2.31 (3H, s) , 3.33, 3.64 (2H, ABq,

J=18Hz), 4.6-5.1 (4H, m), 5.1-5.5 (2H>m), 5.20

(1H, d, J»5Hz), 5.8-6.3 (lH, m), 5.84 (lH, d, J=5Hz)

12) Sodium 7-12-(2,2,2-trifluorooxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4- carboxylate (syn isomer), m.p. 128-132°C (decomposition). I.R. (Nujol)? 3300, 1780, 1710, 1670, 1600, 1530 cm'<1>N.M.R. (D2°'6) J 2'32 <3H's)'3,SO, 3.63 (2H, ABq, J-17HZ), 4.60-5.07 (4H, m), 5.23 (1H, d, J=4Hz), 5.87 (1H, d, J=4Hz) 13) Sodium 7-[2-methylthioroethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido ]-3-acetoacetoxymethyl-3-cephem-4-carboxylate (syn isomer), saup. 180-190°c (decomposition). I.R. (Nujol): 350O-320O, 1770, 1670, 1620, 1530 cm"<1>N.M.R. (DMSO-dg, 6): 2.18 (3H, s), 2.20 (3H, s), 3.16 , 3.48 (2H, ABq, J=18Hz). 3.58 (2H, s), 4.84, 5.08 (2H, ABq, J=12Hz), 4.98 (lH, d^J= 5Hz), 5.22 (2H, s), 5.62 (1H, dd> J=5 and 8Hz-)-, 8.14 (2H, wide s), 9.48 (1H, d,J*8HZ ) 14) 7-12-(2-Propynylpxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamidoI-3-acetoacetox<y>aret<y>1-3-ee five -4-carboxylic acid (syn isomer), mp 90-95°C (decomposition). I.R. (Nujol) p 3400, 3280, 3200, 2100, 1770, 1740, 1710,

1670, 1620 cm**1

N.M.R. (DMSO-dg, 6)s 2.18 (3H, s) , 3.46 (1H, t, J=2Hz) ,

3.46, 3.58 (2H, ABq, J"18Hz), 3.62 (2H, a), 4.76 (2H, d, J=2Hz), 4.78, 5.02 (2H, ABq , J«14Hz), 5.12 (1H, d, J<*>5Hz), 5.80 (1H, dd, J«5 and 8Hz), 8.10

(2H, wide s), 9.60 (lH, d, J«*8Hz)

Production 33

To a mixture of 80 g of sodium iodide and 11.36 g of pyridine in 40 ml of water was added 40 g of @atrium-7-[D-5-carboxy~5-(3-phenylurea<3o)valeramido]cephalosporanate at 50°C with stirring, which was continued at 60 oC for 4.5 hours. The hot reaction mixture was diluted with 80% water, adjusted to pH 3.5 with 6N hydrochloric acid and subjected to column chromatography on 600 ml of non-ionic adsorption resin with the trade name "Diaion HP-20" (manufactured by Mitsubishi Chemical Industries ). After the column was washed with 2.4 L of water, elution was performed with 35% aqueous isopropyl alcohol which was heated to 45°C before use. To the eluate (1 l) was added 100 ml of N,N-dimethylformamide, and the mixture was concentrated to 120 ml under reduced pressure. To the residue, 1 L of isopropyl alcohol was added with stirring, and the stirring was continued for one hour. The resulting precipitates were collected by filtration, washed with isopropyl alcohol and dried to give 7-[D-5-carboxy-5-(3-phenylureido)valeramido]-3-(1-pyridinediomethyl)-3-cephem-4- carboxylate (22.0 g),

sm.p. 180-185°C (decomposition).

I.R. (Nujol) t 3300, 1780, 1720, 1680, 1610, 1540, 1500 cm""<1>N.M.R. (DMSO-d6+D20, å) t 1.4-1.8 (4H, m), 2.0-2.3

(2H, m), 3.14, 3.54 (2H, ABq, J=17Hz), 4.0-4.2

(1H, m), 5.04 (1H, d, J«4Hz), 5.24, 5*62 (2H, ABq, J=14Hz), 5.60 (1H, d, J=4Hz), 6 .7-7.5 (5H, ra), 8.0-8.2 (2H, m)>8>45-8.70 (1H, m), 9.28-9.42

(2H, m)

Production 34

To a mixture of 2.77 g of 7-[D-5-carboxy-5-(3-phenyl-ureido)valeramido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate and 4.2 g of N ,N-dimethylaniline in 30 ml of methylene chloride, 3.3 g of trimethylsilyl chloride was dropped at ambient temperature with stirring, and the stirring continued for 30 minutes. The mixture was cooled to -30°C, and 2.1 g of phosphorus pentachloride was added with stirring, which continued for one hour at -30 to -25°C. The reaction mixture was added to a solution of 4.5 g of 1,3-butanediol in 30 ml of methylene chloride at -20°C with stirring, and stirring was continued for 1.5 hours at ambient temperature. The resulting precipitates were collected by filtration, washed with methylene chloride and dried to give 2.1 g of crude product of 1-C-(7-amino-4-carboxy-3-cephem-3-yl)methyl J p<y>ridinium chloride- hydrochloride dihydrate. To the crude product was added 8 ml of 1N hydrochloric acid, and the mixture was stirred for 30 minutes at ambient temperature. An insoluble material was filtered off,

and the filtrate was cooled in an ice bath, followed by the addition of 20 ml of isopropyl alcohol with stirring. To the mixture was added 25 ml of isopropyl alcohol, and the resulting precipitates were filtered, washed with the same solvent and acetone and dried to give a pure product (1.15 g), m.p. 140-145°C (decomposition).

N.M.R. (D20, 6): 3.53, 3.80 (2H, ABq, J»18Hz), 5.30 (lH,

d, J=4Hz), 5.45 (1H, d, J=4Hz) , 5.53, 5.83 (2H, ABq, J=»14Hz), 8.00-8.33 (2H, m) , 8.50-8.33 (1H, m) , 8.90-9.13 (2H, m)

Production 35

The following compound was obtained in a similar manner to that described for Preparation 30: Sodium 7-1 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-cephalosporanate (syn isomer ), sm.p. 180-185°C (dec.). I.R. (Nujol): 3480, 3430, 3250, 1780, 1730, 1665, 1635,

1610, 1540, 1515, 1400, 1280, 1240, 1040 cm"<*1>

Example 1

To a cold solution of 2.64 g of phosphorus pentachloride in 25 ml of methylene chloride was added 2.48 g of 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) at -20°C, and the mixture was stirred for 35 minutes at -20 to -14°C. 75 ral of cold diisopropyl ether below -10°C were added to the mixture while stirring. And the stirring was continued until the mixture was warmed to ambient temperature. The resulting precipitates were collected by filtration, washed with diisopropyl ether and then kept in a desiccator for several minutes. Furthermore, a mixture of 3.27 g of 1-1-(7-amino-4-carboxy-3-cephem-3-yl)methylpyridinium chloride hydrochloride dihydrate and 16 g of trimethylsilylacetamide in 50 ml of methylene chloride was heated at 35°C as that it became a solution, which was cooled to -20°C. To the cold solution was added the precipitation products discussed above and the mixture was stirred for 25 minutes at -18 to -12°C and for another 20 minutes at -12 to -3°C. A solution of 4 g of sodium bicarbonate in 30 ml of water was added to the reaction mixture, and the aqueous layer was separated from, adjusted to pH 1 with 6N hydrochloric acid, washed with ethyl acetate and then readjusted to pH 4 with an aqueous solution of sodium bicarbonate. The aqueous solution was passed through a column packed with 16 g of alumina, and then subjected to column chromatography on a non-ionic adsorption resin with the trade name "Diaion HP-20" (manufactured by Mitsubishi Chemical Industries) (100 ml). After the column was washed with water, the elution was carried out with 20% aqueous methanol. The eluates containing a desired compound were collected, evaporated to remove methanol under reduced pressure and lyophilized to give a white powder of 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazole- 3-yl)acetamido-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (2.39 g), m.p. 155-165<0>C (decomposition). I.R. (Nujol) t 3400-3150, 1770, 1660, 1610, 1530 cm"<1>N.M.R. (DMS0-d6, 6): 1.21 (3H, t, J*7Hz), 2.9-3.7 ( 2H, m),

4.12 (2H, q, J»7Hz) , 5.05 (1H, d, J=*5Hz) , 5.19, 5.68 (2H, ABq, J»14Hz), 5.7 (1H; m), 8.1 (4H, m), 8.6 (1H, m), 9.4 (3H, m)

Example 2

To a cold solution of phosphorus pentachloride (1.25 g) 1 30 ml of methylene chloride was added 1.5 g of 2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazole- 3-yl)acetic acid (syn isomer)

(at -15°C, and the mixture was stirred for 30 minutes at -13°C).

-10°C. Furthermore, a mixture of 1.82 g of N-17-amino-3-cephem-3-ylmethyl-3-pyridinium-4-carboxylate dihydrochloride and 10 g of trimethylsilylacetamide in 50 ml of methylene chloride was stirred for 10 minutes at room temperature and cooled to -1G°C. Then cooled solution was

added to the above activated mixture and the mixture was stirred for 15 minutes at -16°C. The reaction mixture was poured into 100 ml of an aqueous solution of 3.6 g of sodium bicarbonate and stirred for 15 minutes at room temperature. The aqueous layer was separated from, adjusted to pH 2 with 10% hydrochloric acid and washed with ethyl acetate. The aqueous solution was subjected to column chromatography on a non-ionic adsorption resin with the trade name "Diaion HP-20" (manufactured by Mitsubishi Chemical Industries) (100 ml). After the column was washed with water, the elution was carried out with 40% aqueous methanol. The eluates containing a desired compound were collected, evaporated to remove methanol under reduced pressure and lyophilized to give a white powder of N-t7r-(2-(2-cyclopentene-1-yloxyimino)-2-(5- amino-1,2,4-thiadiazol-3-yl)acetamido)-3-cephem-3-ylmethyl pyridinium-4-carboxylate (syn isomer) (1.5 g), m.p. 190-195°C (decomposition). I.R. (Nujol) at 3350, 3200, 1780, 1660, 1620, 1530 cm"<1>N.M.R. (D20+NaHeQ3,<$>): 1.9-2.5 (4H, m), 3.23, 3, 60 (2H,

ABq, J=16Hz), 5.2-6.1 (7H, m), 7.9-9.1 (5H, m)

Example 3

To a cold solution of 1.46 g of phosphorus pentachloride in 30 ml of methylene chloride was added 2.11 g of 2-(1-ethyl-1-ethoxycarbonyloxyimino)-2-(5-amino-1,2,4-thiadiazole-3 -yl)acetic acid (syn isomer) at -18 C, and the mixture was stirred for 30 minutes at -14 to -1°C. To the reaction mixture was added 90 ml of dry n-hexane under -10 C, and the mixture was stirred for several minutes and the solvent removed by decantation. The residue was triturated with n-hexane and collected by filtration to give a powder ay the activated acid. Furthermore, a mixture of 2 g of S-17-amino-3-cephem-3-ylmethyl-pyridinium-4-carboxylate dihydrochloride and 10 g of trimethylsilylacetamide in methylene chloride was stirred for 10 minutes at room temperature and cooled to -18°C ... To the cold solution was added the powder obtained as above, and the mixture was stirred for 30 minutes at -13 to -10°C and for 30 minutes at -5 to 0°C. The reaction mixture was poured into 100 ml of an aqueous solution of 3.6 g of sodium bicarbonate and stirred for 15 minutes at room temperature and then adjusted to pH 1 with 6N hydrochloric acid.

The aqueous layer was separated from, washed with ethyl acetate and subjected to column chromatography on 100 ml of non-ionic adsorption resin with the trade name "Diaion HP-20". After the column was washed with water, 5% aqueous ethanol and 10% aqueous ethanol in sequence, the elution was performed with 20% aqueous ethanol. The eluates containing a desired compound were collected, evaporated to remove ethanol under reduced pressure and lyophilized to give 1.30 g of »-{7-""2-(1-methyl-1-ethoxycarben onylethoxyimino)-2 -(5-amino-1,2,4-thiadiazol-3-yl)acetamido~"~3-eefem-3-ylmethyl]-^pyridinium-4-carboxylate (syn isomer), in the form of a white powder, m.p. 164-168 oC (decomposition). I.R. (Nujol): 3350-3150, 1770, 1720, 1670, 1620, 1520 cm"<1>N.M.R. (DMSO-dg, 6): 1.15 (3H, t, J«7H2), 1.45 (6H, s),

3.03 and 3.55 (2H, ABq, J-I8H2), 4.10 (2H, q, J=7H2), 5.11 <1H, d, J«5Hz), 5.20 and 5.67 (2H, ABq, J=13Hz), 5.75 (1H, 2d, J»5 and 8H2), 8.20 (4H, m), 8.57

(1H, m), 9.47 (3H, m)

Example 4

The following compounds were obtained in a similar manner to that described in Examples 1 to 3: 1) 7-f 2-propoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamidol-3-{ 1-pyridiniomethyl)-3-eephen-4-carboxylate (syn isomer), m.p. 230-240°C (decomposition).

I.R. (Nujol)s 3400-3200, 1770, 1670-1600, 1530 cm"<1>

N.M.R. (DMS0-d6, S) : 0.85 (3H, t , J°7Hz), 1.6 (2H, m),

3.06, 3.55 (2H, ABq, J<=>18H2), 4.04 (2H, t, J=6Ez), 5.06 (1H, d, J«5HZ), 5.18, 5 .70 (2H, ABq, J=14Hz), 5.74 (1H, dd, J=5 and 8H2), 8.2 (4H, m), . 8.6

(1H, m), 9.5 (3H, m)

2) 7-12-Methoxyimino-2-(5-amino-1,2,4-thiadlaol-3^yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) ,

sm.p. 250-260°C (decomposition).

I.R. (@jol)s 34O0-3100, 1770, 1650, I6I0, 1520cm"<1>

N-M.R. (DMS0-d6, <S): 3.07, 3.57 (2H, ABq, J<«>18Hz), 3.86

(3H, s), 5.06 (1H, d, J»5Hz), 5.19, 5.69 (2H, ABq, J«14Hss), 5.73 (1H, dd, J«5>8B2) , 8.0-8.3 (4H, m), 8.4-8.7 (1H, m), 9.3-9.6 (3H, m)

3) 7-L 2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn-isomer ), sm.p. 160-165°C (decomposition). I.R. (Nujol): 3270, 3180, 1770, 1660, 1610, 1525 era"<1>N.M.R. (DMS0-d6+ 2>20, <5): 1.22 (6H, d, J*=6H2) , 3.15 , 3.57 (2H,ABq,J=18H2), 4.17-4.60 (1H, ra), 5.12 (1H, d, J»5Hz), 5.33, 5.70 (2H, ABq, J»14Hz), 5.78 (lH, d, *J«5Hz), 8.0-8.4 (2H, ra), 8.47-8.83 (lH, m), 9.33 -9.67 (2H.ta) 4) N-[7-{2-(t-butoxycarbonylmethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido)-3-cephem -3-ylmethyl]pyridinium-4-carboxylate (syn isomer), m.p. 150-155°C (decomposition). I.R. (Nujol): 3300, 3200, 1770, 1680, 1620, 1530 cm"<1> 5) N-[7-{2-carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate (syn- isomer) , m.p. 150-155°C (decomposition). I.R. (Nujol): 3350, 3200, 1780, 1680, 1530 cm"<1>6) N-[7-|2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido ^-3-cephem-3-ylmethyl]pyridinium-4-carboxylate (syn isomer), m.p. 180-185°C (decomposition). I.R. (Nujol): 3300, 3200, 1780, 1670, 1620, 1530 cm"<1>7) N-[7-) 2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl).aeetamido }-3-cephem-3- ylmethyl]-4'-carbamoylpyridinium-4-carboxylate (syn isomer), m.p. 170-175°C (decomposition). I.R. (Nujol): 3300, 3160, 1770, 1680, 1610, 1560, 1520 cm"<1>8) N-[7-f 2-(1-t-butoxycarbonyloxyimino)-2-(5-amino-1,2,4 -thiadiazol-3-yl)acetamido ^-3-cephem-3-ylmethyl]pyridinium-4-carboxylate (syn isomer), m.p. 160-165°C (dec.) I.R. (Nujol): 3290, 3160 , 1770, 1725, 1670, 1620, 1525 cm"<1>N.M.R. (CD 3 OD+D 2 O, 6): 1.2-1.6 (12H, m), 3.20 and 3.67 (2H, ABq, J=18Hz), 4.40-4.90 (1H, m) , 5.20 (lH, d,. J=5Hz), 5.33-5.80 (2H, m), 5.92 (lH, d, J=5Hz), 7.9-9.4 (5H , m). 9) N-[7-[2-(1-carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4- carboxylate (syn isomer), m.p. 175-180°C (decomposition). I.R. (Nujol): 3300, 3200, 1775, 1670, 1620, 1520 cm"<1>10) N-[7-(2-(1-benzyloxycarbonyloxyimino)-2-(5-amino-1,2,4-thiadiazole) -3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate (syn isomer), mp 178-182°C (decomposition).IR (Nujol): 3250, 3150, 1770 , 1670, 1620, 1520 cm"<1>N.M.R. (DMS0-db ,+Do Z0, 6): 1.45 (3H, d, J=7Hz), 3.10 and 3.60 (2H, ABq, J =16Hz), 4.87 (lH, q,-J=7Hz), 5.20 (2H, s), 4.97-5.10 (2H, m), 5.25 (lH, d, J= 5Hz), 5.83 (lH, d, J=5Hz) , 7.43 (5H, s), 8.27 (2H, m) , 8.63 (lH, m), 9.38 (2H. m ) 11) N-[7-{2-ethoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate (syn -isomer), m.p. 184-188°C (decomposition).

I.R. (Nujol) : 3400-3100, 1770, 1670, 1610, 1520 cm"<1>N.M.R. (DMS0-d6, <5 ) : 1.17 (3H, t,. J=7Hz), 3.05 and 3, 53

(2H, ABq, J=18Hz), 4.13 (2H, q, J=7Hz), 4.70.

(2H, s), 5.08 (1H, d, J=5Hz), 5.17 and 5.70 (2H,ABq,

.J=13Hz), 5.72 (lH, dd, J=5 and 8Hz), 8.16 (4H, m) , 8.62 (1H, m), 9.50 (3H, m) 12) N -[7-{2-(2-cyclohexen-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido^-3-cephem-3-ylmethyl]pyridinium- 4-carboxylate (syn isomer), m.p. 150-155°C (decomposition). I.R. (Nujol): 3300, 3200, 1775, 1660, 1610, 1520 cm"<1>N.M.R. (DMS0-d6, 6): 1.5-2.0 (6H, m), 3.13, 3.57 ( 2H, ABq,

J=17Hz), 4.6-4.7 (1H, m), 5.07 (lH, d, j=4Hz), 5.27, 5.60 (2H, ABq, J=14Hz), 5, 80 (lH, 2d, J=4 and 8Hz), 5.77-6.0 (2H, m), 8.17 (2H, s), 8.0-8.4 (2I-I, m), 8.43-8.80 (lH, m) , 9.4-9.5 (2H, m) , 9.55

(1H, d, J=8Hz)

13) N-[7-{2-carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido|-3-cephem-3-ylmethyl]-4<1->carbamoylpyridinium- 4-carboxylate (syn isomer), m.p. 175-180°C (decomposition). I.R. (Nujol): 3350, 3200, 1775, 1680, 1615, 1565, 1525 cm"<1>14) N-[7-{2-methoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazole-3 -yl) acetamido|-3-cef em-3-ylmethyl ] xoyridinium-4-carboxylate (syn isomer), m.p. 165-170°C (decomposition). I.R. (Nujol): 3300-3150, 1760, 1670, 1620, 1520 cm"<1>N.M.R. (D20, 6): 3.17, 3.70 (2H, ABq, J=18Hz), 3.80 (3H, s), 4.93 (211, s), 5.30 (lH, d, J =5Hz) , 5.44, 5.73 (2H, ABq, J=14Hz), 5.93 (lH, d, J=5Hz), 8.10 (2H, m), 8.60 (lH, m ), 8.98 (2H, m) 15) N-[7-{2-(1-methyl-1-carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido )-3-cephem-3-ylmethyl]pyridinium-4-carboxylate (syn isomer), white powder, m.p. 176-180°C (decomposition). I.R. (Nujol): 3400-3150, 1770, 1670, 1620, 1520 cm"<1>16) N-[7-^2-(1-methyl-1-t-butoxycarbonyloxyimino)-2-(5-amino-1,2 ,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate (syn isomer), mp 176-180°C (dec.) I.R. (Nujol) : 3300, 3200, 1780, 1730, 1680, 1620, 1520 cm"<1>N.M.R. (DMSO-d 6 -D 2 O, 6): 1.40 (15H, bs), 3.08, 3.42 (2H, ABq, J=18Hz), 5.13 (1H, d, J=5Hz), 5 .40 (2H, m), 5.80 (1H, d, J=5Hz), 8.17 (2H, m) , 8.65 (ll-I, m) , 9.37 (2H, m) 17 ) N-[7-{2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-carbamoylpyridinium-4-carboxylate (syn isomer), m.p. 230-235°C (decomposition). I.R. (Nujol): 3300, 3200, 1770, 1680, 1610, 1560, 1520, 1510 cm"<1>18) N-[7-{2-(2-cyclopenten-1-yl-oxyimino)-2-(5 -amino-1,2,4-thiadiazol-3-yl)acetamido[S-cephem-3-ylmethyl]-4'-carbamoyl-pyridinium-4-carboxylate (syn isomer), mp 155-160 °C (dec.). I.R. (Nujol): 3300, 3150, 1770, 1675, 1610, 1560, 1520 cm"<1>N.M.R. (DMS0-d6, (5): 2.0-2.4 (4H, m) , 3.17-3.67 (2H, m) , 5.08 (1H, d, J=5Hz), 5, 23-6.30 (6H, m), 8.27 (2H, wide s), 8.57 (2H, d, J=7Hz) , 9.53 (lH, d, J=8liz) , 9.70 (2H, d, J=7Hz) 19) N-[7-{2-(1-methyl-1-carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido} -3-cephem-3-ylmethyl]-4'-carbamoyl-pyridinium-4-carboxylate (syn isomer), m.p. 180-185°C (dec.).

I.R. (Nujol): 3300, 1770, 1680, 1620, 1560, 1520 cm"<1>N.M.R. (DMS0-d6, <5) : 1.40 (6H, s), 3.0-3.6 (2H, m ), 5.10

(lH, d, J=4Hz), 5.3-5.7 (2H, m), 5.80 (1H, dd,

J=4 and 8Hz), 9.18 (2H, d, J=7Hz), 9.50 (lH, d,J=8Hz), 9.63 (2H, d, J=7Hz)

20) 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer ), sm.p. 160-165°C (decomposition). I.R. (Nujol): 3290, 3180, 1770, 1660,.1610, 1525 cm"<1>N.M.R. (DMSO-d6+D20, 6): 3.12, 3.50 (2H, ABq, J=18Hz), 4 .44-4.76 (2H, m), 5.10 (lH, d, J=5Hz), 5.0-6.1 (6H, m), 8.0-8.4 (2H, m) , 8.44-8.7 6 (1H, m), 9.32-9.68 (2H, m) 21) 7-(^2-(2-propynyloxy4BQino)-2-(5-ajaino-1, 2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridinediomethyl)-3-cephem-4-carboxylate (syn-isomer), m.p* 145-150°C (decomposition).

I.R. (Nujol): 3250, 2100. 1770, 1660, 1630, 1610, 1525 cm"<1>N.M.R. (DMS0-d6, 6): 3.10, 3.55 (2H, ABq, J=»18Hz) , 3 ,47

(lH, t, J=2Hz), 4.73 (2H, d, J=2Hz) , 5.08

(lH, d, J«5Hz), 5.25, 5.65 (2H, ABq, J=14Hz),

5.60-5.93 (1H, m), 8.0-8.4 (4B, m), 8.4-8.8

(1H, m), 9.3-9.7 (3H, m)

22) 7-12-hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) , sm.p. 170-175 C (decomposition). I.R. (Nujol): 3350, 3200, 1780, 1620, 1530, 1490 cm"<*1>23) 7-(2-Methylthiomethoxyimino-2-(5-araino-1,2,4-thiadiazol-3-yl)- aeetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), mp 195-205°C (decomposition).

I.R. (Nujol): 3350-3150, 1770, 1670, 1620, 1520, 1150 cm"<1>N.M.R. (DMSO-d6+D20, <5): 2.17 (3H, s), 3.00, 3.62

(2H, ABq, J»18Hz), 5.10 (lH, d, J=5Hz), 5.22

(2H, s), 5.73 (1H, d, J*5Hz), 5.00-5.83 (2H, m), 8.13 (2H, m), 8.53 (lH, m), 9.33 (2H, m) 24) 7-12-trityloxyimino-2-(5-amino-{1},2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3- cephem-4-carboxylate (syn isomer), m.p. 165-170°C (decomposition).

I.R. (Nujol): 3450, 1780, 1670, 1620, 1530, 1490 cm"<1>N.M.R. (DMS0-d€, <5): 3.18, 3.64 (2H, ABq, J=18Hz) , 5, 18

(1H, d, J=5HZ), 5.34, 5.74 (2H, ABq, J=12Hz), 5.92 (1H, dd, J*5 and 8Hz), 7.28 (15H, s) , 7.94-8.30 (4H, m), 8.42-8.66 (1H, m), 9.22-9.54 (2H, m), 9.78

(lH, d, J«8Hz)

25) 7-[2-(2,2,2-trifluorooxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem -4-carboxylate (syn isomer), m.p. 150-155°C (decomposition). I.R. (Nujol): 3300, 1780, 1675, 1630, 1530 cm"<1>N.M.R. (DMS0-d6+D20, 3): 3.23, 3.50 (2H, ABq, J«18Hz), 4.63, 4.93 (2H, ABq, J«=9Hz), 5.17 (lH, d, J»5Hz), 5.37, 5.73 (2H, ABq, J=14Hz), 5.83 (lH, d, J=5Hz), 8.1-8.4 (2H, m) , 8.5-8.8 (1H, m) , 9.3-9.6 (2H, m) 26) . 7- *2-Ethoxyimino-2-{5-amino-1,2,4-thiadiazol-3-amido]-3-(4-carbamoyl~1-pyridinemethyl)-3-cef em-4-carbox<y>latrr< ( syn isomer), mp» 160-165°C (decomposition). I.R. (Nujol) : 3300, 3200, 1780, 1680, 1620, 1570, 1530 cm*"1 27) 7-[2-(2- oxotetrahydrofuran-3-yloxyimino)-2-(5-amino-1,2,4- thiadiazol-3-yl) aeetamido 1-3-(1-pyridiniomethyl)-3-cephem-4^ carboxylate (syn isomer), m.p. 140-145°C (decomposition). I.R. (Nujol) i 3350, , 1780, 1670, 1620, 1530, 1490 cm<*>"<1>N.M.R. (DHSO-d;6-»-D2O, 6) : 2.43-2.83 (2H, m ), 3.27, 3 .63 (2H, ABq, J*18Hz) , 4.23-4.67 (2H, m), 5.17-5.37 (lH, m), 5.20 (lH , d, J»5Hz), 5.38, 5.73 (2H> ABq, J«13Hz), 5.87 (1H, d, J«5Hz), 8.07-8.43 (2H, m) , 8.53-8.80 (1H, m), 9.23-9.50 (2H, m) 28) 7-f 2-methoxy<y>imino-2-(5-amino-1,2, 4-thiadiazol-3-yl)acetamido]-3-{4-carbamoyl-1-pyridiniomethyl)*3-ce fem-4-carboxylate (syn isomer), m.p. 165-170 oC (dec.) I.R. (Nujol): 3350, 3200, 1780, 1690, 1610, 1570, 1530 cm<**1>29) 7-f 2-propoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl )aetamido]— 3-(4-carbamoyl— 1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), m.p. 170-175°C (decomposition). I.R. (Nujol) p 3350, 3200 , 1780, 1690, 1610, 1570, 1530 cm""<1>30) 7-12-isopropoxyimino^2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-{ 4-Carbamoyl-1-pyridiniomethyl)-3-ephem-4-carboxylate (syn isomer), m.p.. 155-160°G (dec.). I.R. (Nujol) p 3350, 3220, 1780, 1680, 1615 , 1570, 1530 cm""1 31) 7- 2-alilyoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn- isomer), m.p. 161-165°C (decomposition). I.R. (Nujol). 3400-3150, 1770, 1670, 1610, 1560, 1520 Cm*"1 32) 7-[2-(2,2,2-trifluorooxyimino)-2-(5-amino-1,2,4-thiadiazole-3 -yl) aeetamido] -3 - (4-carbamoyl-1-pyridiniomethyl) -3-cef em-4-carboxylate (syn isomer), m.p. 160-165°C (decomposition). I.R. (Nujol) : 3300, 3150, 1780, 1680, 1610, 1580, 1520 cm"<*1>33) 7-(2-Methylthiomethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido ];-3-(4-carbamoyl-1-pyridiniomethyl)-3-cef era-4-carboxylate (syn isomer), saup. 160-165°C (decomposition). I.R. (Nujol) p 3300, 3150, 1770, 1680, 1610, 1560, 1520 cm""<1>34) 7-f 2-(2-propynyloxyimino)-2-(5-amino-1,2,4-thiadiazole -3-yl)acetamido]-3-(4-carbamoyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), m.p. 155-160 C (decomposition). Jt.R. (Nujol)t 3400, 3250, 3150 , 2120, 1770, 1685, 1610, 1560, 1525cm"<1>35) Sodium-7-I2-cyclopentyloxyiraino~2-(S-amino-1,2,4-thiadia2ol- 3-yl)acetamido3-3-(2-methyl-5-oxo-6-byhydroxy-2,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cefear-4-carboxylate (syn -isomer) , m.p. 169-174°C (decomposition)* I.R. (Nujol)s 3600-3100, 1760, 1690, 1665, 1640, 16lO, 1520, 1005 era"<1>36) Dinatr iumr-7 -f 2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(2-ethyl-5-oxo-6-oxido-2,5-dihydro- 1,2,4-triazin-3-yl)thioethyl 3-cephem-4-carboxylate (syn isomer), m.p. 220-225°C (decomposition). I.R. (Nujol): 3400-3150, 1760, 1660, 1640-1560, 1520, 1040 cm"<1>37)Dinatrilum-7-f 2-ethoxy<y>imino-2-(5-amino-1,2, 4-thiadiazol-3-yl)acetamido]-3-(2-methyl-5-oxo-6~oxido-2,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem- 4-carboxylate (syn isomer), m.p. 255-265 C (decomposition). I.R. (Nujol): 3400-3150, 1760, 1660, 1600, 1500, 1400, 1030 cm"<1>38) 7- f 2-(2-cyclopenten-1-yloxyamino)-2-(5-amino-1,2,4* thiadiazol-3-yl)acetamido]-3-(2-methyl-5-oxo-6-hydroxy- 2,5-dihydr o-l, 2 , 4-tri iazin-O-yl) thiomethyl-3-cef em-4-carboxylic acid (syn isomer), m.p. 158-164 C (decomposition). I.R. (Nujol). 3450-3150, 1770, 1680, 1630, 1510, 1260, 1180, 1100, 1030, 1010 cm"<1>N.M.R. (DMSO-d6, 6): 2.0-2.6 (4H, m), 3, 2-4.0 (2H, ra), 3.62 (3H, s), 4.13, 4.45 (2H, ABq, J=13Hz), 5.13 (lH, d, J«5Hz), 5.2-5.5(1H, m), 5.7-6.0 (2H, m), 6.0-6.2 (1H, m), 8.20 (2H, wide s), 9 .50 (1H, d, J«8Hz) 39) 7-f 2-isopropyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(2-methyl-5 -oxo-6-hydroxy-2,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer),

sm.p. 160-167°C (decomposition).

I.R. (Nujol): 3400, 3280, 3180, 1780, 1770, 1630, 1515,

1410, 1240, 1009 cm"<1>

N.M.R. (DMSO-d6-in-D20, 6): 1.2? (6H, d, J=6Hz), 3.62 (3H, s) ,

3.5-3.9 (2H,Bl), 4.13, 4.41 (2H, ABq, J=14Hs5), 4.40 (1H, t, J=6Hz)» 5.17 (1H, d , J-5Hz), 5.83

(lH, d, J=5Hz)

40) 7-{2-(2-propynyloxyamino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-(2-methyl-5-oxo^6-hydroxy- 2,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem~4~carboxylic acid (syn isomer), m.p. 161-166 C (decomposition). I.R. (Nujol)i 3260, 3180, 1770, 1670, 1620, 1520, 1335 caf<1>N.M.R. (DMS0-dg+B20, 6)? 3.48 (lH, s), 3.61 (3H, s), 3.3-3.9 (2H, ,»), 4.10, 4.38 (2H, ABq, J=14Hz), 4 .77 (2H, s), 5.12 (1H, d, J=5Hz), 5.78 (1H, d, J=5Hz) 41) 7-[2-allyloxyimino-2-(5-amino-1 ,2,4-thiadiazol-3-yl)acetamido]-3-(2-methyl-5-ox©-6-hydroxy-2,5-dihydro-1,2,4-triazin-S-yDthiomethyl^-cephem ^^carboxylic acid (syn isomer),

sm.p. 169-173°C (decomposition).

I.R. (Nujpl): 3360, 3210, 1775, 167.0, 1625, 1560, 1520

1250, 1175, 1100, 1020 cm"1

N.M.R. (DMSO-d6, 6): 3.3-4.0 (2H, m), 3.58 (3H, s), 4.0-4.6

(2H, m), 4.5-4.8 (2H, m), 5.13 (lH, d, J*5Hz), 5.0-5.6 (3H, m), 5.81 (lH , dd, J«5 and 9Hz), 8.18 (2H, wide s), 9.53 (lH, d, J=9Hz)

Example 5

A mixture of 5.1 g 7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanic acid {syn isomer), 840 mg sodium bicarbonate, 50 ml water , 24.3 g of potassium thiocyanate and 1.83 g of isonicotinide were stirred for 22 hours at 50-55 G. The reaction mixture was cooled and added to ethyl acetate. The mixture was adjusted to pH 2 with 10% hydrochloric acid and filtered. The aqueous layer was separated from the filtrate, washed with ethyl acetate and evaporated. The evaporation residue was subjected to column chromatography (nonionic adsorption resin with the trade name<*>Diaion HP20" manufactured by Mitsubishi Chemical industries), and the column was washed with 0.7 L of water and then eluted with 0.7 L of 30?6 aqueous methanol. The eluates which contained the desired compound, was collected, washed with ethyl acetate and then evaporated. yl)acetamido}-3-cephem-3-ylmethyl]-4'-carbamoylpyridinium-4-carboxylate (syn isomer) (1.0 g), mp 230-235°C (dec.). I.R. (Nujol ): 3300, 3200, 1770, 1680, 1610,

1560, 1520, 1510 cm"<1>

N.M.R. (d6-DMS0, 6): 1.30-1.95 (8H, m), 3.15 and 3.50

(2H, ABq, J=18Hz), 5.60-5.75 (lH, m), 5.06 (lH, d,J=4Hz), 5.30 and 5.65 (2H, ABq, J= 14Hz), 5.70 (lH, dd, J=4 and 8Hz), 8.12 (2H, s), 8.45 (2H, d, J=6Hz), 9.42 (2H, d, J= 6Hz), 9.50 (lH, d, J=8Hz)

Example 6

A mixture of 2.8 g of 7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylic acid (syn- isomer), 420 mg of sodium bicarbonate, 28 g of potassium iodide and 590 mg of pyridine in 28 ml of water were stirred for one hour at 55°C. After cooling, 20 ml of ethyl acetate, 5.5 ml of 1N hydrochloric acid and 10 ml of acetone were added with stirring. The aqueous layer was separated off, washed with ethyl acetate and concentrated to 30 mL under reduced pressure. An insoluble substance was filtered off, and the filtrate was subjected to column chromatography on a non-ionic adsorption resin with the trade name "Diaion HP20" (100 ml). After the column had been washed with 500 ml of water, the elution was carried out with 30% aqueous methanol. The eluates containing a desired compound were collected, evaporated to remove methanol under reduced pressure and lyophilized to give N-[7-{2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazole-3 -yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate (syn isomer) (620 mg), white powder, m.p. 180-185°C (decomposition).

I.R. (Nujol): 3300, 3200, 1780, 1670, 1620, 1530 cm"1

N.M.R. (DMSO-dg,'d): 1.4-2.0 (8H, m), 3.17

3.53 (2H, ABq, J=18Hz), 4.60-4.83 (lH, m), 5.10 (lH, d, J=4Hz), 5.30, 5.83 (2H, ABq , J=14Hz), 5.87 (1H, 2d, J=4 and 8Hz), 8.17 (2H, s), 9.50 (lH, d, J=8Hz), 8.0-9.7 (5H, m)

Example 7

The following compounds were obtained in a similar manner to that described in Examples 5 and 6: 1) N-[7-{2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol- 3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate (syn isomer), m.p. 190-195°C (decomposition). I.R. (Nujol): 3350, 3200, 1780, 1660, 1620, 1530 cm"1 2) N-[7-{2-(t-butoxycarbonylmethoxyimino)-2-(5-amino-1,2,4-thiadiazole- 3-yl)acetamido}-3-cef em-3-ylmethyl] pyridine ium-4-carboxylate (syn isomer), mp 150-155°C (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1680, 1620, 1530 cm"<1>

3) N-[7-{2-carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate

(syn isomer), m.p. 150-155°C (decomposition).

I.R. (Nujol): 3350, 3200, 1780, 1680, 1530 cm"<1>

4) N-[7-{2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-pyridinium-4-carboxylate (syn -isomer), m.p. 180-185°C (decomposition). I.R. (Nujol): 3300, 3200, 1780, 1670, 1620, 1530 cm"<1>N.M.R. (DMSO-db,, (5): 1.4-2.0 (8H, m) , 3.17, .3 .53 (2M, ABq, J=18Hz), 4.60-4.83 (lH, m), 5.10 (lH, d, J=4Hz), 5.30 and 5.83 (2H, ABq, J=14Hz), 5.87 (1H, dd, J=4 and 8Hz), 8.17 (2H, s), 9.50 (lH, d,J=8Hz), 8.0-9.7 ( 5H, m) 5) N-[7-{2-(1-carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl] -4<1->carbamoylpyridinium-4-carboxylate (syn isomer), mp 170-175°C (decomposition). IR (Nujol): 3300, 3160, 1770, 1680, 1610, 1560, 1520 cm "<1>N.M.R. (DMSO-d6,, (5): 1.38 (3H, d, J=7Hz), 3.10-3.60 (2H, m), 4.40-4.83 (1H, m), 5 .10 (lH, d, J=5Hz), 5.28-6.00 (3H, m), 8.22 (2H, wide s), 8.48 (2H, d, J=6Hz), 9, 48 (2H, d, J=6Hz), 9.32-9.65 (1H, m) 6) N-[7-{2-(1-t-butoxycarbonyloxyimino)-2-(5-amino-1, 2,4-.thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate (syn isomer), m.p. 160-165°C (decomposition). I.R. (Nujol): 3290, 3160, 1770, 1725, 1670, 1620, 1525 cm"<1>7) N-[7-{2-(1-carboxyethoxyimino)-2-(5-amino-1,2,4 -thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl Jpyridinium-4-carboxylate (syn isomer), m.p. 175-180°C (decomposition). I.R. (Nujol): 3300, 3200, 1775 , 1670,' 1620, 1520 cm"<1>8) N-[7-{2-(1-benzyloxycarbonyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}- 3-cephem-3-ylmethyl]pyridinium-4-carboxylate (syn isomer), m.p. 178-182°C (decomposition). I.R. (Nujol): 3250, 3150, 1770, 1670, 1620, 1520 cm"<1>9) N-[7-{2-ethoxycarbonylImethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl) )aeetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate (syn isomer), mp 184-188°C (dec.) IR (Nujol): 3400-3100, 1770, 1670, 1610 , 1520 cm"<1>10) N-[7-{2-(2-cyclohexen-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3 -cephem-3-ylmethyl]pyridinium-4-carboxylate (syn isomer), m.p. 150-155°C (decomposition). I.R. (Nujol): 3300, 3200, 1775, 1660, 1610, 1520 cm"<1>11) N-[7-{2-carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl )acetamido}-3-cephem-3-ylmethyl J-4'-carbamoylpyridinium-4-carboxylate (syn isomer), m.p. 175-180°C (decomposition). I.R. (Nujol): 3350, 3200, 1775, 1680, 1615, 1565, 1525 cm"<1>N.M.R. (DMSO-d6"D2O, 6) : 3.23, 3.55 (2H, ABq, J=18Hz), 4.67 (2H, s), 5.10 (1H, d, J=5Hz), 5 .35, 5.72 (2H, ABq, J=15Hz), 5.80 (lH, d, J=5Hz), 8.43 (2H, d, J=6Hz), 9.38 (2H, d, J=6Hz) 12) N-[7-{2-methoxycarbonylImethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4- carboxylate (syn isomer), m.p. 165-170°C (decomposition). I.R. (Nujol): 3300-3150, 1760, 1670, 1620, 1520 cm"<1>13) N-[7-{2 -(1-methyl-1-carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate (syn isomer ), white powder, m.p. 176-180°C (dec.). I.R. (Nujol): 3400-3150, 1770, 1670, 1620, 1520 cm"<1>14) N-[7-{2-(1-methyl-1-ethoxycarbonyloxyimino)-2-(5-amino-1,2 ,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethylJ pyridinium-4-carboxylate (syn-isomer), white powder, m.p. 164-168°C (dec.) I.R. (Nujol) : 3350-3150, 1770, 1720, 1670, 1620, 1520 cm"<1>15) N-[7-{2-(1-methyl-1-t-butoxycarbonyloxyimino)-2-(5-amino-1,2, 4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-pyridinium-4-carboxylate (syn isomer), m.p. 176-180°C (dec.). I.R. (Nujol): 3300, 3200, 1780, 1730, 1680, 1620, 1520 cm"<1>16) N-[7-{2-(2-cyclopenten-1-yl-oxyimino)-2-(5-amino -1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-carbamoyl-pyridinium-4-carboxylate (syn isomer), mp 155-160°C (splitn.). I.R. (Nujol): 3300, 3150, 1770, 1675, 1610, 1560, 1520 cm"<1>N.M.R. (DMS0-dr6, <5) : 2.0-2.4 (4H, m), 3.17-3.67 (2H, m), 5.08 (1H, d, J=5Hz), 5, 23-6.30 (6H, m), 8.27 ■ (2H, wide s), 8.57 (2H, d, J=7Hz), 9.53 (lH, d, J=8Hz), 9, 70 (2H, d, J=7Hz) 17) N-[7-{2-(1-methyl-1-carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido }-3-cephem-3-ylmethyl]-4'-carbamoyl-pyridinium-4-carboxylate (syn isomer), m.p. 180-185°C (dec.). I.R. (Nujol): 3300, 1770, 1680, 1620, 1560, 1520 cm"<1>18) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido] -3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer),

sm.p. 155-165°C (decomposition).

I.R. (Nujol): 3400-3150, 1770, 1660, 1610, 1530 cm"<1>. 19) 7-[2-propoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl) acet-amido]-3-(1-pyridinediomethyl)-3-cephem-4-carboxylate (syn isomer), mp 230-240°C (decomposition). IR (Nujol): 3400-3200, 1770, 1670-1600, 1530 cm"<1>20) 7-[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3 -cephem-4-carboxylate (syn isomer), m.p. 250-260°C (decomposition). I.R. (Nujol): 3400-3100, 1770, 1650, 1610, 1520 cm"<1>21) 7-[2-isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido ]-3-(1-pyridinediomethyl)-3-cephem-4-carboxylate (syn isomer), m.p. 160-165°C (decomposition). I.R. (Nujol): 3270, 3180, 1770, 1660, 1610 . -4-carboxylate (syn isomer), m.p. 160-165°C (decomposition). I.R. (Nujol)t 3290, 3180* 1770, 1660, 1610, 1525 cra"<1>23) 7-f 2-(2-propynyloxyimino)-2-(5-amino-1,2,4-thiadiazole-3- yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), mp 145-150°C (decomposition). IR (Nujol): 3250, 2100, 1770, 1660, 1630, 1610, 1525 cm""<1>24) 7-f 2-hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridinediomethyl )-3-cefém-4-carboxylate (syn isomer), m.p. 170-175°C (decomposition). I.R. (Nujol): 3350, 3200, 1780, 1620, 1530, 1490 cm""1 25) 7-f 2-Methylthiomethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), m.p. 195-205°C (decomposition). I.R. (Nujol): 3350-3150, 1770, 1670, 1620, 1520, 1150 cm"1 26) 7-f 2-trityloxyimino-2-(5-amino- 1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridinediomethyl)-3-cephem-4-carboxylate (syn isomer), m.p. 165-17d°C (decomposition). I.R. (Nujol) : 3450, 1780, 1670, 1620, 1530, 1490 cm<**1>27) 7-f 2-(2,2,2-trifluoroethoxyimino)-2-(5-amino-1,2,4 -thiadiazol-3-yl)acetamido]-3-(1-pyridinediomethyl)-3-cephem-4-carboxylate (syn isomer), m.p. 150-155 C (decomposition). I.R. (Nujol): 3300, 1780, 1675, 1630, 1530 cm"<1>28) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3- (4-Carbamoyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), mp 160-165°C (dec.).

I.R. (Nujol): 3300, 3200, 1780, 1680, 1620, 1570, 1530 cm"1 N.M.R. (DMSO-d6+D20,<*>)s 1.33 (3H, t, J=7Hz), 3.33, 3.67

(2H, ABq, J=18Hz), 4.35 (2H, q, J=7Hz), 5.30

(1H, d,, J=4Hz), 5.47, 5.67 (2H, ABq, J»14Hz), 5.90 (1H, d, J=4Hz) , 8.40 (2H, d, J =7Hz), 9.17 (2H,

d, J*7Hz)

29) 7-{2-(2-oxotetrahydrofuran-3-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cef em-4-^ carboxylate (syn isomer), sra.p. 140-145°C (decomposition). I.R. (Nujol): 3350, 1780, 1670, 1620, 1530, 1490 cm"<1>30) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido] -3-(4-carbamoyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), mp 165-170°C (decomposition). IR (Nujol): 3350, 3200, 1780, 1690, 1610, 1570, 1530 cm"1 N.M.R. (D20, 5): 3.33, 3.67 (2H, ABq, J=18Hz), 4.07 (3H, s), 5.30 (1H, d, J»4Hz), 5.47, 5 .67 (2H, ABq, J=14Hz), 5.90 (lH, d, J=4Hz), 8.40 (2H, d, J=7Hz), 9.17 (2H, d, J=7Hz) 31) 7-[2-propoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-{4-carbamoyl-1-pyridiniomethyl)-3-cephem-4-carboxylate ( syn isomer), m.p. 170-175°C (decomposition). I.R. (Nujol): 3350, 3200, 1780, 1690, 1610, 1570, 1530 cm"<1>N.M.R. (D20, <5) : 0.95 (3H, t, J=7Hz), 1.5-2.0 (2H, m) ,

3.33, 3.68 (2H, ABq, J-17HZ), 4.28 (2H, t, J=7Hz) , 5.33 (1H, d, J*=4Hz), 5.47, 5, 70 (2H, ABq, J=*14Hz) , 5.92 (lH, d, J«4Hz), 8.42 (2H, d, J«7Hz), 9.17

(2H, d, J«7Hz)

32) 7-12-isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-(4-carbamoyl-1-pyridinediomethyl)-3-cephem-4-carboxylate (syn isomer), m.p. 155-160°C (decomposition). I.R. (Nujol): 3350, 3220, 1780, 1680, 1615, 1570, 1530 cm"<1>N.M.R. (DMSO-d6+D2G, 6): 1.22 (6H, d, J=6Hz), 3.17, 3.48 (2H,ABq,J»18Hz), 4.1-4.6 (lH, m), 5.03 (lH, d, CZj J-5Hz), 5.25, 5.63 (2H, ABq, J»14Hz), 5.70 (lH, d, J-5H2), 8.40 (2H, d, J=6Hz), 9.45 (2H, d, J=»6Hz) 33) 7- f 2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-1-pyridiniomethyl)-3-recefem-4-carboxylate (syn isomer), m.p. 161-165 o C (decomposition). I.R. (Nujol): 3400-3150, 1770, 1670, 1610, 1560, 1520 cm"1 N.M.R. (DMSO-d 6 +D 2 O, 8): 3.09, 3.50 (2H, ABq, J»18Hz), 4.5-4.7 (2H, ra), 4.9-5.4 (4H, m), 5.06 (lH, d, J«5Hz) , 5.6-6.1 ;(1H, m) , 5.71 (lH, d, J=5Hz), 8.43 (2H, d, J=6Hz), 9.50 (2H, d, J=6Hz) 34) 7-12-(2,2,2-trifluorooxyimino)-2-(5-amino-1,2,4 -thiadiazol-3-yl)acetamido]-3-{4-carbamoyl-1-pyridiniomethyl)-3-cef em-4-carboxylate (syn isomer), m.p. 160-165°C (decomposition).

I.R. (Nujol): 3300, 3150, 1780, 1680, 1610, 1580, 1520cm"<1>

N.M.R. (D20, <5): 3.3Q, 3.67 (2H, ABq, J»17Hz), 4.73, 4.97

(2H, ABq, J=8Hz), 5.30 (lH, d, J«4Hz), 5.47, 5.67 (2H, ABq, J=14Hz), 5.92 (lH, d, J= 4Hz), 8.40 (2H,

d,J»7Hz), 9.20 (2H,d,J*7Hz)

35) 7-[2-methylthioiaethoxyimino~2-15-amino~1,2,4-thiadiazol-3-yl)-acetamido}-3-(4-carbamoyl-1-pyridiniomethyl)-3-cephem-4-carb ~oxylate (syn isomer), m.p. 160-165°C (decomposition). I.R. (Nujol) at 3300, 3150, 1770, 1680, 1610, 1560, 1520 cm<*>"<1>N.M.R. (DMSO-d6+D20, <5) : 2.23 (3H, s) , 3.15, 3.67 (2H, ABq,J=18Hz), 5.17 (1H, d, J=5Hz ), 5.32 (2H, s), 5.00-5.57 (2H, m), 5.80 ( 1H, d, J*5Hz), 8.68 (2H, d, J=6Hz), 9.50 (2H, d, J«6Hz) 36) 7-t2-(2-propvnyloxyimino)-2-(5 -amino-1,2,4-thiadiazol-3-yl)acetamido-3-(4-carbamoyl-1-pyr:idiniomethyl)-3-cephem-4-carboxylate (syn isomer), m.p. 155 -16ø°c (decomposition).

X.R. (Nujol) J 3400, 3250, 3150, 2120, 1770, 1685, 1610,

1560, 1525 cm"<1>

N.M.R. (DMS0-d6+D20, <S) : 3.23, 3.58 (2H, ABq, J=18Hz),

3.45 (1H, t, J»2Hz), 4^80 (2H, d, J=2Hz), 5.13

(1H, d, J«5Hz), 5.35, 5.72 (2H, ABq, J=14Hz), 5.78

(1H, d, J<*>=5Hz), 8.47 (2H, d, J»7Hz), 9.50

(2H, d, J*=7Hz)

Example 8

7-12-Eyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido)-3-acetoacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer) was reacted with 2- methyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazine-3-thiol in a similar manner as described in examples 5 and 6, so that sodium 7-t2-cyclopentyloxyimino- 2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(2-methyl-5-dxo-6-hydroxy-2,5-dihydro-1,2,4-triazine -3-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer), m.p. 169-174 C (decomposition). I.R. (Nujol); 3600-3100, 1760, 1690, 1665, 1640, 1610,

1520, 1005 cm<**1>

N.M.R. (B2O+NaHCO3, <$): 1.3-2.1 (8H, m), 3.63 (3H, s),

3.4-3*9 (2H, m) , 4.08, 4.40 (2H, ABq, J=14Hz), 4.7-5.1 (1H, m), 5.22 (lH, d , J«5Hz), 5.80 (1H,

d, J<«>5Hz)

Example 9

The following compounds were obtained in a similar manner to that described in Examples 5, 6 and 851) Disodium 7-12-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-( 2-methyl-5-oxo-6-oxido-2,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer),

sm.p. 220-225°c (decomposition).

I.R. (Nujol)t 3400-3150, 1760, 1660, 1640-1560, 1520, 1040cm""<1>N.M.R. (£>20, 6)s 3.64 (3H, s), 3.48 , 3.78 ( 2H, ABq, J*»18Hz), 4.08 (3H, s), 4.00-4, 56 (2H, m). 5.20 (1H, d, J=5Hz), 5.82 (1H, d, J~5Hz) 2) Dinatriuta-7-1 2-ethoxyiraino-2-(5-amino-1, 2,4-thiadiaz (1-3-yl)acetamido]-3-(2-methyl-5-oxo-6-ol-cydo-2,5-dihydro-1,2,4-triazin-3-yl)thioethyl- 3-cefera-4-carboxylate (syn isomer),

sm.p. 255-265°G (decomposition). ,

l. K. (Nujol): 3400-3150, 1760, I660, 1600, 1500,

1400, 1030 cm"1

N.M.R. (D20, <5): 1.35 (3H, t, J*7Hz), 3.42, 3.80 (2H, ABq,

J=18Hz), 3.65 (3H, s), 4.07, 4.43 (2H, ABq, <T*»13Hz), 4.38 (2H, q, J=7Hz), 5.22 ( 1H, d, J«5Hz), 5.83

(1H, d, J=5Hz)

3) 7-f 2-(2-cyclopentene-1-syloxyimino)-2-(5-amino-1,2,4~thiadi*&azol-3~yl)acetamido]-3-(2-methyl-5 -oxo-6-hydroxy-2,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), m.p. 158-164°C (decomposition). I.R. (Nujol): 3450-3150, 1770, 1680, 1630, 1510, 1260, 1180, 1100, 1030, 1010cm"<1>4) 7-12-isopropoxyimino-2-(5-amino-1,2,4- thiadiazol-3-yl)acetamido]-3-(2-methyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4- carboxylic acid (syn isomer), m.p. 160 - 167°C (decomposition). I.R. (Nujol): 3400;, 3280, 3180, 1780, 1770, 1630, 1515, 1410-, 1240, 1009 cm"<1>5) 7-12-{2-propynyloxyimino)-2-(5-amino-l . 3-cephem-4-carboxylic acid (syn isomer),

sm.p. 161-166°C (decomposition).

I.R. (Nujol): 3260, 3180, 1770, 1670, 1620, 1520, 1335 cm"<1>6) 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl) -acetamido]-3-(2-methyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-tri-azin-3-yl)thiomethyl-3-cephem-4-carboxylic acid. syn isomer),

sm.p. 169-173°C (decomposition).

I.R. (Nujol): 3360, 3210, 1775, 1670, 1625, 1560, 1520,

1250, 1175, 1100, 1020 cm"<1>

Example 10

To a solution of N-[7-{2-t-butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido)-3-cephem-3-ylmethyl]-pyridinium-4 -carboxylate (syn isomer) (1.8 g) in 18 ml of formic acid, 0.5 ml of conc. hydrochloric acid, and the mixture was stirred for one hour at room temperature. The solvent was distilled off under reduced pressure, and the distillation residue was pulverized with acetone, collected by filtration, washed with acetone and diisopropyl ether to give a powder. The powder was dissolved in 5 ml of water and subjected to column chromatography on 50 ml of non-ionic adsorption resin with the trade name "Diaion HP 20" (manufactured by Mitsubishi Chemical Industries). After the column had been washed with 500 ml of water, the elution was carried out with 40% aqueous methanol. The eluates containing a desired compound were collected, evaporated to remove methanol under reduced pressure and lyophilized to give a white powder of N-[7-{2-carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)- acetamido}-3-cephem-3-ylmethyl]-pyridinium-4-carboxylate (syn isomer) (800 mg), m.p. 150-155°C (decomposition).

I.R. (Nujol): 3350, 3200, 1780, 1680, 1530. cm"1

N.M.R. (D2O+NaHCO3, 6): 3.27 and 3.63 (2H, ABq, J=18Hz),

4.70 (2H, p), .5.30. (1H, d, J=4Hz), 5.40 and 5.60 (2H, ABq, J=14Hz), 5.93 (lH, d, J=4Hz), 8.0-9.1 (5H, m)

Example 11

To a cold mixture of 22 ml of trifluoroacetic acid and 4.4 ml of anisole was added 3.18 g of N-[7-{2-(1-methyl-1-t-butoxycarbonyl-ethoxyimino)-2-(5-amino-1,2 ,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate, and the mixture was stirred for 40 minutes at room temperature. The mixture was evaporated to remove trifluoroacetic acid, and the residue was triturated with isopropyl ether to give a yellowish powder. The powder was dissolved in aqueous sodium bicarbonate, adjusted to pH 1 with 6N hydrochloric acid and washed with ethyl acetate. The aqueous solution was subjected to column chromatography on 140 ml of non-ionic adsorption resin with the trade name "Diaion HP-20". After the column was washed with water, the elution was performed with 5% and 10% aqueous isopropyl alcohol. The eluates containing a desired compound were collected, evaporated to remove isopropyl alcohol under reduced pressure and lyophilized to give N-[7-{2-(1-methyl-1-carboxyethoxyimino)-2-(5-amino-1 ,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate (syn isomer) (2.20 g), white powder, m.p..17 6- 180°C (decomposition). I.R. (Nujol): 3400-3150, 1770, 1670, 1620, 1520 cm"<1>N.M.R. (DMS0-d6+D20, 5): 1.48 (6H, s), 3.10, 3.62 (2H,

ABq, J=18Hz), 5.12 (1H, d, J=5Hz), 5.45. (2H, m), 5.78 (lH, d,J=5Hz), 8.13 (2H, m), 8.58 (lH, m), 9.38 (2H, m)

Example 12

The following compounds were prepared in a similar manner to that described in Examples 10 and 11: 1) N-[7-{2-(1-carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl) acetamido}-3-cephem-3-ylmethyl J-4<1->carbamoylpyridinium-4-carboxylate (syn isomer), m.p. 170-175°C (decomposition). I.R. (Nujol): 3300, 3160, 1770, 1680, 1610, 1560, 1520 cm"1 2) N-[7-[2-(1-carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazole) -3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate (syn isomer), mp 175-180°C (decomposition).

I.R. (Nujol): 3300, 3200, 1775, 1670, 1620, 1520 cm"<1>N.M.R. (D20+NaHC03, <S ) : 1.50 (3H, d, J=7Hz), 3.25 and

3.67 (2H, ABq, J=18Hz), 4.40-4.90 (lH, m), 5.32

(1H, d, J=5Hz), 5.42 and 5.60 (2H, ABq, J=15Hz),

5.83-6.00 (1H, m), 7.9^-9.1 (5H, m) 3) N-C 7-{2-carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazole) -3-yl)acetamido}-3~eef em-3-ylraethyl J -4 * -carbamoylpyridiniura-4-carboxylate (syn isomer), m.p. 175-180°c (decomposition). I.R. (Nujol): 3350, 3200, 1775, 1680, 1615. 1565, 1525 cm"<1>4) N-1 7-(2-(1-methyl~1-carboxyethoxyamino)-2-(5-amino-1,2 ,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4<*->carbamoyl- pyridiniura-4-carboxylate (syn isomer), m.p. 180-185°C (splitting .).

I.R. (NujOl): 3300, 1770» 1680, 1620, 1560, 1520 cm"1

Example 13

A mixture of 5.55 g of 7-T2-trityloxyamino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-{1-pyridiniomethyl)-3-cef em^-4 -carboxylate (syn isomer) and 2.3 ml conc. hydrochloric acid in 60 al formic acid was stirred for two hours at ambient temperature. After an insoluble material was filtered off, the filtrate was evaporated to dryness and the evaporation residue was pulverized with acetone and collected by filtration. The powder was dissolved in 13 ml of water and subjected to column chromatography on 100 ml of non-ionic adsorption resin with the trade name "Diaion HE20" (manufactured by

Mitsubishi Chemical Industries), with water as eluent.

The eluates containing a desired compound were collected and lyophilized to give a yellowish white powder of 7-12-hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3- (1-Pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (675 rag), m.p. 170-175°C (decomposition). I.R. (Nujol): 3350, 3200, 1780, 1620, 1530, 1490 cm"<1>N.M.R* (DMS0-dg+D20, 6): 3.14, 3.54 (2H, ABq, J==L8Hz),

5.08 (lH, d, J=5Hz), 5.28, 5.62 (2H, ABq, J«12Hz), 5.86 (1H, d, J~5&z), 7.96-8.24 (2H, m), 8.40-8.68 (1H, ra), 9.16-9.42 (2H, m)

Example 14

To a cold solution of 20.8 g of phosphorus pentachloride in 375 ml of methylene chloride was added 25.4 g of 2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazole-3 -yl)acetic acid (syn isomer) at -18°C, and the mixture was stirred for 40 min at - 12 more

-10°C. To the reaction mixture was added 1.2 1 of diisopropyl ether below -10°C with stirring, and stirring was continued until the mixture was warmed to ambient temperature. The resulting precipitates were collected by filtration, washed with diisopropyl ether and then kept in a desiccator for several minutes. Furthermore, a mixture of 30.77 g of 1-[(7-amino-4-carboxy-3-cephem-3-yl)methyl]pyridinium chloride hydrochloride dihydrate and 154.5 g of trimethylsilylacetamide in 800 ml of methylene chloride was heated at 35 °C so that there was a solution, which was cooled to -18°C. To the cold solution was added the precipitates prepared as above, and the mixture was stirred for 30 minutes at -12 to -10°C. A solution of 26 g sodium bicarbonate in 400 ml water was added to the reaction mixture, and the aqueous layer was separated, adjusted to pH 1.5 with 6N hydrochloric acid and washed with ethyl acetate. The aqueous solution was adjusted to pH 4 with an aqueous solution of sodium bicarbonate and passed through a column packed with 117 g of acidic alumina.- To the eluate (1.2 L) was added 56.2 g of potassium thiocyanate and 171.5 g sodium chloride, and then the mixture was adjusted to pH 2.6 with 1N hydrochloric acid while cooling in an ice bath. After an insoluble material was filtered off, 171.5 g of sodium chloride was added to the filtrate, and the solution was adjusted

to pH 1.6 with 1N hydrochloric acid while stirring and cooling in an ice bath. The resulting precipitates were filtered, washed with

cold water (2 x 150 ml) and dried to give 1-[[7-{2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3- yl)-acetamido}-4-carboxy-3-cephem-3-yl]methyl]-pyridinium thiocyanate (syn isomer) (28.1 g), m.p. 151-156°C (decomposition).

I.R. (Nujol): 2050, 1780, 1670, 1630, 1610, 1530 cm"<1>N.M.R. (DMS0-d6 ,+D_ Z0, å) : 1.6-2.7 (4H, m), 3.33, 3.66

(2H, ABq, J=18Hz), 5.20 (lH, d, J=5Hz), 4.9-6.3 (5H, m), 5.86 (lH, d, J=5Hz), 8 .2 (2H, m), 8.7 (1H, m), 9.15 (2H, m)

Example 15 1-[.[ 7-{2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-4-carboxy-3- Cephem-3-yl]methyl]pyridinium iodide (syn isomer) was obtained in a similar manner to that described in Example 14, using sodium iodide instead of potassium thiocyanate.

I.R. (Nujol): 3400-3100, 1775, 1670, 1620, 1520 cm"<1>N.M.R. (DMS0-d^6 +D Z„0, <5 ) : 1.6-2.8 (4H, m), 3 .35, 3.80

(2H, ABq, J=19Hz), 5.31 (lH, d, J=5Hz), 5.93 (lH, d, J=5Hz), 5.0-6.4 (5H, m), 8 .28 (2H, m), 8.74

(lH, m), 9.15 (2Hf m)

Example 16

To a solution of 11.7 g of 1-[[7-{2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-4 -carboxy-3-cephem-3-yl]methyl]pyridinium thiocyanate (syn isomer) in 30 ml of dimethylformamide, a solution of 1.7 g of lithium chloride in 20 ml of methanol was added with stirring, and stirring was continued for 10 minutes at ambient temperature . An insoluble material was filtered off, washed with 6 ml of dimethylformamide, and then the filtrate and washings were combined. The combined solution was added to 300 ml of acetone with stirring, and stirring was continued for 5 minutes at ambient temperature. The resulting precipitates were filtered, washed with acetone (40 mL x 3) and dried in vacuo to give 1-[[7-{2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1 ,2,4-thiadiazol-3-yl)acetamido}-4-carboxy-3-cephem-3-yl]methyl]pyridinium chloride (syn isomer (11.0 g).

I.R. (Nujol): 3400-3100, 1780, 1660, 1630, 1530 cm"<1>

N.M.R. (DMS0-dg, 5). 1.6-2.6 (4H, m), 3.39, 3.61 (2H, ABq,

J»18Ha), 5.19 (lH, d, J»5Hz), 4.9-5.6 (2H, m) , 5.64 (1H, wide s), 5.81 (1H, dd, J =5 and 8Hz), 5.7-6.2 (2H, m), 8.20 (2H, m), 8.64 (lH, m), 9.22 (2H, m), 9.48 ( 1H, d,J«8Hz)

Example 17

To a solution of 10 g of sodium iodide and 1.28 g of pyridine in 8 ml of formamide was added 4.0 g of sodium 7-t2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl )aetamido]-cephalosporanate (syn- isomer) at 75°C with stirring, and stirring was continued for 1.5 hours at 80-85°C. The mixture was cooled to ambient temperature and poured into 100 ml of ethanol. A resulting precipitate was collected by filtration, and another was obtained from the filtrate by the addition of 100 ml of diisopropyl ether. These precipitation products were dissolved in 50 ml of water, and the solution was adjusted to pH 3 with 6N hydrochloric acid and washed with ethyl acetate. The aqueous solution was subjected to column chromatography on 160 ml of nonionic adsorption resin with the trade name "Diaion HP-20" (manufactured by Mitsubishi Chemical Industries. After the column was washed with water, the elution was carried out with 30% aqueous methanol. The eluates containing a desired compound , was collected, evaporated to remove methanol under reduced pressure and lyophilized to give a white powder of

7-[2-Ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-r4-carboxylate (syn isomer) ( 1.52 g), m.p. 155-165°e (decomposition).

I.R. (Nujol). 3400-3150, 1770, 1660, 1610, 1536 cm"<*1>

Example 18 (Purification of the compound to be produced according to the invention)

0.2 g of a powder of 7-f2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4- carboxylate (syn isomer) was dissolved in 0.8 ml of water, and 1.6 ml of acetone dropped into it with stirring at ambient temperature. After a few minutes, the stirring was stopped, and the solution got

stand for 1.5 hours at ambient temperature for crystallization. The resulting colorless needles were filtered, washed with 90%

aqueous acetone (1 ml x 2) and acetone (1 ml x 3) and dried for 9

hours under reduced pressure so that loose needles were removed

7-f 2-etoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido-3-(1-pyridiniomethyl)-3-cef em-4-carboxylate-acetone adduct-mono- hydrate (syn-isomer) (120 mg)', m.p.^155°C (dec.).

I.R. (Nujol): 3430-3120, 1760, 1700, 1680, 1615, 1530 cm"<1>N.M.R. (D20, 6): 1.32 (3H, t, J=»7Hz) , 2.26 (6H, s ), 3.20

6g 3.72 (2H, ABq, J«17Hz) , 4.37 (2H, q, J=7Hz), 5.30 (1H, d, j»5Hz), 5.35 and 5.66 (2H, ABq, J«14Hz), 5.91 (1H, d, J=5Hz), 8.12 (2H, m), 8.61 (1H, m), 8.98 (2H, m)

Analysis for C^gHlgN7O5S2«C3HgO«H20

Example 19 (Purification of the compound produced according to the invention)

11.4 g of 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) and 24 g of 1-1(7-amino-4-carboxy-3-cephem- 3-yl)methylpyridinium chloride hydrochloride dihydrate was reacted in a similar manner as described in example 1.

To the reaction mixture was added 300 ml of water, and the mixture was adjusted to pH 1.5 with an aqueous solution of

sodium hydroxide and subjected to column chromatography on 960 ml of non-ionic adsorption resin with the trade name "Diaion HP-20". After the column was washed with 3.6 L of water and eluted with 1.26 L of 30% aqueous methanol, the eluates were collected and concentrated under reduced pressure to a volume of 110 ml. The solution was subjected to column chromatography on 120 g of acidic alumina and eluted with water. The eluates containing 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamidol-3- (1-Pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (310 mL) was collected and 1.1 L of acetone was added with stirring at ambient temperature for 5 minutes. The mixture was stirred for 1.5 hours

under ice-cooling, and precipitates were collected by filtration, washed in turn with 90% aqueous solution of acetone (SO mi) and acetone (240 mi) and then dried under reduced pressure

so that 20 g of crystals of 7-f 2-ethoxyyiraino~2-(5-^amino-1,2,4-thiadiazol-3-yl)acetamidol-3-(1-pyridinediomethyl)-3-cephem-4 were obtained -carboxylate-acetone adduct (syn isomer). The crystals were dissolved

in 40 ml of water and the solution passed through a column packed with 40 g of acidic alumina. The elution was carried out with water and the eluates (140 ml) collected. To the solution was added

300 ml of acetone at ambient temperature with stirring, which was stopped for one minute. The mixture was allowed to stand for 20 minutes at ambient temperature and for 1.5 hours in a refrigerator. The resulting colorless needles were filtered off, washed with 90% aqueous acetone (25 mL at 3) and acetone (25 mL x 3) and dried for 3.5 hours under reduced pressure to give colorless needles of 7-12 -ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamidoJ-3-(1-pyridiniomethyl)-3-cef em-4-carboxylate-acetone adduct (syn isomer) (14, 3 g), m.p. >157°C.

Example 20 (Purification of the compound produced according to the invention)

A solution of 1.0 g of 7-12-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cef em*-4 -carboxylate-acetone adduct (syn-isomer) in 1 ml of water was left for 15 days in a freezer at -20°c. A mixture of ice and precipitation products was allowed to stand at ambient temperature until the ice had melted. The resulting precipitates were collected by filtration, washed with 0.3 ml of water and dried in vacuo to give 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)- aeetamido 1-3-(1-pyridiniomethyl)-3-eephem-4-carboxylate (syn isomer) (0.52 g) as f heirless needles, m.p. 165-170°c (decomposition). I.R. (Nujol) t 3450-3200, 3070, 1765, 1665, 1630, 1600,

1530, 1485 cm<**1>

N.M.R. (D20, 6)31.32 (3H, t, J=7Hz), 3.20 and 3*72 (2H,

ABq, J-17H2), 4.33 (2H, q, J»7Hz), 5.27 (lH, <3, J=»5Hz), 5.34 and 5.65 (2H, ABq, J*14Hz ) , 5.89 (lH, å, J»5Hz), 8.10 (2H, m), 8.60 (lH, m), 8.97 (2H, m)

Example 21 (Purification of the compound produced according to the invention)

To a solution of 40 g of 7-f2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate- acetone adduct (syne isomer) in 50 ml of water, a small amount of colorless needles of 7-f2-ethoxyimino-2-

(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-eephen-4-carboxylate (syn isomer), and the mixture was stirred for one hour in an ice bath . The resulting precipitation products were

collected by filtration, washed with 33 ml of cold water and dried in vacuo for 10 hours to give 7-[.2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)aeetamido] -3-(1-pyridiniomethyl)-3-cephem-4-carboxylate dihydrate (syn isomer) (24.7 g), in the form of colorless needles, m.p. 170-175°C (decomposition).

Water content (K.F. method) Calculated: 6.72%,.

Found: 6.20%

Example 22 (Purification of the compound produced according to the invention)

A powder of 7.7 g of 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4 -carboxylate (syn isomer) was dissolved in 15.4 ml of water, and the solution was left overnight in a refrigerator. Precipitates were filtered off, washed in turn with 80% isopropyl alcohol (5 ml) and isopropyl alcohol (5 ml), air-dried for 1 hour and then dried in vacuo for 2 hours to give colorless needles of 4.2 g of 7 -[2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), sm.p. 165-170°C (decomposition). I.R. (Nujol): 3300, 3200, 1765, 1670, 1630, 1605,

1550-1520 cm<-1>

N.M.R. (D20, <5): 3.24, 3.70 (2H, ABq, J=18liz), 4.06 (3H,

s), 5.28 (1H, d, J=5Hz), 5.36, 5.60 (2H, ABq, J=14Hz) , 5.87 (1H, d, J=5Hz), 8.06 ( 2I-I, m) , 8.54 (1H, m), 8.95 (2H, m)

Claims (1)

1. Process for the preparation of new cefem compounds of the following formula: where R<1> is amino or a protected amino group; 2 R is hydrogen, lower alkyl which may be substituted with a or more suitable substituents, lower alkenyl, lower alkynyl, cyclo(lower)alkyl, cyclo(lower)alkenyl, or O-containing 5-membered heterocyclic group substituted with one or more oxo groups; R"^ is a group of formula : where X is hydrogen or carbamoyl; and 4 R is C00~; or R 3 is 2-lower alkyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazinylthio; and R 4 is carboxy or protected carboxy, or pharmaceutically acceptable salts thereof, characterized by converting a compound of following formula: where R 3 and R 4 are each as defined above, or its reactive derivative at the amino group or a salt thereof, with a compound of the following formula: 1 2 where R and R are each as defined above, or its reactive derivative at the carboxy group, or a salt thereof.• 2. Process for the preparation of new cephem compounds of the following formula: where R<1> is amino or a protected amino group; R 2 is hydrogen, lower alkyl which may be substituted with a or more suitable substituents, lower alkenyl, lower alkynyl, cyclo(lower)alkyl, cyclo(lower)alkenyl, or O-containing 5-membered heterocyclic group which is substituted with one or more oxo groups" R <3> is a group of formula: X is hydrogen or carbamoyl and 4 R is -C00"; or R 3 is 2-lower alkyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4- triazinylthioj and R 4 is carboxy or protected carboxy, or pharmaceutically acceptable salts thereof, characterized by reacting a compound of the following formula: where 12 R and R each are as defined above? R 3a is a group which may be substituted with a group of 3 formula R where R 3 is like. defined above; and R<4a> is carboxy when TW- R <3> b is a compound of formula:: ■ s ■ where X is as defined above; or ' ' R <4a> is carboxy or protected carboxy when 31} ' 3e 3c RJ" is a compound of formula R -H where R is 2-lower alkyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazinylthio; or a salt thereof, with a compound of the following formula: where R is as defined above, or its reactive derivative. 3. Process for the preparation of a compound of the following formula: where R<1> is arane or a protected amino group; R is carboxy(lower)alkyl; 3 „ R is a group of formula: X is hydrogen or carbamoyl; and 4 R is -C00~; or R 3 is 2-lower alkyl-5-6xo-6-hydroxy-2,5-dihydro-1,2,4- triazinylthio; and R 4© is carboxy or protected carboxy; or pharmaceutically acceptable salts thereof, characterized by exposing a compound of the following formula: where 13 4 R , R and R are each as defined above and R 2a is protected carboxy(lower)alkyl, or that salt thereof, for elimination reaction of the protecting group of carboxy.4. Procedure© for the preparation of a compound of the following formula: where R 1 is amino or a protected amino groupj R 3 is a group of the following formula: where X is hydrogen or carbamoyl* and 4 R is -C00 : or 3 R is 2-lower alkyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazinylthio; ouch 4 R is carboxy or protected carboxy, or pharmaceutically acceptable salts thereof, characterized by exposing a compound of the following formula: where 13 4 R , R , and R are each as defined above, and 2c R is a protecting group of hydroxy, or a salt thereof, for elimination reaction of the protecting group of hydroxy,5. Procedure for the preparation of a compound of formula: wherein R is amino or a protected amino group; 2 R is hydrogen, lower alkyl which may be substituted with one or more suitable substituents, lower alkenyl, lower alkynyl, cyclo(lower)alkyl, cyclo(lower)alkenyl, or 0-containing 5-membered heterocyclic group which is substituted with one or more oxo groups» 3d R is lower alkanoyl(lower)alkanoyloxy, 4b and R is carboxy or, protected carboxy; or a salt thereof, characterized by) to react a compound of the following formula: where 3d 4b R and R are each as defined above, or its reactive derivative at the amino group or a salt thereof, with a compound of the following formula: where 12 R and R are each as defined above, or its reactive derivative at the carboxy group or a salt thereof, orb) to expose a compound of the following formula: where Il 3 "3 4b R , R , and R are each as defined above and R<2> aerb escutated carboxy (lower) alkyl, or a salt thereof, for elimination reaction of the protecting group of carboxy, so that a compound of the following formula is obtained: where R1, R3d and R41> are as defined above, and R<2b> is carboxy-(lower)alkyl, or a salt thereof. i, 6. Process for the preparation of a compound of the following formula: where X is hydrogen or carbamoyl, or a salt thereof, characterized by reacting a compound of formula: 3rd where R is a group which may be substituted with a group of formula where X is as defined above. or a salt thereof, with a compound of formula: where X is as defined above.