NZ196448A - Cephem compounds antibacterial pharmaceutical compositions containing them; cephem intermediates - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 96448 n- ■*. «-* 7*' yl-S-Sor'tr-t, -8o:So; Priors./ ^axe\s):^ y^. y ^. ...

Cornpisto Specification Filed: (?.•£•.$(.

Class: cQ1?5ql% ., fu'3 5 O ^ tjO^l 13 s Co'. ■■■*« •■■*«•■■•■■■•■ P.O. Journal Mo: . J A5.?. m I IP ^ H5 **}> jg| | pi jn © Patents Form No . 5 |^6HAR^8I I •VEO NEW ZEALAND PATENTS ACT 195 3 COMPLETE SPECIFICATION "NEW CEPHEM COMPOUNDS AND PROCESSES FOR PREPARATION THEREOF" -J-/WE FUJISAWA PHARMACEUTICAL CO., LTD. a Japanese company, of No. 3,4- Chome, Doshomachi, Higashi-ku, Osaka, Japan, hereby declare the invention, for which 5/we pray that a patent may be granted to rae-/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- I (foUowed by page I * A - 1A - I 96448 NEW CEPHEM COMPOUNDS AND PROCESSES FOR PREPARATION THEREOF The present invention relates to new cephem compounds and pharmaceutically acceptable salts thereof. More particularly, it relates to new cephem compounds and pharmaceutically acceptable salts thereof, which have 5 antimicrobial activities and to processes for preparation thereof, to pharmaceutical composition comprising the same, and to a method of using the same therapeutically in the treatment of infectious diseases in human being and animals.

Accordingly, it is one object of the present invention to provide new cephem compounds and pharmaceutically acceptable salts thereof, which are active against a number of pathogenic microorganisms. provide processes for the preparation of new cephem Another object of the present invention is to 196448 compounds and pharmaceutically acceptable salts thereof.

A further object of the present invention is to provide pharmaceutical composition comprising, as active ingredients, said new cephem compounds and 5 pharmaceutically acceptable salts thereof.

Still further object of the present invention is to provide a method for the treatment of infectious diseases caused by pathogenic bacteria in human being and animals.

The object new cephem compounds are novel and can be represented by the following general formula (I). wherein R^ is amino or a protected amino group; 2 R is hydrogen, lower alkyl which may be substituted with suitable substituent(s), lower alkenyl, 15 lower alkynyl, cyclo(lower)alkyl, cyclo(lower)- alkenyl, or 0 containing 5-membered heterocyclic group substituted with oxo groupfs); R^ is a group of the formula: iN/ wherein X is hydrogen or carbamoyl; and 20 R4 is -COO~; or 3 R is 2-lower alkyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazinylthio; and R4 is carboxy or protected carboxy.

According to the present invention, the object 25 compound (I) can be prepared by the following processes.

I 96448 Process 1 i ^"—n 1 1" ir~ C-COOH (III) V N &-R2 ^^~CH9R^ or its reactive derivative at the carboxy group or a salt thereof (II) or its reactive derivative at the amino group or a salt thereof .N ■ C-CONH N &-R2 / O V U L Id R ch2r~ (I) or a salt thereof Process 2 RJ ■/"^-C-CONH- N , ^2 OR fSl_ —c: I4a H2R3a + R3b (XIII) or a salt thereof (IV) or its reactive derivative CONH n N .

V 2 OR 0: -u ch2r- (^ or a salt thereof 196448 Process 3 n .N—v Elimination of the R C-CONH—i 3 protective group of S ' NSv^'^—CI^R carboxy 0R2a I 4 ~~ * X\ (lb) or a salt thereof r1—jF -^—C-CONH (lc) or a salt thereof Process 4 R1—~^ C-CONH \ N 11 > r» S N 2c OR c (Id) or a salt thereof Elimination of the ^ protective group of hydroxy (Ie) or a salt thereof 196448 ] ? 3 4 wherein R , R, R and R are each as defined above; R^a is a group which can be substituted with a group of the formula: R^ wherein R^ is as defined above; R3*5 is a compound of the formula: —■ x wherein X is as defined above and •if >4 a is carboxy; or 3 b 3 c 3 c R is a compound of the formula: R -H wherein R is 2- lower alkyl-5-oxo-6-hydroxy-2 ,5-dihydro-l,2,4-triazinylthio 4 Ei and R is carboxy or protected carboxy; 2 3.

R is a protected carboxy(lower)alkyl; R2b - is a ,2c carboxy(lower)alkyl; and is a protective group of hydroxy.

Among the starting compounds of the present invention, some of the compounds of the formula (XIII) can be prepared by the following methods. 1.

R 1 N—\ C-COOH N S 2 OR (III) ai2R (V) 3d or its reactive derivative or its reactive derivative at the carboxy group or a at the amino group or a salt thereof salt thereof C-CONH —j—J^SV) i4b N ^R2 (VI) or a salt thereof 2. r1— c «•, y;—-N. n // w* ° T"b Elimination of the protec-tive group of carboxv ^ -ch2R 3d —fVc-coNH-r—f ^ s' M L2b k4b (VII) or a salt thereof CH2R3d (VIII) or a salt thereof a t 1 96 4 4 8 T O Og wherein.R , R R ...and R are each as defined abovey 7 j t ^ R is lower alkanoyl(lower)alkanoyloxy and R is carbozy or protected carboxy.

Further, sqme of the compound (II) can be prepared by the following methods. i0Tz HOOC — g- • ~Z1 > 0 CO OH (IX) or a salt thereof Elimination of HOOC-CH-(CH~),CONH-,—t^e Pfotective group J— ^ ^ ill —of amino at 7-positiozK COCT (XI) or a salt thereof l2\_/ coo- (XII) or a salt thereof Tg wherein X is as defined above and R is a group which can be substituted with a group of the formula: * Among these compounds, the compound (XI) is novel .

Regarding the object compounds (I), (lb), (Ic), (Id) and (Ie) and the starting compounds (III), (TTI), (711), (Till) and (XIII), it is to be understood that they include tautomeric isomers.

That is, in case that the group of the formula: N 1— (R1 is as defined above) is contained in D1 | • I the molecules of said object and starting ** J tct compounds, said group -of the formula can also be alternatively represented by its .tautomeric | O - 7 - : .j ■ j- formula: ^""T" (r1' is imin0 or a Protected r^==L_^H imino group.) That is, the both of said groups are in the state of equilibrium each other .and such tautomerism can be represented by the following equilibrium. 11' 3_0 wherein R and R are each 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 arts that 15 both of the tautomeric isomers are easily convertible reciprocally and are included within the same category of the-compound per se.

Accordingly^, the both of the tautomeric forms of the object and starting compounds as mentioned above are clearly included within the scope of the present invention. In the present specification and claims, the object and starting compounds including the group of such tautomeric isomers are represented by using one .of the expressions therefor, that is the formula: -N—~jj~ ,JL R-^S' * .

Furthermore, regarding the object compounds (I), (I), (lb), (Ic), .(Id) and (le) and the starting compounds (III), (71), (711), (VIII) and (nil), it-is to be understood that said object and starting compounds include syn isomer, anti isomer and a mixture thereof. For example, with regard to the object compound (I), syn isomer means one geometrical isomer having the partial structure represented•by the following formula: ts 0 M t " 1 R1 —c-co- ■ ,2 tsrr .

N-o-r (wherein R1 and R2 are each as defined above) and anti isomer means the other geometrical isomer having the partial structure represented by the following formula (L_£~~i_c-co- r2-O- (wherein R1 and R2 are each as defined above).

Regarding the other object and starting corrao'unds as mentioned above, the syn isomer and the anti isomer can also be referred to the same geometrical isomers as illustrated for the compound (I). 2o Suitable pharmaceutically acceptable salts of the object compounds CI) sre conventional non-toxic salt and include a -metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium 25 salt, etc.)* an ammonium salt, an organic base salt (e.g. trimethylamine •■salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), an organic acid salt (e.g. acetate, maleate, tartratemethanesulfonate 30 benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt (e.g. hydrochloride, hydrobTomide, hydroiodide, thiocyanate, sulfate, phosphate, etc."), or a salt with an amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.), 35 and the like. - 9 - 186448 In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention include within the scope thereof are explained in details as follows.

The term "lower" is intended to mean up to 6 carbon atoms, unless otherwise indicated.

Suitable "protected amino" for R"*" may include an acylamino or an amino group substituted by a conventional protecting group such as ar(lower)alkyl which may have at least one suitable substituent(s), (e.g. benzyl, trityl, etc.) or the like.

Suitable acyl moiety in the term "acylamino" may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring. And, suitable examples of the said acyl may be lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.); lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiarybutoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.); lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.); arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.); aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc.); ar(lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl, etc.); ar(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.), and the like. The acyl moiety as stated above may have at least one suitable substituent(s) such as halogen (chlorine, bromine, fluorine and iodine), lower alkanoyl as stated above, or the like. 2 Suitable "lower alkyl" for R is one having 1 to 6 carbon atom(s) and may include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, tert-pentyl, hexyl and the like, and preferably one having 1 to 4 carbon atom(s).

Suitable "lower alkyl" being the substituent on 1,2,4- •3 triazmylthio for R and lower alkyl moieties in the terms "protected carboxy(lower)alkyl" and "carboxy(lower)alkyl" can be referred to the ones as exemplified above.

"Lower alkyl" for R may be substituted with 1 to 3 suitable substituent(s) cuoh as seAe-crlcd -Cr-o^ halogen (e.g. chlorine, bromine, fluorine or iodine); carboxy; protected carboxy as mentioned below; lower alkylthio (e.g. methylthio, ethylthio, .Qnd propylthio, butylthio, etc.)^ aryl (e.g., phenyl, tolyl, xylyl, mesityl, cumenyl, etc.)/—er the lilct/.

Suitable lower alkenyl may include vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl, 3-pentenyl and the like, preferably one having 2 to 4 carbon atoms.

Suitable lower alkynyl include one having 2 to 6 carbon atoms, for example, ethynyl, 2-propynyl, 2-butynyl, 3-pentynyl, 3-hexynyl, or the like preferably one having 2 to A carbon atoms.

Suitable cyclo(lower)alkyl include one having 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like, preferably one having 4 to 6 carbon atoms.

Suitable cyclo(lower)alkenyl include one having 3 to 6 carbon atoms, for example, cyclopentenyl, cyclo-hexenyl, or the like, preferably one having 5 or 6 carbon atoms.

Suitable 0 containing 5-membered heterocyclic group may include saturated or unsaturated one, for example, dihydrofuryl. tetrahydrofuryl, _ 196448 or the like, which is substituted with 1 or 2 oxo group(s).

Suitable protected carboxy and protected carboxy moiety in the term "protected carboxy(lower)alkyl" 5 may include esterified carboxy in which said ester may be the ones such as lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, 10 hexyl ester, 1-cyclopropylethyl ester, etc.), wherein lower alkyl moiety may be preferably one having 1 to 4 carbon atom(s); lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g., ethynyl ester, propynyl ester, etc.); mono (or di or tri)-halo-15 (lower)alkyl ester (e.g., 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower alkanoyloxy(lower)alkyl ester (e.g., acetoxymethyl ester, propionyloxymethyl ester, 1-acetoxypropyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 20 hexanoyloxymethyl ester, 1-acetoxyethyl ester, 2-propio-nyloxyethyl ester, 1-isobutyryloxyethyl ester, etc.); lower alkanesulfonyl(lower)alkyl ester (e.g., mesyl-methyl ester, 2-mesylethyl ester etc.); ar(lower)alkyl ester, for example, phenyl(lower)alkyl 25 ester which may be substituted with one or more suitable substituent(s) (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, diphenylmethyl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-diterti-30 arybutylbenzyl ester, etc); lower alkoxycarbonyloxy(lower)alkyl ester (e.g., metho-xycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, ethoxycarbonyloxyethyl ester, etc.) which may be substi35 196448 tuted with amido; a heterocyclic ester, preferably benzotetrahydrofuryl ester which may be substituted with oxo group, more preferably phthalidyl ester; aroyloxy(lower)alkyl ester (e.g., benzoyloxymethyl ester, benzoyloxyethyl ester, toluoyloxyethyl ester, etc.); aryl ester which may have one or more suitable substi-tuent(s) (e.g., phenyl ester, tolyl ester, tertiary-butylphenyl ester, xylyl ester, mesityl ester, cumenyl 10 ester, etc.), and the like.

Preferable example of protected carboxy may be lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, etc.) having 2 to 15 7 carbon atoms, preferably one having 2 to 5 carbon atoms, and phenyl(lower)alkoxycarbonyl which may be substituted with nitro (e.g., 4-nitrobenzyloxycarbonyl, benzyloxycarbonyl, 4-nitrophenethyloxycarbonyl, etc.).

Preferable example for R3a and R3e may include 20 acyloxy, halogen, azido and the like, wherein acyl moiety in the term "acyloxy" and halogen can be referred to the ones as exemplified hereinbefore.

Suitable protective group of hydroxy may include aforesaid acyl, ar(lower)alkyl (e.g., benzyl, trityl, etc.) 25 and the like.

Suitable lower alkanoyl(lower)alkanoyloxy may include acetoacetoxy, propionylacetoxy, acetopropionyloxy and the like.

Preferred embodiments of the object compound (I) 30 are as follows. - 13 - 196448 Preferred embodiment of R^" is amino; R is hydrogen, lower alkyl, ar(lower)alkyl[more preferably triphenyl(lower)alkyl], lower alkylthio(lower)alkyl, halo-(lower)alkyl[more preferably trihalo(lower)alkyl], carboxy-5 (lower)alkyl, esterified carboxy(lower)alkyl[more preferably lower alkoxycarbonyl(lower)alkyl or phenyl(lower)alkoxycarbonyl (lower) alkyl] , lower alkenyl, lower alkynyl, cyclo-(lower)alkyl, cyclo(lower)alkenyl, or tetrahydrofuryl substituted with oxo group; R3 is a group of the formula: wherein X is hydrogen or carbamoyl and is -COO ; or 3 R is 2-lower alkyl-5-oxo-6-hydroxy-2,5-dihydro-l,2,4- 4 triazmylthio and R is carboxy.

The processes for preparing the object compounds are explained in details in the following.

Process 1 The object compound (I) can be prepared by reacting the compound (II) or its reactive derivative 2 0 at the amino group or a salt thereof with the compound (III) or its reactive derivative at the carboxy group or a salt thereof.

Suitable reactive derivative at the amino group of the compound (II) may include conventional reactive 25 derivative used in amidation, for example, Schiff's base type imino or its tautomeric ena>nine type isomer formed by the reaction of the compound (II) with a carbonyl compound; a silyl derivative formed by the reaction of the compound (II) with a silyl compound 30 such as bis (trimethylsilyl)acetamide, trimethylsilyl-acetamide or the like; a derivative formed by reaction of the compound (II) with phosphorus trichloride or phosgene, and the like. 196448 Suitable salt of the compound (II) may include an acid addition salt such as an organic acid salt (e.g., acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate, etc.) or an inorganic acid salt 5 (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); a metal salt (e.g., sodium salt, potassium salt, calcium salt, magnesium salt, etc.); ammonium salt; an organic amine salt (e.g., triethylamine salt, 10 dicyclohexylamine salt, etc.), and the like.

Suitable reactive derivative at the carboxy group of the compound (III) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like. The suitable example may be an 15 acid chloride; an acid amide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenyl-phosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, 20 sulfurous acid, thiosulfuric acid, sulfuric acid, alkylcarbonic 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 (e.g., 25 benzoic acid, etc.); a symmetrical acid anhydride; an activated amide with imidazole, dimethylpyrazole, tria-zole or tetrazole; or an activated ester (e.g., cyano-methyl ester, methoxymethyl ester, dimethyliminomethy1 - CH-J ester, vinyl ester, propargyl ester, 30 p-nitrophenyl ester, 2,4^-dinitrophenyl ester, trichloro-phenyl ester, pentachlorophenyl ester, mesyl phenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxy-methyl thioester, pyranyl ester, pyridyl ester, piperidyl 35 ester, 8-quinolyl thioester, or an ester with N,N- 196448 dimethylhydroxylamine, l-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide or 1-hydroxy-6-chloro-lH-benzotriazole, and the like. These reactive derivatives can be optionally selected from 5 them according to the kind of the compound (III) to be used.

The salts of the compound (III) may be salts with an inorganic base such as an alkali metal salts (e.g., sodium or potassium salt), or an alkaline earth 10 metal salt (e.g., calcium or magnesium salt), a salt with an organic base such as trimethylamine, triethyl-amine, pyridine, a salt with an acid (e.g., hydrochloric acid or hydrobromic acid) or the like.

The reaction is usually carried out in a con-15 ventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethyl-formamide, pyridine or any other organic solvent which does not adversely influence to the reaction. Among 2 0 these solvents, hydrophilic solvents may be used in a mixture with water.

When the compound (III) is used in free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of a conventional 25 condensing agent such as N,N-dicyclohexylcarbodiimide; N-cyclohexyl-N1-morpholinoethylcarbodiimide; N-cyclo-hexyl-N1-(4-diethylaminocyclohexyl)carbodiimide; N,N-diethylcarbodiimide; N,N-diisopropylcarbodiimide; N-ethyl^-N' *- (3-dimethylaminopropyl) carbodiimide; N,N-30 carbonylbis(2-methylimidazole); pentamethylene-ketene-N-cyclohexylimide;diphenylketene-N-cyclohexylimine; ethoxyacetylene; ethyl polyphosphate; isopropyl polyphosphate; diethyl phosphorochloridite; phosphorus oxychloride; phosphorus trichloride; phosphorus 35 pentachloride; thionyl chloride; oxalyl chloride; I 96448 triphenylphosphine; N-ethyl-7-hydroxybenzisoxazolium fluoroborate; N-ethyl-5-phenylisoxazolium^'-sulfonate; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-lH-benzotriazole; so-called Vilsmeier reagent, for example (chloromethylene) 5 dimethylammonium chloride produced by the reaction of dimethylformamide with thionyl chloride or phosgene, a compound produced by the reaction of dimethylformamide with phosphorus oxychloride, etc.; or the like.

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

In the present reaction, a syn-isomer of the object compound (I) can be obtained preferably by conducting the reaction of the compound (II) with a syn-isomer of the starting compound (III).

Process 2 The object compound (I) or a salt thereof can be prepared by reacting the compound (XIII) or a salt thereof with the compound (IV) or its reactive derivative.

Suitable salt of the compound CXIII) can be referred to the ones exemplified for the compound (II).

Suitable reactive derivative of the compound (IV) may include a metal salt such as an alkali metal salt (e.g., sodium salt, potassium salt, etc.) or the like. 1 96448 The present reaction may be carried out in a solvent such as water, phosphate buffer, acetone, chloroform, nitrobenzene, methylene chloride, ethylene chloride, dimethylformamide, methanol, ethanol, ether, tetrahydro-5 furan, dimethylsulfoxide, or any other organic solvent which does not adversely affect the reaction, preferably in ones having strong polarities. Among the solvents, hydrophilic solvents may be used in a mixture with water. The reaction is preferably carried out in 10 around neutral medium. When the compound (XIII) or the compound (IV) is used in a free form, the reaction is preferably conducted in the presence of a base, for example, inorganic base such as alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, 15 organic base such as trialkylamine, and the like. The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or under slightly heating.

The present reaction includes, within its scope, the 20 case that protected carboxy group is converted to free carboxy group during the course of the reaction.

Process 3 The object compound (Ic) or a salt thereof can be 25 prepared by subjecting the compound (lb) or a salt thereof to elimination reaction of the protective group of carboxy.

Suitable salt of the compound (lb) can be referred to the ones as exemplified for the compound (II). 30 The present reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like. 196443 In case that the protective group is an ester, the protective group can be eliminated by hydrolysis. Hydrolysis is preferably carried out in the presence of a base or an acid. Suitable base may include an inor-5 ganic base and an organic base such as an alkali metal (e.g., 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, 10 1,5-diazabicyclo [4,3,0]none-5-ene, 1,4-diazabicyclo [2, 2,2]octane, 1,8-diazabicyclo [5,4,0]undecene-7, or the like. Suitable acid may includie an organic acid (e.g., formic acid, acetic acid, propionic acid, trifluoro-acetic acid, etc.) and an inorganic acid (e.g., hydro-15 chloric acid, hydrobromic acid, sulfuric acid, etc.).

The reaction is usually carried out in a solvent such as water, an alcohol (e.g., methanol, ethanol, etc.), a mixture thereof or any other solvent which does not adversely influence to the reaction. A liquid base 20 or acid can be also used as the solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.

Reduction can be applied preferably for elimination of the protective group such as 4-nitrobenzylr 2-25 iodoethyl, 2,2,2-trichloroethyl, or the like. The reduction method applicable for the elimination reaction may include, for example, reduction by using a combination of a metal (e.g., zinc, zinc amalgam, etc.) or a salt of chrome compound (e.g., chromous chloride, 30 chromous acetate, etc.) and an organic or inorganic acid (e.g., acetic acid, propionic acid, hydrochloric acid, etc.); and conventional catalytic reduction in the presence of a conventional metallic catalyst (e.g., palladium-carbon, etc.). 196448 Process 4 The object compound (le) or a salt thereof can be prepared by subjecting the compound (Id) or a salt thereof to elimination reaction of the protective group 5 of hydroxy.

Suitable salt of the compound (Id) can be referred to the ones as exemplified for the compound (II).

The present elimination reaction can be carried out according to substantially the same manner as that 10 of acidic hydrolysis in Process 3.

The preparation for preparing the starting compounds are explained below in detail. preparation 1 The compound (VI) or a salt thereof can be prepared by reacting the compound (III) or its reactive derivative at the carboxy group or a salt thereof with the compound (V) or its reactive derivative at the amino group or a 20 salt thereof.

Suitable reactive derivative and salt for the compound (V) can be referred to the ones as exemplified for the compound (II).

The present reaction can be carried out in substan-25 tially the same manner as that of Process 1.

Preparation 2 The compound (VIII) or a salt thereof can be prepared by subjecting the compound (VII) or a salt thereof to 30 elimination reaction of the protective group of carboxy.

Suitable salt of the compound (VII) can be referred to the ones as exemplified for the compound (II).

The present reaction can be carried out in substantially the same manner as that of Process 3.

Preparation 3 The compound (XI) or a salt thereof can be prepared by reacting the compound ( the compound (X). 196448 Suitable salt of the compound (IX) can be referred to the ones as exemplified for the compound (II).

The present reaction can be carried out in substantially the same manner as that of Process 2.

Preparation 4 The compound (XII) or a salt thereof can be prepared by subjecting the compound (XI) or a salt thereof to elimination reaction of the protective group of amino 10 at 7-position.

The present elimination reaction is. carried out by a method by reacting the compound (XI) or a salt thereof with imino- halogenating agent and then with iminoether-ifying agent, and, if necessary, subjecting the resulting 15 compound to hydrolysis.

The present reaction is carried out according to a conventional method.

In the aforementioned reactions and/or the post-20 treating of the reactions of the present invention, the aforementioned geometrical isomer and/or tautomeric isomer may occasionally be transformed into the other geometrical isomer and/or tautomeric isomer and such cases are to be also included in the scope of the 25 present invention.

In the case that the object compound (I) has a free carboxy group and/or a free amino group, it may be transformed into its pharmaceutically acceptable salt 30 as aforementioned by a conventional method.

The object compound (I) of the present invention exhibits high antimicrobial activity and inhibits the growth of a number of microorganisms including 35 pathogenic Gram-positive and Gram-negative bacteria. ~ 21 - I 96448 For therapeutic administration, the cephalosporin compounds according to the present invention are used in the form of pharmaceutical preparation which contain said compounds in admixture with a pharmaceutically 5 acceptable carriers such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration. The pharmaceutical preparations may be in solid form such as capsule, tablet, dragee, ointment or suppository, or in liquid 10 form such as solution, suspension, or emulsion.

If desired, there may be included in the above preparations auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.

While the dosage of the compounds may vary from and also depend upon the age and condition of the patient, an average single dose of about 50 mg., 100 mg., 250 mg., and 500 mg. of the compounds according 20 to the present invention has proved to be effective for treating of infectious diseases caused by a number of pathogenic bacteria. In general amounts, daily dose between 1 mg/body and about 1000 mg/body or even more may be administered.

Now in order to show the utility of the object compounds (I), test data on anti-microbial activity of representative compounds of the present invention are shown below.

Test method One loopful of an overnight culture of each test O strain in Trypticase-soy broth (10 viable cells per ml.) was streaked on heart infusion agar (Hl-agar) containing graded concentrations of antibiotics, and 35 the minimal inhibitory concentration (MIC) was expressed in terms of pg/ml after incubation at 37°C for 20 hours. 196448 Test Compound (1) 7-[2-Ethoxyimino-2- (5-amii^Ci-l, 2 , 4-triadiazol-3-yl-acetamido]-3-(1-pyridiniomethyl)-3-cephen-4-carboxylate 5 (syn isomer) (2) 7-[2-Allyloxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carbo-xylate(syn isomer) (3) 7-[2-(2-Propynyloxyimino)-2-(5-amino-l,2,4-thia-diazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (4) 7-[2-Cyclopentyloxyimino-2-(5-amino-l,2,4-thia-diazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer) (5) 7- [2-(2-Cyclopenten-l-yloxyimino)-2-(5-amino- 1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl) 3-cephem-4-carboxylate(syn isomer) (6) 7-[2-Methoxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carbo- xylate(syn isomer) (7) 7-[2-Isopropoxyimino-2-(5-amino-l,2,4-thiadia-zol-3-yl)acetamido]-3-(2-methyl-5-oxo-6-hydroxy-2,5-dihvdro-1,2/4-triazin-3-yl)thiomethyl-3-cephem-4- carboxylic acid (syn isomer) (8) 7-[2-Ethoxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)-acetamido]-3-(4-carbamoyl-l-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) Tent Results Test Bacteria 4 (1) E. coli WIIIJ J0-2 0.10 Kl. pneumoniae 12 0.10 Pr. vulgaris 2 0.10 Ps. aeruginosa NCTG-10490 1.56 B. subtilis ATCG 6633 0.78 Test Compound M.I.C. (yUg/ml) (2) (3) (4) (_5_) (6) (7) (8) 0.10 0.78 0.39 1.56 0.78 0.20 0.39 0.20 1.56 0.78 0.78 1.56 3.13 6.25 0.20 1.56 1.56 . 3.13 6.25 0.39 0.39 0.20 0.20 1.56 0.78 0.39 0.39 <0.025 1.56 3.13 0.05 0.20 0.20 i 3.13 0.78 o o 196448 Regarding the nomenclature of the compounds of the present invention (3-pyridiniummethyl compound), there exists some nomenclatures. • For example, the following compound (A) is named as 7-[2-methoxyimino-2-(5-amino-5 1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) or N-[7-^2-methoxy-imino-2-(5-amino-l,2,4-thiadiazol-2-yl)acetamido^-3-cephem-3-ylmethyl]pyridinium-4-carboxylate (syn isomer). Further, hydrochloric acid salt of the compound (B) 10 is named as ]-[(7-amino-4-carboxy-3-cephem-3-vl)methyl]-pyridinium chloride or N-[7-amino-3-cephem-3-ylmethyl]-pyridinium-4-carboxylate hydrochloride.

N-^-C-CONH —/*-> +r- H-.N—N-OCH3 Vk^~~CE2U\=) COO coo- (A) (B) The other compounds in the present specification and claims are similarly named and they are all included in the scope of the present invention.

The following Preparations and Examples are given 25 for the purpose of illustrating the present invention. 1 96 4 Preparation 1: Preparation of Methyl 5-amino-l,2,4-thiadiazole-3-carboxylate.

To a solution of 1-ethoxycarbonylformamidine hydrobromide (16.6 g.) in- absolute methanol (84 mi) was added a solution of sodium (1.93 g) ■ in absolute methanol (42 ml) at 0°C. To the mixture were added alternately bromine (12.8 g) and a solution of sodium (1.93 g) in absolute methanol (42 ml) at 0°C and then to the suspension was added potassium thiocyanate (8.1 g) in absolute methanol (100 ml). The reaction mixture was stirred for an hour at 0°C and for an additional 6 hours at .ambient temperature. The mixture was filtered through cellulose powder and the filtrate was evaporated to dryness. The 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 20 was evaporated and the residue was triturated with diethyl ether to give the title compound (9.0 g) , mp. 202 to 205°C.

I.R. (Nujol) : 3400, 3250, 3100, 1710, 1610, 1540 cm"1 25 N.M.R. (dg-DMSO) 6 : 3.85 (3H, s)., S.2S C2H, s) Preparation 2: Preparation of Methyl S-formamido-1,2,4-' thiadiazole-3-carboxylate. ■2° ' To a mixture of formic acid (33 g) and -acetic anhydride (22 g) was added methyl 5-amino-l ,2 ,4— thiadiazole-3-carboxylate (6.2 g), and then the mixture was stirred for 2 days at ambient temperature. The reaction mixture was concentrated under reduced 35 pressure and the residue was triturated with .a mixture -2€ /? ' o of diethyl ether and n-hexane to give the title compound (7.2 g) , mp. 210 to 215°C.

I.R. (Nujol) : 3100, 1720, 1680 cm"1 N.M.R. (dg-DMSO) To a mixture of methyl'5-£ormamido-l,2,4-10 thiadiazole-3-carboxylate (9.2 g) and methyl methyl-thiomethyl sulfoxide (6.1 g) in N,N-dimethylformamide (100 ml).was added 501 sodium hydride (7.1 g) with cooling in an ice-bath. The mixture was stirred for an hour at ambient "temperature and for an additional 15 one hour at 40 °C. After cooling to ambient ^temperature, methylene chloride (300 ml) was added to ^the reaction mixture, and the resulting precipitates were collected by filtration and washed with methylene chloride. The precipitates were added to 20 a stirred mixture of hydrochloric acid (14-7 ml), ice-water (200 ml) and methylene chloride (200 ml). An insoluble material was filtered off and the methylene chloride layer was separated from the 0 filtrate. The solution was dried over anhydrous 25 magnesium sulfate, evaporated and the residue was triturated with diethyl, ether to give the title compound (4.5 £), mp. 130 to 132®C.

I.R. (Nujol) : 3100, 1680, 1670 cm"1 N.M.R. (dg-DMSO) 6 : 2/22 } (3H, 2s) 2.28 2-68_) (2H, 2s) 2.85 % 1^. ao -27" -70 > (1H, 2s) . SO 8.86 C1H, s) Preparation 4: • Preparation o£ S-methyl (5-formairn do-1,2,4-thi adia z o1-3-yl)thi o gly oxylat e .

A mixture of 5-fotmamido-3-(2-methylthio-2-methylsulfinylacetyl)-1,2,4-thiadiazole (0.85 ,g) and sodium periodate (0.2 g) in glacial acetic acid (10 ml) was stirred for 45 minutes at 70 °C. -The reaction mixture was evaporated and the 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 -residue was triturated with a mixture of diethyl ether and petroleum ether to give the title compound (280 mg)., mp. 186 to 187°C.

I.R. (Nujol) : 3100, 1680, 1660 cm"1 N.M.R. ^(d6-DMS0) '6 : 2.55 (SH, sj, 8.95 (1H, s) Preparation 5.: Preparation of 2-Methoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer), A mixture of -S-methyl (5-formamido-1,2,4-thiadiazol-3-yl)thioglyoxylate (231 mg} in -methanol (2 ml) and IN-aqueous solution of potassium hydroxide (3.5 ml) was stirred for an hour at ambient temperature. The mixture was adjusted to pH 7.6 with IN hydrochloric acid, followed by -an addition .of 0** methylhydroxylamine hydrochloride (90 mg) and stiT-ring for 30 minutes at ambient temperature. f 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 layeT 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 residue was triturated with diethyl ether, collected by filtration and then dried to give the title compound (80 mg), mp. 185 to 186°C.

I.R. (Nujol) i 3150, 1720, 1690 cm"1 N.M.R. (d6-DMS0) 6 : 3.98 (3H, s), 8.84 (1H, s) Preparation 6: Preparation of 2 -Methoxyimino-2 - (5-furmaniido-l,2,4-thiadiazol-3-yl)acetic a.cid (syn isomer} A mixture of 5-f ormamido-3- (2~methyl-thio-2-me thy lsulf inylacetyl) -1,, 2 ,4-thiadiazole (3.2 g) and sodium periodate (0 .8 g) in glacial acetic acid (32 ml) was stirred for 45 minutes at 70°C. The resulting mixture was evaporated and the residue was washed with,n-hexane and then thereto were added methanol (20 ml) and IN aqueous solution of potassium hydroxide (40 ml). The solution was stirred for an hour at ambient temperature. The -reaction mixture was adjusted to pH 5 with IN hydrochloric acid, followed by an addition of 0 -me thy lhy dr oxyl amine hydrochloride (0.96 g) and stirring for sin 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 vith ethyl acetate, adjusted to pH 1 with 101 hydrochloric acid, saturated with sodium chloride and extracted with with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, evaporated, and the residue was triturated with diisopropyl ether to give the title compound CI.02 g), mp.. 185 to 186°C. Preparation 7: Preparation of 2-Methoxyimino-2-(5-amino-l ,2.,4» thiadiazol-3-yl)acetic acid (syn isomer). i A solution of 2 -methoxyimino-2- (S-f ormamido-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer}(1.4 g) in IN aqueous solution of sodium hydroxide (13,1 ml) was heated at 50° to 55°C for an hour. To the solution was added conc.hydrochloric acid (1.9 ml) under 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 residue was triturated with diethyl ether to give the title compound (0.9 g), mp. 180 to 182"®C (dec.).

.I.R. (Nujol) : 3450, 3250, 3100, 1715, 1610, 1530 cm"1 N.M.R. (d6-DMS0) <5 ; 3.90 (3H, s) , 8.10 (3H, broads.) Preparation 8 A mixture of 5-formamido-3- (2-methylthio-2-methylsulfinylacetyl) -1,2,4-thiadiazole (10 g) and sodium periodate (2 .0 'g) in glacial acetic acid (50 ml) was stirred for 50 minutes at 70°C- The solvent was evaporated .and the residue was -washed with n-hexane. To the residue was -added IN aqueous solution of sodium hydroxide (160 ml) and the mixture was stirred for an hour at ambient temperature.. To the reaction mixture was added O-ethylhydroxylamine hydrochloride (3.5 g) .and the solution was adjusted to pH 3 to 4 with 10%'hydrochloric acid and then stirred for an .hour at ambient temperature. After 1 96 4 4 8 an insoluble material was filtered off, the filtrate was washed with ethyl acetate, adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated to dryness. The residue was triturated with a mixture of diethyl ether and diisopropyl ether to give 2-ethoxyimino-2- (5-formamido-l,2,4-thiadiazol-3-yl)aeetic acid (syn'isomer)(4.5 g) , mp. 165 to 168°C (dec.) .

I.R. (Nujol) : 3450, 3170, 3050, 1730, 1690, 1595, 1565 cm"1 N.M.R. (d6-DMS0) 6 : 1.30 (3H, t, J«7Hz), 4.30 (2H, q, J=7Hz), 8.87 (1H, s) Preparation 9 The following compounds were obtained according to a similar manner to that of Preparation 8. (1) 2-Propoxyimino-2- (5-f ormamido-1,2 ,4-thiadiazol-3-yl)acetic acid (syn isomer),, mp.168 to 170°C (dec.}.

I.R. (Nujol) : 3250, 3140, 1720, 1690, .1590, 1530 cm'1 N.M.R. (d6- DMSO) , 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-Isopropoxyimino-2- (5-formamido-l ,2 ,4-^thiadiazol-3-yl)acetic acid (syn isomer), mp.-180 to 182"C (dec.).

I.R. (Nujol) i 5230., 1720, 1690,, 1590, 1530 cm"1 N.M.R. (dg— DMSO) 6 : 1.25 (6H, .d, J»6Hz) , 4.2-4,7 (1H, m), 8.85 (1H, s) 31- s 1'5 Preparation 10 A mixture of 2-exhoxyimino-2- (5-formamido-l,2,4-"" thiadiazol-3-yl) acetic acid (syn isomer) (4.4 ,g) and IN aqueous solution of sodium hydroxide (54 ml) was stirred for 2 hours at 50 to 55°C. The mixture was cooled in an 20 ice bath, acidified with hydrochloric acid (5„4 ml} and extracred with ethyl acetate. The extract, was dried over magnesium sulfate and evaporated t:o dryness. The residue was triturated with diethyl ether to give 2-ethoxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetic acid (syn isomer) 25 (2.92 g), mp. 168 to 170°C (dec.).

I.R. (Nujol) : 3450, 3370, 3250, 3150, 1665, 1610, 1530 cm"1 3J.M.R. (d6-DMS0) o : 1.22 (3K, t:, J»7Hz) , 4.17 (2K, c, J*7Hz) -30 8.17 (2H, broad s) Preparation 11 The following compounds were obtained according to a similar manner to that of Preparation 10 -(1) 2-Propoxyiziino-2- (5-amino-l,2,4-thiadiazol-3-35 yl)acetic acid (syn isomer)mp. 100 to 1.03°C (dec, ) .

I.R. (Nujol) : 3620, 3320, 333Q, 3120 , 2600, 2S00, 1720, 1620., 1350 cm"1 N.M.R. (dg-DMSO) o : 1.00 (3H, t, J*oH=), 1.3-2.Q C-H, a), 4.13 (2H, t, J«6Ht) , 8.17 C-H, broad, s) (2) 2-Isopropoxy,imino-2-(5-amino-l ,2 ,4-thiadiasol-3-yl)acetic acid (syn isomer), mp. 132 to 153°C (dec.). I.R. (Nujol) : .345,0., 3300, 3200, 1730, 1620, 1330 cm"1 N.M.R. Cd6-DMSC0 e : 1.22 (6H, d, J-6Hz), 4.1-4.6 (1H, m) , 8.20 (2H, broad s) Preparation 12 CI) A mixture of N-hydroxyphthalimide (8.15 g) , triethylamine (5.05 g) , N,N-dimethylformamide (60 ml) and l-bromo-2-cyclohexene (8.05 g) was stirred for 3.3 .hours at room temperature. The reaction mixture was poured into water {300 ml). The precipitated crystals were collected by filtration, washed successively with water and n-hexane and then dried to give N-(2-cyclohexen-l-yloxy)phthalimide (9.8 g). mp 87°C.

I.R. (Nujol) : 1770, 1720, 1610 cm"1 N.M.R. (dg-DMSO,6) : 1.30-2.17 (6H, m) , 4.60-4.77 (1H, m), S.73-6.27 (2H, m) , 7.90 (4H, s) (2) A mixture of N-hydroxyphthalimide (58.2 g) , 1-chloro-2-cyclopentene (36.9 g), triethylamine (5.3 .-9 g) in acetonitrile (370 ml) was treated in similar manner i to .-that of Preparation l2-(l) -j to give N- (2-cyclopenten-l-yloxy)phthalimi&e (56.3 s) - -I.R. (Nujol) : 1780, 1730, 1610 cm"1 N.M.R. (dg-DMSO,6) : 7.92 (4H, s), 6.28 ClH,m), 6.00 (1H, m), 5.42 (1H, m), 2.9-1.98 {4H, m) Preparation 23 (1) A mixture of N-(2-cyclopenten-l-yloxy)-phthalimide (22.9 g) and'hydrazine hydrate (4.75 g) in ethanol (115 ml) was xefluxed for 5 minutes. The reaction mixture was filtered. „ The filtrate containing (2-cyclopenten-l-yl)oxyaiiiine was added ■to a solution of sodium 2-(S-formamido-2,2,4-thiadiazo2-3-yl)glyoxylate (22.4 g) .in water.. The mixture was adjusted to pH 2 with 201 hydroch2oric acid, stirred for 2 hours and then concentrated. The concentrate was adjusted to pH 2 with 2D I hydrochloric acid. The* precipitates .were collected by filtration and dried to give 2-(2-cyclopenten-2-yl)t)xyimino~2- ' (5^.formamido-1,2,4-thiadiazoI-3-yl)acetic acid (syn isomer)(20.0 g), mp 150°C (dec.}.

I.R. (Nujol) ; 3400, 3100, 1720, 2690, 1540 cm"1 N.M.R. (dg-DMSO, £) i 2.80-2.50 (4H, m) , 5.30-5.50 CIH, m)t 5.83-6.30 (2H, m) , -8*9.0 (1H, s) (2) A mixture of .N-(2-cyclohexen-l-yloxy) -phtha2imide (7-29 g), hydrazine hydrate (2.5 g) in ethanol (40 ml) was refluxed £ox 5 minutes.. The reaction mixture was coo2ed and £i2tered to give the filtrate containing (2-cyclohexen-2-y2)-oxyamine (filtrate A). On the other hand, a mixture of S-methyl ■ 2-(5-formamido-1,2,4-thiadiazol-3-yl) thioglyoxylate (6.53 g) in IN-aqueous solution of sodium hydroxide '(90 ml) was stirred for 30 minutes at room temperature.' The reaction mixture" containing sodium 2-(5-formamido-1,2,4-thiadiazol-3-yl)gl^roxylate was adjusted to pH 7 with 101 hydrochloric acid and thereto was added the filtrate A and then the pH was adjusted to 3 with 101 hydrochloric acid. The mixture was stirred for 3 hours at room temperature. The reaction mixture-.was concentrated ' and to the concentrate was added, ethyl, acetate. The mixture was adjusted to pH 1 *rith 10% hydrochloric acid. The precipitates were collected by filtration to give 2-(2-cyclohexen-l-yl)oxyimino-2- (5-f ormamido-1,2,4-thi3.diazol-3-yl) -acetic acid (syn isomer)(2.5 g). On the other hand, the ethyl acetate layer was separated from the filtrate and evaporated. The residue was triturated with diethyl ether to give the same object compound (1*5 g)*. Total yield :: 4. 0 g, mp 190 to 192®C (dec*)* I.R. (Nujol) t 355.0, 3400, 3200, 2500, 1-690, 1590, 154.0 cm"1 N.M.R. (dg-DMSO, £) : l*-5-2*3 (6H, 4.73-5.0 (1H, m), 5.76-6.23 (2H, , 8.97 (1H, s)^ 13.60 (1H, broad s) (3) To b. solution of sodium hydroxide (11.2 g) in water (140 ml) -was added S-methyl 2- (5-f ormamido-1, 2,4-thiadiazol-3-yl)thioglyoxylate (27 g) at 10*C ^nd the mixture was stirred foT 30 minutes at 20 °C* . The reaction mixture containing sodium 2- (5-formamido-l,2,4-thiadiazol-3-yl0glyoxylate was cooled, adjusted to pH 7 with 101 hydrochloric acid and thereto was added a solution of cyclopentyloxyamine (15.3 g") in ethanol (15Pal), The mixture was adjusted to pH 3 with 104 hydrochloric acid, and stirred for 1.5 hours*. The reaction mixture was adjusted to pH 7 with an -35 1 96 4 4 8 aqueous •solution of sodium bicarbonate and then evaporated, to remove ethanol. The residue was washed with ethyl acetate. To the aqueous layer vas addfed ethyl acetate and the mixture was adjusted to pH 1 with 10% hydrochloric acid. The precipitates were collected by filtration to give 2-cyclopentyloxy-imino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer)(3.99 g). The filtrate vas 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 object compound (8.1 g) . Total yield : 12.09 g, mp 180 to 185eC (dec.).

I.R. (Nujol) : 3130, 3040, 2680, 2610, 2520, 1720, 1690, 1660, 1600, 1550 cm"1 *?.M.R. (d6-DMSO, 6) : 1.33-2.10 (8H, m) , 4.-67-5.0 (1H, m), 8. 88 (1H, *) » 13.50 (1H, s) Preparation 14- « J. mixture of 2-t 2 - cycl op en.ten-1-yl) oxy imino -2 - ( 5 - . f ormamido-1,2,4-thiadiazol-3-yl)acetic vacid (syn isomer) (20.0 g) and IN aqueous solution of sodium hydroxide (200 ml) was stirred for an hour at 50 to 55eC* The reaction mixture was cooled, adjusted to pH 7 with 10% hydrochloric acid and thereto was added ethyl acetate. The laixture was adjusted to pH 1 with 10% hydrochloric " 36~ _ 19644 acid and extracted with, ethyl .acetate. The extract ■was vashed with a saturated, aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated'. The residue vas pulverized vith di-5 isopropyl ether to give 2-(2-cyclopenten-l-yl)oxyimino~ 2-(5-amino-1,2,4-thiadia2ol-3-yi)acetic acid (syn isomer), mp 150cC (dec.).

I.R. (Nujol) : 3300, 3150, 1710, 1620., 1520 cm"1 N.M.R. (dg-DMSO, .6) : 1.80-2.50 (4H, m) , 5.30-5.50 10 (1H, m), 5. 83-6.30 (2H, m) , 8.20 (2H, s) Preparation 15 The following compounds vere obtained according to a similar manner to that of Preparation jL4. (1) 2-(2-Cyclohexen-l-yl)oxyimino-2- (5-amino-l,2,4-15 .thiadiazol-3-yl)acetic -acid -(syn isomer) , mp 17.3 I.R. (Nujol) 3400, 3300, 3200, 1720, 1620, 1600, 1520 cm"1 N.M.R. (d6-DMS0, 6) 1.50-2.17 (6H, m), 4.53-4.83 (1H, m), 5.57-6.13 (2H, m) , 8.18 20 . (2H, s) (2) 2-Cyclopentyloxyimino-2- Q5-amino-l,2,4-thiadiazol~ 3-yl)acetic acid (syn isomer), mp 160 to 165*C (dec.)* I.R. (Nujol) : 3470, 3290, 3200, 2400, 1715, . •' 1615, 1600, 1520 cm"1 25 N.M.R. (dg-DMSO, 6) : 1.17-2.10 (8H, m), 4.60-4*97 (1H, m), 8.22 (2H, s) ,35 Preparation i& A mixture of 5-f OTmamido-3- (2-methylthio-2-methylsulfinylacetyl)-1,2 ,4-thiadiazole (10 g) and sodium periodate (2.0 g) in glacial acetic acid (50 ml) was stirred for 50 minutes at 70°C. The solvent was evaporated and the -residue vas washed with n-hexane. To the residue vas added IN aqueous solution of sodium hydroxide (160 ml) and the mixture was stirred for an hour at ambient temperature* To the reaction'mixture was added O-ell ylhydroxylamine hydrochloride (4*3>lg) and the solution was adjusted to pH 3 to 4 with 10% hydrochloric acid and then stirred for an hour at ambient temperature.. After an insoluble material was filtered off, the filtrate was washed with ethyl acetate, adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract'was dried over magnesium sulfate and evaporated to dryness. The residue was triturated with a mixture of diethyl ether and diisopropyl ether to give 2- a21y2oxyimino-2-(5-fonae2nido-l,2,4-"th±adiazol— 5-y2)aeretic acid (syn iBomer)(5. 6g), mp 169 i;o 172°C{dee«)*.

I.R. (Nujol) : 3130» 2500, 1720, 1690, 2590, 1550 cm"^ N.M.R. (dg-DMSO) 5 4.79 (2E, d, J=6Ez), 5-2-5* 6 (2H, m)* 5.B-6.4(IE, m), 8.88 (22»s) Preparation27 The following compounds were obtained -according to a similar manner to that of Preparation 16* Cl) 2-(2-Propynyloxyimino)-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid Csyn isomer), mp. 150 to 155cC (dec.).

I.R. (Nujol) : 3570, 3360, 5260, 3120, 1720, 1670, 1550, 1530 cm"1 N.M.R. (d -DMSO) 6 6:- 3.55 (Ifi, t, J*2Hz), 4 .88 (2H, i, J«2Hz), 8.85 (1H, s) (2) 2-Hydroxyimino-2- (5-f o rmami d o-.1,2,4-thiadiazol-3-yl)acetic acid (syn isomer),, mp. 240 to 241*0 (dec.) I.R. (Nujol) : 3550, 3460, 1665, 1635, 1560 cm"1 I •Preparation 18 A solution of S-methyl (5-formamido-1,2,4- • thiadiazol-3-yl)thioglyoxylate (6.64 g) in IN aqueous solution of sodium hydroxide (80 ml) was adjusted to pH 8.5 with 10% hydrochloric acid and stirred for 50 minutes at ambient temperature . On the other hand, a mixture of (2, 2 ,2-tri£luoroethoxy)phthalimide (8.78 g) arid hydrazine hydrate (1.7 g) in ethanol (40 ml) vas refluxed for 5 minutes and then cooled in an ice bath. A resulting precipitates were filtered off and washed with ethanol. The filtrate 5 and the washings were combined and the combined solution containing 0-(2,2,2-trifluoroethyl)hydroxy!-amine vas added to the above aqueous solution. The k mixture vas adjusted to pH 3 to 4 vith 101 hydro- w chloric acid and -stirred for 1.5 hours at ambient temperature. The solution was neutralised with an \ aqueous solution of sodium bicarbonate, concentrated to half volume in vacuo and washed with ethyl acetate • The aqueous solution was acidified vith 10% hydrochloric acid and extracted with ethyl acetate. The 15 extract vas dried over magnesium sulfate., evaporated to dryness and the residue was triturated vith diisopropyl ether to give 2-(2,2,2-trifluoroethoxyimino)-2 - (5 -f ormamido -1,2., 4-thiadiazol~3-yl) acetic acid (syn isomer) (2-46 g) , mp. 180 to. 185*0 (dec,)- N.M.R. (dg-DMSO) £ : 4 .80 and 5.07 (2H, ABq, J«9Hz) , 8.85 (1H, s) Preparation 19 The following compound was obtained according to a similar manner to that of Preparation 18 . 2-Methylthiomethoxyimino-2- (S-formajnido-l^^-thiadiazol-S-yiyacetic acid (syn isomer), mp. 146 to 148eC (dec.). ' I.R. (Nujol) : 3300, 2600, 2550, 1730, 1705, 1680, 1600, 1530 cuf1 N.M.R. (d6-DMSO) 6 : 2.23 (3H, s), 5.40 (2H, s), 8.87 (1H, s) ' .u Preparation 20 A mixture of S-methyl(5-formamido-1,2,4-thia-diazol-3-yl)thioglyoxylate (6 g) and an aqueous solution (SO ml) of sodium hydroxide (4,2 g) was 5 stirred for sn hour at 50 to 55 *C. The mixture was cooled to ambient temperature and adjusted to pH 7 vith 10% hydrochloric acid. On the other hand, a mixture of N-(ethoxycarbonylmethoxy)phthalimide (12.9 g) and hydrazine hydrate (2,08 g) in ethanol (60 ml) 10 vas refluxed foT 5 minutes and cooled in an ice bath, A resulting precipitate was filtered off and vashed vith ethanol. Th£ filtrate and the vashings were combined and the combined solution containing 0-(ethoxycarbonylmethyl)-hydroxylamine vas added to the above aqueous solution. The 15 mixture vas adjusted to pH 3 to 4 vith 10% hydrochloric acid and stirred for 1.5 hours at ambient temperature. The solution vas neutralized vith an aqueous solution of sodium bicarbonate, concentrated to half volume in vacuo and vashed with ethyl acetate. The aqueous solution vas acidified vith 20 1,0! hydrochloric acid and extracted vith ethyl acetate.. The extract vas dried over magnesium sulfate^ evaporated to dryness and the residue vas triturated vith diisopropyl ether to give 2-ethoxycarbonylmethoxyimino-2-(S-amino-l ,2,4-thia-* diazol-3-yl)acetic acid (syn isomer) (.1.8 g) , mp.135 to 140°C 25 (dec,).

I.R. (Nujol) : 3500,3330,3210,2670,2550,1740,1610,1540 cm N.M.R. (d6-DMS0) 6 : 1.24 (3H,t, J«7Hz), 4 .14 (2H,q, -J«7Hz), 4.80 (2H, s), 8.15 (2H, broad 's) Preparation 21 The follpwing compound vao~ obtained according to a similar manner to that of Preparation20 .

-X 41~ 1 964 4 8 2-(2-Ethoxycarbonyl-l-methylethoxyimiiio)-2-(5-amino-l,2,4-thiadia2ol-3-yl) acetic acid Cs7^ isomer), mp.165 to .16SeC (dec-O.

I.R. (Nujol) : 3450,3350,3240,1750,1730,1630,15.30 cm"1 5 K.M.R. (d6-DMS0) 6: 1.18 C3H,t,J«7H2D, 1.50 (6H,s), 4.15 (2H, q, J=7Hz)., 8.23 C2H, broad s) Preparation JZ The following compounds were obtained according "to 10 £ similar manner to "that of Preparation 14. (2) 2-Allyloxyimino-2-C5-amino-l,2 ,4-thiadiazol-3-yl)acetic acid Csyn isomer), mp.. 93 to 95°C Cdec.). I.R. CNujol) : 3430, 3100, 1710, 1615,1525 cm"1 K.M.R. Cdg-DMSO) «$ : 4.72 (2H* d, J=6Rz), 5.1-5.5 (2H, m), .7-6.3 (1H, m), 8.17 C1H, broad s) C 2) 2- (2-Propynyloxyimino) -2- (5-amino-l,2,4-thiadia2ol-3-yl)acetic acid (syn isomer) , mp. 155 to 157 eC (dec.). i,R. CNujolO : 3500, 3310, 3160, 2600, 2480„ 1745, 1610, 1535 cm"1 K.M.R. Cd6-DMS0) 6 3.53 C1H, t, J«2Hz) , 4.87 (2H, d, J«=2H2), 8.23 (2H, broads) 25 0 ) 2- (2,2,2-Trifluoroethoxyimino)-2- C5-amino- 1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) , up. 140 to 143eC (dec.).

I.R. CNujol) ; 3450, 3350-, 326t), 1745, 1670, 1645, 1615, 1515 cnf1-30 K.M.'R. (d6-DMS0) 6 : 4.7.2 and 4.95 (2R, ABq", J-SHz), - - - 8.25 (2H, broad s) 4 2 1 O " -7 i? " ' ■ - "t- &) 2-Methylthiomethoxyimino-2-(5-ajaino-l,2 ,4-"' thiadia2ol-3-yl)acetic acid (syn isomer), mp. 140 to 143eC (dec.).

I.R. (Nujol) : 3500, 3300, 3150, 2670, 2580, 1740, 1615, 1605, 1530 cnf1 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-l,2,4-.thiadia2ol-3-yl)~ acetic acid (syn isomer), -mp.. 173 to 174°C (dec.). I.R.. (Nujol) .• 3450, 1735, 1620, 1540 cm"1 N.M.R. (d6-DMS0) 6 : 7.35 (15H, s) , 8.22 (2H, s) Preparation 25 To a mixture of 2-hydroxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (9.5 g) and dimethylformamide (80 ml) was added vi>h stirring at ambient temperature trityl chloride (22.8 g) , and triethylamine (4.1 g) was gradually added thereto after 3 minutes stirring. The resulting mixture was stirred for 10 minutes and ethyl acetate (250 ml) was added thereto. 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 were added an aqueous solution of sodium bicarbonate (50 ml) and diisopropyl ether (100 ml). Precipitates were collected by filtration and the aqueous layer in the - filtrate was -separated. The collected precipitates weTe suspended in the separated aqueous layeT and ethyl acetate vas 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 iiexane to give .2-trityloxyimino-2-(5-formamido-l,2 ,4-thiadiazol-3-yl)acetic acid (syn isomer) (17.1 g), mp. 175 to 176°C (dec.).

I.R. (Nujol) : 3180, 3070, 1700, .1600, 1540 cm"1 N.M.R. (dg-DMSO) 6 : 7;35 (15H, s), 8.83 (1H, s), 13.52 (1H broad s) Preparation 24 The following compounds were obtained according to similar manner • to that of Preparation.12—(l).. (1) N-(l-t-ButoxycaTbonylethoxy)phthalimide, mp 80 to 82°C.

NMR (d6-DMS0, 6) : 1.42 (9H, s), 1.48 (3H, d, J=7Hz) , 4.72 (1H, q, J«=7Hz) , 7.86 (4H, s) » -(2) N- (l-t-Butoxycarbonyl-l-methylethoxy)phthalimide, mp 96 to 100°C.

NMR (d6-DMS0, 6) : 1.42 (9H, s), 1.48 (6H, s), 7 .87 (4H, s) (3) N-(l-Benzyloxycarbonylethoxy)phthalimide, mp 65 to 68°C.

IR (Nujol) 1790, 1740, 1450, 1210', 1190, 1110, 1080, 980, 88 0, 735, 700 cm (.4) N-(2-Oxo-3-tetrahydrofuryloxy)phthalimide, mp 140 to 142°C.

IR (Nujol) : 1785, 1760, 1720, 1605, 1215, 1185, 870, 695 cm"1 -44" Preparation 25 The following compounds were obtained according to a similar manner to that of Preparation20 . (1) 2-(t-Butoxycarbonylmethoxyimino)-2-(5-amino-l,2,4-thiadiazol-3-yl)acetic acid (syn isomer), mp 150 to 155°C (dec.),.

IR (Nujol) : 3420, 3230, 3100, 1725, 1610, 1530 cm"1 € NMR (DMSO-dg, 6) : 1.45 (9H, s) , 4.70 (2H, s)., 8.12 (2H, broad s) (g) 2-(l-t-Butoxycarbonylethoxyimino)-2-(5-amino-l,2,4= thiadiazol-3-yl)acetic acid (syn isomer), mp 155 to 156°C (dec.).

IR (Nujol) : 3400, 3300, 3200, 1720, 1710, 1620, 1520 cm"1 NMR (dg-DMSO, 6) : 1.2-1.7 (12H, m), 4.72 (1H, q, JIs7Hz) , 8.2 (2H., "broad s) (3 3 2-(l-t-Butoxycarbonyl-l-methylethoxyimino) -2- (5- amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer), mp 180 to 181°C (dec.).

IR (Nujol) : 3400, 3300, 3200, 1745, 1715, 1630, 1530 cm"1 25 NMR (dg-DMSO, 6) : 1.38 (9H, s), 1.43 (6H, s), 8.15 (2H, broad..s) (-4 ) 2-(l-Benzyloxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer), mp 129 to 133°C (dec.).

IR (Nujol) : 3300, 3200, 1720, 1620, 1530 cm"1 NMR (DMSO-dg, 6) : 1.45 (3H, d, J»6Hz), 4.97 (1H, q, Jc6Hz), 5.18 (2H, s), 7.31 (5H* s), 8.17 (2H, broad s) - 45 Preparation 26 S-Methyl (5-formamido-l,2,4-thiadiazol-3-yl)-thioglyoxylate (64.8 g) and 1-carboxy-3-hydroxypropoxy-amine, which was prepared by refluxing a mixture of N-(2-oxo-3-tetrahydrofuryloxy)phthalimide (65.0 g) , conc. hydrochloric acid (50 ml) and water (200 ml) for 1 hour, were treated according to a similar manner to that of Preparation 20 to give 2-(1-carboxy-3-hydroxy-propoxyimino)-2-(5-amino-l,2,4-thiadiazol-3-yl)acetic acid (syn isomer)(33.2 g) , mp 186 to 188°C (dec.).

IR (Nujol) : 3400, 3250, 3100, 1710, 1620, 1540 cm"1 NMR (DMSO-d6,6) : 1.73-2.10 (2H ., m) , 3.50 (2H, t, J=6Hz), 4.73 (1H, t, J=6Hz), 8.13 (2H, s) Preparation 27 To a solution of 2-(l-carboxy-3-hydroxypropoxyimino) 2-(5-amino-l ,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (33.0 g) in methanol (2.8 £) were added anhydrous magnesium sulfate (120 g) and acetic anhydride (60 g). The mixture was stirred at ambient temperature for 30 minutes, filtered and the filtrate was evaporated to dryness. The Tesidue.was triturated in acetone (200 ml) and ethyl acetate (li) was added thereto.. The mixture was stirred at ambient temperature for 1 hour and the precipitates were collected by filtration and •washed with ethyl acetate.

The precipitates were dissolved in water (200 ml) and then ethyl acetate (500 ml), acetone (200 ml) and 6N hydrochloric acid (40 ml) were added thereto..

An OTganic layer was separated out and the aqueous layer was extracted with ethyl acetate. The organic layers weie combined, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated in diethyl ether, filtered and washed with diisopropyl ether to give 2-(2-oxo-3- . 1964 4 8 tetrahydrofuryloxyimino)-2-(5-amino-l,2,4-thiadiazol-3-yl)acetic acid (syn isomer)(26.5 g) , mp 185-187eC (dec.).

IR (Nujol) : 3400, 3300, 3200, 1775, 1730, 5 1640, 1605, 1535 cnf1 NMR (d6-DMSO,S) : 2.27-2.70 (2H, m), 4.17-4. 50 (2H, m), 5.27 (1H, J=8Hz), 8.22 (2H, s) Preparation 28 ^0 The following compound was prepared according to a similar manner to that of Preparation 20. . 2-Methoxycarbonylmethoxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetic .acid (syn isomer), mp. 190 -193°C (dec.).

IR (Nujol) : 3380, 3280, 3180, 1750, 1710, 15 1610, 1510, 1260, 1230 cnf1 NMR (DMS0-d6, 5) : 3.73 (3H, s) , 4.87 (2H, s), 8.2 (2H, bs) Preparation 29 The ■following compound was obtained according to a similar manner to that of Preparation 30. 7-[2-Cyclopentyloxyimino-2- (5-amino-l,2,4-thiadiazol-3-yl)acetamido]cephalosporanic acid (syn isomer), mp 140 to 145°C (dec.).

I.R. (Nujol) : 3480, 3370, 32 50, 17S3, 1730, 1680, 1630, 1530 cnf1 N.M.R. (d^-DMSO,6) : 1.33-2.17 (8H, m), 2.03 (3H, s), 3.57 (2H, bToad s), 4.60-4.90 (1H, m), 4.73 -and 4.97 (2H, ABq, Jc13Hz) , 5.15 (1H, d, J-5Hz") , 5.80 (1H, dd, J*5 and 8Hz), 8.10 (2H, broad s), 9.47.(1H, d, J«8Hz) 47 1 9 6 4 4 Preparation 30 To a cold solution of phosphorus pentachloride (10.4 g) in methylene chloride (250 ml) was added 2-cyclopentyloxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetic acid (syn isomer)(12.8 g) at -18°C and the mixture was stirred for 15 minutes at -13 to -10°C.

On the other hand, a mixture of 7-amino-3-acetoacetoxy-methyl-3-cephem-4-carboxylic acid (15.7 g) and trimethylsilylacetamide (50 g) in methylene chloride (250 ml) was warmed to make a clear solution and 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 an aqueous solution (500 ml) of sodium bicarbonate (29.5 g) and stirred for 15 minutes at room temperature. The aqueous layer was separated out, 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 residue was triturated with diethyl ether to give a powder of 7- [2~cyclopentyloxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer) (13.5 g), mp 130 to 135®C (dec.)* IR (Nujol) : 3300, 1780, 1720, 1680, 1620, 1525 cm"1 NMR (DMSO-d6, 6) : 1.3-2.0 (8H, m), 2.15 (3H, s), 3.52 (2H, bs) , 3. 60 (2H, s), 4-5-4.7 (1H, m), 4.77, 5.00 (2H, ABq, J«=14Hz) , 5.13 (1H, d, Jas4Hz) , 5.80 (1H, 2d, J-4 and 8Hz), 8.10 (2H, s), 9.50 (1H, d, J=8Hz) Preparation 31 To a solution of 7-[2-(1-t-butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3- 48 acetoacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer)(5.16 g) in formic acid (50 ml) was added conc. hydrochloric acid (1.'7 ml) and the mixture was stirred for 30 minutes at room temperature. The solvent was distilled off under reduced pressure and the 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 under stirring. The aqueous layeT was separated out and ethyl acetate was added thereto. 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 residue was pulverized with diethyl ether, collected by filtration, washed with the same solvent and dried over anhydrous phosphorus pentoxide to give brownish powder of 7-[2-(1-carboxyethoxyimino)-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer)(3.7 g), mp 95 to 100°C (dec.).

IR (Nujol) : 3450, 3350, 3230, 1780, 1720, 1630, 1525 cm"1 NMR (DMSO-dg, 6) : 1.45 (3H, d, J«7Hz), 2.20 (3H, s) , 3.58 (2H, broad s), 3.67 (2H, s), 4.65-5.30 (3H, m), 5.22 (1H, d, J-5Hz), 5.77-6.10 (1H, m), 8.23 (2H, broad s) , 9.40-9.68 (1H, m) Preparation 32 The following compounds were obtained according to similar manners to those of Preparations 30 and 31* (1) 7- [2- (2-Cyclopenten- 1-yloxyimino)-2- (5-amino- 1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxy-methyl-3-cephem-4-carboxylic acid (syn isomer), 49 mp 135 to 140°C (dec.).

IR (Nujol) : 3400, 3300, 3200, 1775, 1735, 1710, 1675, 1620, 1525 cm"1 NMR (DMS0-d6, 6) : 1.93-2.47 (4H, m) , 2.18 3 (3H, s), 3.55 (2H, bs), 3:65 (2H, s), 4.80, 5.07 (2H, ABq, J=13Hz), 5.13 (1H, d, J=5Hz), 5.23-5.53 (1H, m), 5.70-6.23 (3H, m), 8.12 (2H, bs), 9.50 (1H, d, J=8Hz) (2) 7- [2-Carboxymethoxyimino-2-(5-amino-.!,2,4-thia-diazol-3-yl) acetamido ]-3-ace toacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer), mp 95 to 100°C (dec.).

IR (Nujol) : 3400, 3290, 3190, 1770, 1720, 15 1615, 1520 cm"1 NMR (DMSO-d6, 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=5Hz), 5.87 (1H, 2d, Je5 and 8Hz) , 8.15 (2H, bs) , 20 9.53 (1H, d, J=8Hz) (3) 7-[2-t-Butoxycarbonylmethoxyimino-2-(5-amino- 1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxy-methyl-3-cephem-4-carboxylic acid (syn isomer), 25 mp 105 to 110°C (dec„).

IR (Nujol) : 3350, 3250, ,1780, 1720,, 1620, 1525 cm"1 NMR (DMSO-d6, 6) : 1.43 (9H, s), 2.17 (3H, s), 3.53 (2H, bs), 3.63 (2H, s), 4.63 (2H, s) , 30 4.82, 5.05 (2H, ABq, J=13Hz), 5.15 (1H, d, Jc5Hz) , 5.85 (1H, 2d, J-5 and 8Hz), 8.15 (2H, bs), 9.53 (1H, d, J=8Hz) (4) 7-[2-(1-t-Butoxycarbonylethoxyimino)-2-(5-amino-35 1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxy- 50 methyl-3-cephem-4-carboxylic acid (syn isomer), brownish powder, mp 110 to 115°C (dec.).

IR (Nujol) : 3400, 3300, 3200, 1780, 1720, 1620, 1525 cm'1 NMR (DMSO-dg, 6) : 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), 5.73-5.97 (1H, m), 8.10 (2H, bs), 9.33-9.57 (1H, m) 7-[2-(1-Methyl-l-carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethy1-3-cephem-4-carboxylic acid (syn isomer), mp 180 to 185°C (dec.).

IR (Nujol) : 3350, 3250, 1780, 1720, 1625, 1525 cm"1 NMR (DMSO-d6, 6) : 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 (1H, 2d, J=4 and 8Hz) , 8.13 (2H, s) , 9.47 (1H, d, J=8Hz) 7-[2-(1-Methyl-l-t-butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thia di azo1-3-yl)ace tami do]-3-acetoacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer), mp 140 to 145°C (dec.).

IR (Nujol) : 3350, 3250, 1785, 1720, 1620, 1530 cm 1 NMR (DMSO-d6, 6) : 1.47 (6H, s), 1.50 (9H, s) 2.17 (3H, s), 3.57 (2H, bs), 3.63 (2H, s) 4.80, 3.07 (2H, ABq, J=14Hz), 5.17 (1H, d J=4Hz), 5.86 (1H, 2d, J«4 and 8Hz), 8.13 (2H, s), 9.43 (1H, d, J«8Hz) Sodium 7-[2-ethoxyimino-2-(5-amino-l,2,4- 1 96 4 4 51 thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylate (syn isomer), mp 175 to 180°C (dec.).

IR (Nujol) : 3450, 3300, 3100, 1790, 1720, 1670, 1640, 1610, 1550 cm"1 NMR (D20, 6) : 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 (IH, d, J-4Hz) (8) 7- [2-Methoxyimino-2- (5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer), mp 120 to 125°C (dec.).

IR (Nujol) : 3350, 3250, 1780, 1710, 1680, 1630, 1530 cm"1 NMR (D20+NaHC03i 6) : 2.32 (3H, s) , 3.40, 3.62 (2H, ABq, Jc18Hz), 4.10 (3H, s), 4.84, 5.04 (2H, ABq, Jc14Hz), 5.22 (IH, d, J=4Hz), 5.86 (IH, d, J«4Hz) (9) 7- [2-Propoxyimino-2-(5-amino-l ,2 ,4-th.iadiazol-3-yl) acetamido] -3-acetoacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer), mp 125 to 130°C (dec.).

IR (Nujol) : 3350, 3250, 1780, 1710, 1680, 1620, 1530 cm"1 NMR (D20+NaHC03, 6) : 0.94 (3H, t., J«6Hz)., 1.5-1.9 (2H, m), 2.30 (3H, s), 3.40, 3.62 (2H, ABq, Jc18Hz), 4.26 (2H, t, J=6Hz), 4.84, 5.04 (2H, ABq, J=12Hz), 5.22 (IH, d, J«4Hz), 5.86 (IH, d, J=4Hz) (10) 7-[2-Isopropoxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4= 1 o n 52 carboxylic acid (syn isomer), mp 95 to 100°C (dec.).

IR (Nujol) : 3400, 3300, 3200, 1775, 1740, 1710, 1670, 1620, 1525 cm"1 NMR (DMS0-d6, 6) : 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 (IH, m), 4.78, 5.02 (2H, ABq, J«13Hz), 5.14 (IH, d, J«=5Hz) , 5.80 (IH, dd, J-*5 and 8Hz), 8.06 (2H, broads), 9.44 (IH, d, J=8Hz) (11) Sodium 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylate (syn isomer), mp 160 to 170°C (dec.).

IR (Nujol) : 3450, 3300, 3100, 1790, 1720, 1670, 1550 cm"1 NMR (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 (IH, d, J=5Hz), 5.8-6.3 (IH, m), 5.84 (IH, d, J«=5Hz) (12) Sodium 7-[2-(2,2,2-trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylate (syn isomer), mp 128 to 132*0 (dec.)- IR (Nujol) : 3300, 1780, 1710, 1670, 1600, 1530 cm"1 NMR (D20, 6) : 2.32 (3H, s), 3.50, 3.63 (2H, ABq, J*17Hz), 4.60-5.07 (4H, m), 5.23 (IH, d, J=4Hz), 5.87 (IH, d, J=4Hz) (13) Sodium 7-[2-methylthiomethoxyimino-2-(5-amino- 1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxy-methyl-3-cephem-4-carboxylate (syn isomer), 53 mp 180 to 190°C (dec.).

IR (Nujol) : 3500-3200, 1770, 1670, 1620, 1530 cm"1 NMR (DMS0-d6, 6) : 2.18 (3R, 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 (IH, d, Jc5Hz) , 5.22 (2H, s) , 5.62 (IH, dd, J«=5 and 8Hz) , 8.14 (2H, broad s), 9.48 (IH, d, J=8Hz) (14) 7-[2-(2-Propynyloxyimino)-2-(5-amino-l,2,4- thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer), mp 90 to 95°C (dec.).

IR (Nujol) : 3400, 3280, 3200, 2100, 1770, 1740, 1710, 1670, 1620 cm"1 NMR (DMS0-d6, 6) : 2.18 (3H, s), 3.46 (IE, X, Jc2Hz), 3.46, 3.58 (2H, ABq, J=18Hz), 3.62 (2H, s) , 4,76 (2H, d;. J«?2Hz)^ 4.78, 5.02 (2H, ABq, J=14Hz) , 5.12 (IH, d, J«=5Hz) , 5.80 (IH, dd, J«5 and 8Hz), 8.10 "(2H, broad 9.60 (IH, d, J«8Hz) Preparation 33 To a mixture of sodium iodide (80 g) and pyridine (11.36 g) in water (40 ml) was added sodium 7-[D-5-carboxy-5-(3-phenylureido)valeramido]cephalosporanate (40 g) at 50°C under stirring, which was continued at 60°C for 4.5 hours. The warm reaction mixture was diluted with water (80 ml), adjusted to pH 3.5 with 6N hydrochloric acid and subjected to column chromatography on a non-ionic adsorption resin "Diaion HP-20" (Trademark, prepared by Mitsubishi Chemical Industries) (600 ml). After the column was washed with water (2.4 £,) elution was carried out with 35% aqueous isopropyl 54 alcohol, which was warmed to 45°C prior to use. To the eluate (1 £) was added N,N-dimethylformamide (100 ml) and the mixture was concentrated to 120 ml under reduced pressure. To the residue was added isopropyl alcohol (1 &) under stirring, which 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-phenylure i do)vale rami do]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (22.0 g), mp 180 to 185°C (dec.). IR (Nujol) : 3300, 1780, 1720, 1680, 1610, 1540, 1500 cm"1 NMR (DMS0-d6+D20, 6) : 1.4-1.8 (4H, m), 2.0-2. 3 (2H, m) , 3.14, 3.54 (2H, ABq, J«=17Hz), 4.0-4.2 (IH, m), 5.04 (IH, d, J=4Hz), 5.24, 5.62 (2H, ABq, J NMR (D20, 6) : 3.53, 3.80 (2H, ABq, J Sodium 7-[2-ethoxyimino-2°-(5-amino-l,2,4~thiadiazol~ 5-yl)aoetamido]-cephalosporanate (syn isomer), mp 180 to 185°C(dec. )„ I.R,(Nujol): 5480, 3430, 3250, 1780, 1750, 1665, 1635) 1610, 1540, 1515, 1400, 1280, 1240, 1040 ciT1 -56 1 96 4 4 8 Example 1 *HC£ S CI HzN" .j-0C2hs to—t— C-COOH H2 '2H2° COOH S » h2n-^S/N |.oc h N—^—C-CONH COO To a cold solution of-phosphorus pentachloride (2.64 g) 1.5 in methylene chloride (2.5 ml) was added 2-ethoxyimino~ 2-(5-amino-l,2,4-thiadiaz01-3-yl)acetic acid (syn isomer) (2.48 g) at -206C and the mixture was stirred for 35 minutes at -.2 0 to -14°C. 'To the mixture was added cold diisopropyl ether (75 ml) below -10°C undeT 20 stirring, -which 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 foT several minutes- On the other hand, a mixture of 1-25 •[ (7 - amino-4-carboxy-3-cephem-3-yl)methyl]pyridinium chloride hydrochloride dihydrate (3.27 g) and trimethylsilylacetamide (16 g) in methylene chloride (50 ml) was warmed at 35°C to make a ^solution, which was cooled to -20°C. To the cold solution weTe added 30 the precipitates prepared above.and the mixture was stirred for 2.5 minutes at -18 to -12°C and for an additional 20 minutes at -12 to -3°C. A solution -of sodium bicarbonate (4 g) in wateT (30 ml) was added to the reaction mixture and the aqueous layeT was 35 separated out, 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 alumina C16 g) and then subjected to column chromatography on a non-ionic adsorption resin Diaion HP-20 (trademark: prepared by Mitsubishi -Chemical Industries) (100 ml). After the column was washed with water, the elution was carried out with 2-0% aqueous methanol. The eluates containing an object compound were collected,, evaporated, to remove methanol under reduced pressure and lyophilized to give white powder of 7-[2-ethoxyimino-2-(5-amino-l ,2 ,4-thiadiat.ol- 3-yl) acetamido] -3- (1-pyridiniomethyl) -3-cephem-4-.carboxylate (syn isomeT) (2.3:9 g) , mp. 155 to 165°.C (-dec..) ♦ IR (Nujol) : 3400-3150., 1770, 1660, 1610, .1530 cm"1 NMR (DMSO-dg, 6): 1.21 (3H, t, J«7Hz), 2.9-3.7 (2H, m) , 4.12 (2H, q., J« 7Hi)., 5.05 (IH., d, J-SHs), 5.19, 5.68 (2H, ABq, J«14Hz), 5.7 (IH, m) 8.1 (4H, m) , 8.6 (IH, m),, 9.4 (3H, m) 58 Example '2, To a cold solution of phosphorus pentachloride (1.25 g) in methylene chloride (30 -ml) was added 2-(2-cyclopenten-l-yloxyimino)-2-(5-amino-l,2,4-thiadiazol-5 3-yl) acetic acid (syn isomer) (1.5 g) at -'15°€ and the mixture was stirred for 30 minutes -at -13 to -10°C. On the other hand, a mixture of N-[7-amino-3-cephem-3-ylmethy1]pyridinium-4-carboxylate dihydrochloride (1.82 g) and tTimethylsilylacetamide (10 g) in methylene 10 chloride (50 ml) was stirred for 10 minutes at room temperature and cooled to -10°C, The cooled solution was added to the above activated mixture .and the mixture was stirred for 15 minutes at -10cC. The reaction mixture was poured into an aqueous solution (100 ml) 15 of sodium bicarbonate (3.6 g) and stirred for 15 minutes at room temperature. The aqueous layer vas separated out, adjusted to pH 2 vith 10% hydrochloric acid .and washed with ethyl .acetate. The -aqueous solution vas subj ected to column chromatography on a non ionic 20 adsorption resin, Diaion HP-20 (Trademark., prepar-ed by Mitsubishi Chemical Industries)(100 ml). After the column was washed with water, the elution was carried out with 401 aqueous methanol. The eluates containing an object compound were collected, evaporated to 25 remove methanol under reduced pressure and lyophilized to give white powder of N-[7-{2-(2-cyclopenten-l-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}• 3-cephem-3-ylmethyl]pyrid.inium-4-carboxylate (syn isomer) (1.5 g),, mp. 190 to 195*C (dec.). .30 T.R. (Nujol) : 3350, 3200, 17.80, 1660, 1620., 1530 cm 1 N.M.R. (D20+NaHC03,5) : 1.9-2.5 (4H, -m), 3.23, 3.60 (2H, ABq, J*16Hz)^ 5,2-6.1 (7H, m) , 35 . 7.9-9.1 (5H, m) Example 5 S H2N coo • 2HC* 0-lf-C00CH2CH3 CH3 To a cold solution of phosphorous pentachloride (1.46 g) in methylene chloride (30 ml) was added 2-(1-methyl-l-ethoxycarbonylethoxyimino)-2-(5-amino-l,2,4-thiadiazol-3-yl)acetic acid (syn isomer)(2.11 g) at -18°C and the mixture was stirred for 50 minutes at -14 to -11°C. To the reaction mixture was added dry n-hexane (90 ml) below -106C and the mixture was stirred for several minutes and the solvent was removed by decantation. The residue was tTiturated with n-hexane and collected by filtration to obtain a powder of the activated acid. On the other hand, a mixture of N-[7-amino-3-cephem-3-ylmethyl]pyridinium-4-carboxylate dihydrochloride (2 g) and trimethylsilyl-acetamide (10 g) 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 above and the mixture was stiTred for 30 minutes at -13 to -10°C and for 30 minutes at -5 to 0°C. The reaction mixture was poured into an aqueous solution (100 ml) of sodium bicarbonate (3.6 g) and stiTred for IS minutes at room temperature and then adjusted to pH 1 with 6N hydrochloric acid. The aqueous layer was separated out, washed with -ethyl acetate and subjected to column chromatography on a non ionic adsorption Tesin, Diaion HP-20 (100 ml). After the column was washed with water, 5% aqueous ethanol and 10% aqueous ethanol u successively, the elution was carried out with 201 aqueous ethanol. The eluate-s containing an object compound were collected, evaporated to remove ethanol under reduced pressure and lyophilized to give N-[7-5 (2- (1-methyl-l-ethoxycarbonyl.ethoxyimino) -2- (5-amino-1,2,4-thiadiazol - 3-yl) acetamido }-3-cephem-3-ylmethyl] -pyridinium- 4- carboxy late (syn isomer) (1.. 30 g) , white-powder, mp. 164 to 168°C (dec,)' IK (Nujol) : 3350-3150, 1770., 1720, 1670, 10 1620 , 1220 cm"1 NMR (DMSO-dg, 6) -; 1.15 (3H, t, J«7Hz) , 1.45 (6Hs) , 3. 03 and 3.55 (2H, ABq, J«18Hz)., 4,10 (2H, q, J-THz), 5.11 (IH, d, J»5Hz) , 5.20 and 5.67 (2H, ABq, J-l:3Hz) , 5.75 15 (IH, 2d, J«5 and 8Hz), 8.20 (4H, m), 8.57 (IH, m) , 9.47 (3H, m) Example 4 The following compo.unds were obtained according to similar manners to • those of ^Examples 1 to 3» (I) 7- {2-Propoxyimino»2- (5-amino-l ,2,4-thiadia20l-3-yl) acetamido] -3- (1 -pyridiniome thy1) -3-cephem-4- carboxy late (syn isomer), 115). 2:30 to 240 °C (dec.). IR (Nujol) ; 3400-3200, 1770., 1670-1600, 1.530 cm"1 25 NMR (DMS0-d6, 6) : 0,85 (3H, t, J«7H2.), 1.6 (2H, m), 3.06, 3.55 (2H, ABq, J«18Hz), 4.04 (2H, t., J«SRz), 5.06 (IH, d, J-5Hz) , 5.18, 5.70 (2H, ABq, J»14H2) , 5.74 (IH, dd, J»5 and 8H2), 8.2 (4H, m) , 8.6 (IH, m), 9.5 (3H, m) (2) 7-[2-Methoxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl) acetamido]-3- (l-pyridiniometiiyX)—3-cephenM— carboxylate (syn isomer), mp. 250 to :260°C (dec-)* IR (Nujol) : 3400-3100., 1770, 1650,. 1610, 1520 cm"1 IS 1 964 4 8 NMR (DMSO-dg, o) : 3.07, 3.57 (2H, ABq, J-I8H2), 3.86 (3H, s), 5.0.6'C1H, d, J=5H2) , 5.19, 5.69 (2H, ABq, J-14H2)5.75 (IH, dd,Jc5, 8Hz)t 8.0-8.3 (4H, m), 8.4-8.7 (IH, m), 9.3-9.6 5 (3H, m). (3) 7-[2-Isopropoxyimino-2-(5-amino-l,2,4-thiadi.a2ol- 3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem- 4-carboxylate (syn isomer), mp. 160 to 165°C (dec.).

IR (Nujol) 3270, 3180, 1770, 1660, 1610., 1525 cm"1 NMR (BMSO-d6+D20, 6).: 1.22 (6H, d, J-6Hz), 3.15, 3.57 (2H, ABq, J-lBHz)*4.17-4.60 (IH, m) , 5.12 (IH, d, J«5H2), 5.33, 5.70 (2H, ABq, J-14H2) , 5.78 (IH, d, J«5Hz), 8.0-8.4 (2H, m) , 8.47-8.83 (IH, m), 9.33-9.67 (2H,m) (4) N- [7- {2- (t-Butaxycarbonylmethoxyimino)-2- (5-.amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-yImethy 1 ]pyrid ini um-4- carboxylate (syn isomer) , mp. 15.0 to 155°C (dec.), I.R. (Nujol) : 3300, 3200, 1770, 1680, 1620, 1530 cm"1 (5) N- [7-{2-Carboxymethoxyimino -2- (5-amino-l,2 ,4-thiadiazsl- 3 -y.l) acetamido > - 3 - cephem-3 - ylmethyi] pyridiniuro -4-carboxylate (syn isomer), mp- 150 tro 155°C (dec-).

LR. (Nujol) : 3350, 32.00, 1780, 1680, 15.30 cm"1 (6) N- [7-{2-Cyclopentyloxyimino-2-(5-amino-l ,2,4-thiadiazol-3 -yl)acetamido}-3 - cephem-3 -ylmethyi] pyridinium-4-carboxylate (syn isomer), mp. 180 to 185°C (dec.).

I.R. (Nujol) : 3300, 3200, 1780, 1670, 1620, 1530 cm"1 y i f '• * I n <"A O -62 - " ^ (7) N- [7-{.2- (1-Carboxyethoxyimino)-2- (5-amino-l.,2.,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-carbamoylpyTidinium-4-carboxylate (syn isomer), mp. 170 to 17S°C (dec.).

I.R. (Nujol) : 3300, 3160, 177.0, 1680, 1610, 1560, 1520 an"1 (8) N- [7-{2-(1-t-Butoxycarbanylethoxyimino) -2-(5-amino-l .,2-, 4-thiadiazol-3-yl) acetamido }-3~cephem-3-ylmethyl]pyridinium-4-carboxylate (syn isomer), mp. 160 to 165°C (dec.).

I.R. (Nujol) : 3290., 3160, 1770, 1725, 1670, 15 1.620, 1525 cm"1 N.M.R. (CD50IKI)20,5) : 1.2-1.6 (12H., m) , 3.20 and 3.67 (2H, ABq, J=18Hz), 4.40-4.90 (IH, m) , 5.20 (IH, d, J-SHz) , 5.33-5.'80 (2H., m)., 5.92 (IH, d, J-5Hz), 7.9-9.4 (5H, m) . (5) N- [7-{2- (1-Carboxyethoxyimino)-2-(5-amino-l.,2,4-thiadiazol-3-yl) acetamido }-3- cephem-3 -ylmethyljpyr id±s±mn-4- carboxy late (syn isomeT), mp. 175 to 180° C (dec.).

I.R. (Nujol) : 3300, 3200, 1775,, 1670, 1620,1520 cm"1 ClXj N- [7-{2- (1-Benzyloxycarbonylethoxyimino) -2- (5-amino-1,2,4-thiadiaxol-3'-yl)acetamido >-3-cephem-3-y lme thy 1 ] pyridinium-4 - carboxylate (syn isomer ) ,, -mp .. 178 to 1.82 °C (dec,.).

I.R. (Nujol) : 3230, 3150, .177'0, 167 0, 1620.,1520 cm"1 N.M.R. (DMSD-dg-t-D^O.,6) •: 1.45 (3H, d, J«7Hz) , 3.10 and 3.60 (2H, ABq, J«16Hz), 4.87 (IH, 55 q, J»7Hz), 5.20 (2H, s), 4.97-5.10 (2H, m), .25 (IH, d, J«=5Hz) , 5.83 (IK, d, J=5Hz), 7.43 (5H, s), 8.27 (2H, m), 8.63 (IH, m) , 9.38 (2H, m) (11) N-[7-{2-Ethoxycarbonylmethoxyimino-2-(5-amino -5 1,2,4-thi.adiazol-3-yl)acetamido}-3-cephem-3-ylmethyl] -pyridinium-4-carboxy late (syn isomer)., mp . 184 to .188°C (dec.).

I.R. (Nujol) : 3400-3100, 1770, 1670, 1610, 1520 cm"1 10 N.M.R. (DMSO-d6,6) : 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 (IH, d, J=5Hz) , 5.17 and 5.70 (2H, ABq, J«13Hz), 5.72- (IH, dd, Jc5 and 8Hz) , 8.16 (4H, m), 8.62 (IH, m) , 15 9.50 (3H, m) (12) N- [7- (2- (2-Cyclohexen-l-yloxyimino) -2- (5-amino- ~~ 1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl] pyridinium-4-carboxy late (syn isomer)., rap. 150 to 155°C (dec.).

IR (Nujol) : 3300, 3200, 1775, 1660, 1610, -1 1520 cm NMR -(DMS0-d6, 6) : 1.5-2.0 (6H, mj, 3.13,3.57 (2H, ABq, J*17Hz) , 4..6-4.7 (IH, m) , 5.07 (IH, d, J»4Hz) , 5.27,5.. 60 (2H, ABq, J*14Hz), 5.80 (IH, 2d, J«4 and 8Hz J , 5.77-6.0 (2H, m), 8.17 (2H, s), 8.0-8.4 (2H, m), 8.43-8.80 (IH, m), 9.4-9.5 (2H, m), 9.55 (IH., d., J»5Hz) -q (15) N- [7-{2-CaTboxymethoxyimino-2- (5-amino-l ,2 ,4- thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-carbamoylpyridinium-4-carboxylate (syn isomer), mp. 17.5 to .180°C (dec.).

IR (Nujol) : 335 0, 3200, 1775, 1680, 1615, 35 . 1565, 1525 cm"1 (i*) N-[7-(2-Methoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3 -ylmetnyl]pyridinium-4-carboxylate (syn isomer) , mp. 165 ic 1700C (dec.).

IR (Nujol) : 3300-3150,1760, 1670, 1620, 1520 cm"1 NMR CD20, 6) : 3.17,3.70 (2H, ABq, J*18Hz), 3.80 (3H-, s), 4.93 (2H., s) , 5. 30 (IH, d, J-SHz), 5.44,5.73 (2H, ABq, J=14Hz), 5.93 CIH,- d, J«3Hz), 8,10 (2H, m) , 8.60 CIH, m), B, 98 (2H, m) CL5 ) N-[7-{2-(l-Methyl-l'-carboxyethoxyimino)-2-(5- amino -1., .2 ,4 - th. iadiaz ol- 3-y 1) ace t ami do } - 3 -cepliem-3-ylmethyl]pyTldinium-4-carboxylate (syn isomer) white powder. .mp, 176 to 1.80 °C (dec..) . . IR (Nujol) : 3400-3150, 1770., 1670., 1620, 1520 cm"1 (16) N- [7- {2- (1 - Me thyl -1 -1 - b .ut o xycarb onyle tho xyimino) -2- (5-aanino-l,2,4-th.iadia20l-3-yl)acetamido}-3-cepbem-3-ylmethyl]pyTidinium-4-carboxylate (syn isomeT), mp. 176 to 180°C (dec,).

IR (Nujol) : 3300, 3200, 1780, 1730, 1680, 16.20, 1520 cm"1 NMR (DMS0-d6-D20., 5) 1,40 (15H, is), 3.08, 3.42 (2H, ABq, J»18Hz), 5,13 (IH, d, J*5Hz) , 5,40 C2H, m) , 3.80 (IH, d, J-5Hz).. .8,17 (2H, m) , 8,6.5 CIH, m) , 9,37 (2H, m) CL7 ) N- [7-{2-Cyclopentyloxyimino-2- (5-amino-l ,2,4-'thiadiazor-3-yl)acetamido}-3-cephem-3-ylmethyl]-4-carbamoylpyridi2iium-4-carboxylate (syn isomer), mp 230 to 233°C (dec-).

I.-R. (Nujol) : 3300, 3200, 177 0, 16B0, 1610, 1.560, 1520, 1510 cnf1 (X8) N- (7— (2—(2-Cyelope nten—1—yl —oxyimino )-2-(5-amino-l, 2,4-thiadiazol-3-yl ).acetamido )-3-cephem-3-ylmethyl)—4 carbamoyl-pyridinium-4—carboxylate (syn isomer). mp 155 to 160 fiC ("DEC . ) IR (Nujol)t 3300, 31-50, 1770, 1G15, 1610, 1560, 1520 cm-1 BMR (DHSO-d6, l)i 2.0-2. 4 (4H, m), 3,17-3.67 (2E, m), 5.08 (IH, d, J«5Hz), 5.23-630(6Ht m), 3.27 (2H, hroad s), £.57 (2E, d, J=7Ez), 9.53 (IS, IR (Nujol) : -3250, 2100, 1770, 1660, 1630 , 1610, 1525 cm"1 NMR (DMSO-d6, 6) : 3.10, 3.55 (2H, ABq., J-=18Hz) , 3.47 (IH, t, J=2Hz) , 4.73 (2H, d, J«2Hz) , - 5.08 (1H, d, J=5Hz) , 5.25, 5,65 (2H, ABq, J=14Hz), 5.60-5.93 (IH, m) , 8.0-8.4 (4H, m), 8.4-8.8 (IH, m) , 9.3-9/7 (3H, m) (22) 7-[2-Hydroxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyri diniome thy1)- 3-cephem-4-carboxylate (syn isomer), mp 170 to 175cC (dec,). • - IR (Nujol) t 3350., 3200, 17 80* 1620, 1530, 1490 cm"1 (23) 7--X2-Methylthiomethoxyimino-2- (5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), mp 195 to 205°C (dec.).

IR (Nujol) : 3350-3150, 1770, 1670, 1620, 1520, 1150 cm"1 NMR (DMS0-d6^D20, 6) : 2.17 (3H, s), 67 i f\ * /a, i ■ x\ a 3.00, 3.62 (2H, ABq, J-18Hz), 5.10 (1H, d, J«5Hz), 5.22 (2H, s) , 5.73 (IH, d, J=5Hz), 5.00-5.83 (2H, m), 8.13 (2H, m) , 8.53 (IH, m) , 9.33 C2H, m) (24) 7- [2-Trityloxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]- 3-CI-pyridiniomethy1)-3-cephem-4» carboxylate Csyn isomer), mp 165 to 170°C Cdec.).

IR (Nujol) : 3450, 1780, 1670, 1620, 1530, 1490 cm"1 NMR CDMSO-d6, 6) : 3.18, 3.64 C2H, ABq, J=18Hz) 5.18 CIH, d, J=5Hz), 5.34, 5.74 (2H., ABq, J-12Hz), 5.92 CIH, dd, J«=5 and 8Hz) , 7.28 C15H, s), 7.94-8.30 (4H, m), 8.42-8.66 CIH, m), 9.22-9.54 (2H, m) , 9.78 CIH, d, J=8Hz) C25) 7-£2— C2,2,2-Trifluoroethoxyimino)-2-(5-amino-l,2,4 thiadiazol-3-yl)acetamido]~3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), mp 150 to 155°C (dec.).

IR (Nujol) : 3300, 1780, 1675, 1630, 1530 cm'1 NMR (DMS0-d6+D20, 6) : 3.23, 3.50 (2H, ABq, J-18Hz), 4.63, 4.93 (2H, ABq, J=9Hz), 5.17 (IH, d, J«=5Hz) , 5.37, 5.73 (2H, ABq, J"14Hz), 5.83 (IH, d, J«5Hz), 8.1-8.4 (2H, m), 8.5-8.8 (IH, m), 9.3-9.6 (2H, m) (26) 7-[2-Ethoxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-(4 - carbamoyl-1-pyri dini ome thyl)-3-cephem-4-carboxylate (syn isomeT), mp 160 to 165°C (dec.).

IR (Nujol) : 3300, 3200, 1780, 1680, 1620, 1570, 1530 cm"1 (27) 7-[2-(2-OxotetrahydTofuran-3-yloxyimino)-2-(5- 68 amino-1,2,4-thiadiazol-3-yl)acetamio]-3-(1-pyridiniomethy1)-3-cephem-4-carboxylate (syn isomer), mp 140 to 145°C (dec.)* IR (Nujol) : 3350, 1780, 1670, 1620, 1530, 1490 cm"1 NMR (DMS0-d6+D20, 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 (1H, m) , 5.20 (IH, d, J=5Hz), 5.38, 5.73 (2H, ABq, J=13Hz), 5.87 (IH, d, J«=5Hz) , 8.07-8.43 (2H, m), 8.53-8.80 (IH, m), 9.23-9.50 (2H, m) (28) 7- [2-MethJDxyimino-2- (5-amino-l,2 ,4-thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-1-pyridiniomethyl) 3-cephem-4-carboxylate (syn isomer), mp 165 to 1700C (dec.).

IR (Nujol) : 3350, 3200, 1780, 1690, 1610, 1570, 1530 cm"1 (29) 7-[2-Propoxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]- 3-(4-carbamoyl-l-pyTidiniomethyl) 3-cephem-4-carboxylate (syn isomer), mp 170 to 175°C (dec.).

IR (Nujol) : 3350, 3200, 1780, 1690, 1610, 15 70, 1530 cm"1 (30) 7-[2-Isopropoxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)ace tami do]- 3-(4-carb amoy1-1-pyri dini ome thy1) 3-cephem-4-carboxylate (syn isomer), mp 155 to 160°C (dec.).

IR (Nujol) : 3350, 3220, 1780, 1680, 1615, 1570, 1530 cm"1 (31) 7-[2-Allyloxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-1-pyridiniomethyl) 69 3-cephem-4-carboxylate (syn isomer), mp 161 to 165°C (dec.).

IR (Nujol) : 3400-3150, 1770, 1670, 1610, 1560, 1520 cm"1 (32) 7-[2-(2,2,2-Trifluoroethoxyimino)-2-(5-amino- 1,2,4-thiadiazol-3-yl)acetamido]- 3-(4-carbamoyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), mp 160 to 165°C (dec.).

IR (Nujol) : 3300, 3150, 1780, 1680, 1610, 1580, 1520 cm"1 (33) 7-[2-Methylthiomethoxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-1-pyridiniomethy1)-3-cephem-4-carboxylate (syn isomer), mp 160 to 165°C (dec.).

IR (Nujol) : 3300, 3150, 1770, 1680, 1610, 1560, 1520 cm"1 (34) 7-[2-(2-Propynyloxyimino)-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-l-pyridiniomethy1)-3-cephem-4-carboxylate (syn isomer), mp.155 to 160°C (dec.).

IR (Nujol) : 3400, 3250, 3150, 2120, 1770, 1685, 1610, 1560, 1525 cm"1 (35) Sodium 7-[2-cyclopentyloxyimino-2-(5-amino-l,,2,4-thiadiazol-3-yl)acetamido]-3-(2-methyl-5-oxo-6- hy dro xy- 2,5 -dihydro-1,2,4-1ri az in - 3-y1)thi omethy1-3-cephem-4-caTboxylate (syn isomer), mp 169 to 174°C (dec.).

IR (Nujol) : 3600-3100, 1760, 1690, 1665, 1640., 1610, 1520, 1005 cm"1 (36) Disodium 7-[2-methoxyimino-2-(5-amino-l,2,4- 70 1 964 4 8 thiadiazol- 3-yl) acetamido] -.3-"('2 -methyl-5-oxo-6-oxido-2,5-dihydro-l,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer), mp 220 to 225°C (dec.).

IR (Nujol) : 3400-3150, 1760, 1660, 1640-1560, 1520, 1040 cm"1 (37) Disodium 7-[2-ethoxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-(2^methyl-5-oxo-6-oxido-2,5-dihydro-l,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer), mp 255 265°C (dec.).

IR (Nujol) : 3400-3150, 1760, 1660, 1600, 1500, 1400, 1030 cm'1 (38) 7- [2-(2-Cyclopenten-l-yloxyimino)-2-(5-amino-l.,2 ,4-thiadiazol-3-yl)acetamido]-3-(2-methyl-5-oxo-6-hydroxy-2,5-dihydro-l,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 158 to 164°C (dec.).

IR (Nujol) : 3450-3150, 1770, 1680, 1630, 1510, 1260, 1180, 1100, 1030, 1010 cm"1 NMR (DMSO-d6, 6) : 2.0-2.6 (4H, m) , 3.2-4.0 (2H, m), 3.62 (3H, s), 4.13, 4.45 (2H, ABq, J«13Hz), 5.13 (IH, d, J-5Hz), 5.2-5.5 (IH, m), 5.7-6.0 (2H, m) , 6.0-6.2 (IH, m) , 8.20 (2H, broad s) , 9.50 (lH,#d, J«8Hz) (39) 7-[2-Isopropoxyimino-2-(5-amino-l,2,4-thiadiazol- -3-yl)acetamido]-3-(2-methyl-5-oxo-6-hydroxy-2,5-dihydto-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 160 to 167®C (dec.).

IR (Nujol) : 3400, 3280, 3180, 1780, 1770, 1630, 1515, 1410, 1240, 1009 cm"1 f O f r * - • I 4 ^ is 71 NMR (DMSO-d6 + D20> 6) : 1.27 (6H, d, J<=6Hz) , 3.62 (3H, s), 3.5-3.9 (2H, m) , 4.13, 4.41 (2H, ABq, Je14Hz), 4.40 (IH, t, J=6Hz), .17 CIH, d, J«5Hz) , 5.83 (IH, d, J«=5Hz) (40) 7-[2-(2-Propynyloxyimino)-2-(5-amino-l,2,4- th i a di a z o 1 - 3 - y 1) a ce t ami do]-3-(2-methy1- 5-oxo-6 -hydroxy-2,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 161 to 166°C (dec.).

IR (Nujol) : 3260, 3180, 1770, 1670, 1620, 1520, 1335 cm"1 NMR (DMS0-d6+D20, 6) : 3.48 (IH, s), 3.61 (3H, s), 3.3-3.9 (2H, m), 4.10, 4.38 (2H, ABq, J-14HZ), 4.77 (2H, s), 5.12 (IH, d, J-5Hz), 5.78 (IH, d, J«5Hz) (41) 7-[2-Allyloxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)ace tami do]-3-(2-methyl-5-oxo-6-hydroxy-2,5-dihy dro-l,2,4-triazin-3-yl)thi omethy1- 3-cephem-4 -carboxylic acid (syn isomer), mp 169 to 173°C (dec.).

IR (Nujol) : 3360, 3210, 1775, 1670, 1625, 1560, 1520, 1250, 1175, 1100, .1020 cm"1 NMR (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 (IH, d, J-5Hz), 5.0-5.6 (3H, m), 5.81 (IH, dd, J=5 and 9Hz), 8.18 (2H, broads), 9.53 (IH, d, J=9Hz) i 9 6 72 .Example 5 A mixture of 7-[2-cyclopentyloxyimino-2-(5-amino--1,2,4-thiadiazol-3-yl)acetamido] cephalosporanic acid Csyn isomer) (5.1 g) , sodium bicarbonate (.84-0 mg) , water ~ C50 ml), potassium thiocyanate {24.5 g) and isonicotinamide (1- S3 g) was stirred for 22 hours at SO to 55 ° C, 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 residue was subjected to column chromatography (non-ionic adsorption resin, Diaion HP20 prepared by Mitsubishi Chemical Industries) and the column was washed with water (0.7 &} andt&sn eluted with 30% aqueous methanol (0-7 jl) „ The eluates containing the object compound were collected^ washed with ethyl acetate and then evaporated.

The residue was lyophilized to give N-I7~{2- cyclopentyloxy imino-2- (3-amino-1,2,4-thiadiazol-3-♦ yl) acetamido}-3- cepbem-3-yimethyl3 -4carbamoyl-pyridinium-4-carboxylate (syn isomer) (1- 0 g) , mp 230 to 235®C (dec.).

I.R. (Nujol) - 3300, 3200, 1770, 16B0., 1610, 1560, 1520, 1310 cm'1 N.M.R. (d6-3)MSO, 6) 1.30-1.93 (8H, m), 3,13 and 3,30 (2H, ABq, J~18Hz), 3.60-3-75 (IH, m) , 5.06 (IH, d, J«4H2), 5.30 and 5.65 (2H, ABq, J-14Hz), 5.70 (IH, dd, J«4 and BH2) , 8.12 (2H, s) , :8.45 (2H, d, J-6Hz) , 9.42 (2H, d, J-6Hz), 9-30 (IH, d, J«=8Hz) 1 964 4 8 Example 6 ^ fT?'031®] N—rr-C-COHN") + N^S^|I d^-N-Y^LCH2OCOCH2COCH3—►N-^ Jfcj J-Nxs^CH2^0 H2 N\ __ COOH H2 N 0 | . \)-^j co° A mixture of 7-[2-cyclopentyloxyi mi no- 2-(.5-amino-10 l,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer) (2,8 g) , sodium bicarbonate (420 mg), potassium iodide (28 g) and pyridine (5 90 mg) in water (28 ml) "was stirred for one i hour at 55°C. After cooling., ethyl acetate (20 ml) , IS : IN hydrochloric acid (5.5 ml) and acetone (10 ml) were added thereto undeT stirring. The aqueous layer was separated out, washed with ethyl acetate and concentrated to 30 ml under reduced pressure. An insoluble substance was filtered off and the filtrate was -sub-20 I jected to column chromatography on a non ionic adsorption resin, Diaion HP20 (100 ml). After the column was washed with wateT (500 ml), the elution was carried out with 30% aqueous methanol.. The eluates containing a object compound were collected, evaporated to remove 25 mei^ianol undeT reduced pressure -and lyophilized to give N- [7- {2-cyclopentyloxy imino-2- (5-amino-l ,2 ,4-thiadiazol-3-yl )acetamido } - 3-cephem-3-ylmethyl ] pyridinium-4-carb.oxyla.te (syn isomer) (620 mg) , white, powde.r , mp. 1B0 to 185®C (dec.,)., IH (Nujol) : 3300, 3200, 1780, 167D, 1620* 1530 -cm"1 NMR (DMSO-dg, 6) : 1,4-2,0 (8H, m), 3.17 3.. 53 (2H, ABq, J«18Hz).f 4,60-4.33 (1H„ m) , 5,10 (IH, d., J»4H:z) , 5 . 30 ,5 . 8 3 (2H, ABq, 35 J-14Hz)., 5. 8 7 (IH, 2d, J«4 and SHz) , 8.17 74 §. n (2H, s), .9. 50 CIH, d, J=8Hz),' 8.0-9 . 7 CSH, m) Example 7 The following compounds were obtained according to similar manners to those of Examples 5 and -6+ CI) N- [7-{2-C2-Cyclopenten-l-yloxyimino)-2-C5- amino-1,2,4-thiadi a zol-3-yl)acetamido}-3-cephem-3-ylmethyl] pyridinium- 4- carboxylate Csyn isomer)., mp. 190 to 195*C Cdec,)- I.R. CNujol) : 3350,3200,1780,1660.,1:620,1530 cm"' (.2) N-[7-{2-(t--Butoxycarbonylmethoxyimino)-2-(5-amino -1,2,4 - thi a diaz o 1 - 3 - y 1) a ce tamido } - 3 - c ep hem-3-ylmethyl]pyridinium-4-carboxylate Csyn is omer) , mp.. 150 to .15.5°C (dec.).- 3, R. CNujol) : 3300, 3200, 1770, 1680., 1620., 1530 cm"1 C3) N-[7-{2-£arboxymethoxyimino-2-C5-amino-l,2,4-thia diaz o1-3-y1)ac e tami do } - 3 -c ephem - 3 -ylmethyl ] -pyridinium-4-carboxy!ate Csyn isomsT) , mp.150 to 15 5° C Cdec.) .

I.R. CNujol) : 3350, 3200, 1780, 1680, 1530 cm"1 (4) N- [7-{2- Cy clopentyloxyimino-2- (5-amino-l.,2,4-. thiadiazol -3-yl) acetamido } -3-cephem-3-ylmethyl] -pyridinium-4-carboxylate Csyn isomeT), mp.. 180 to 185 °C (dec.).

I.R. CNujol) : 3300, 3200, 1780, 1670, 1620, 1530 cm"1 -75 - f L N.M.R. CDMSO-d6,6) : 1.4-2.0 (8H, m), 3.17, 3.53 (2H, ABq, J»18Hz) , 4.60-4.83 (IH, m) , 5.10 (IH, d, J«4Kz), 5.30 and 5.83 (2H, ABq, J=14Hz), 5.87 (IH, dd, J«4 and 8Hz) , 5 8.17 (2H, s)., 9.50 (IH, d, J=8Hz), 8.0-9.7 (5H, m) (5) N- [7-{2- (l-Carhoxyethoxyimino)-.2- (5-amino-l,2,4-thiadiaz o 1 - 3 - y 1) acetamido } - 3 - c ep hem - 3 -ylme thy 1 ] -41 -10 carbamoylpyridinium-4 - carboxylate (syn isomer)* mp. 170 to 175°C (dec.).

I.R. (Nujol) : 3300, 3160, 1770, 1680, 1610, 1560, 1520 cm"1 15 N.M.R. (DMSO-d6,S) : l-3'8 (3H, d, J»7Hz) , 3.10-3-6 0 (2H-, m) , 4.40-4.83 (IH, m) , 5.10 (IH, d, J«5Hz), 5.28-6.00 (3H, m) , 8.22 (2H, broad s), 8.48 (2H, d, J»6Hz), 9.48 (2H, d, J«6Hz), 9.32-9.65 (IH, m) A (6) N-[7-{2-(1-t-Butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate (syn isomer)., mp. 160 to 165°C (dec.).

I.R, (Nujol) : 32S0, 3160, 177:0, 1725, 1670, 1620, 1525 cm"1 (7) N- [7 - { 2- (1- Carboxyethoxyimino) -2 -_(5-amino-30 1,2,4-thiadiazol-3-yl) acetamido}-3-cephem-3- ylmethyl] pyridinium-4-carboxylate (syn isomer),, mp. ' 175 to 180®C (dec.). 3.5.

I.R. (Nujol) : 330.0,, 3200, 1775, 1670, 1620, 152 0 cm"1 "78" (8) N- [7- {2- (1-Benzyloxycarbonylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido }.-3-cephem-3-ylmethy1]pyridinium-4-carboxylate (syn isomer), mp. 178 to 182cC (dec.).

I.R. (Nujol) : 3250, 3150, 1770, 1670, 1620, 1520 cnf1 (9 ) N- [7- {2-Ethoxycarbonylmethoxy.iTnino-2- (5-amino-1,2,4-thiadia20l-3-yl) acetamido }-3-c-ephem-3-ylmethyl] -10 pyridinium-4-carboxylate (syn isomer)* mp. 184 -to 188"°C (dec.).

I.R-. (Nujol) : 3400-3100-, 1770., 1670, 1610, 1520 cm" HO) N-[7- {2-(2-Cyclohe xen-1-yloxyimino)- 2-(5-amino-IS 1,2,4-thiadiazol-3-yl)acetamido}-5-cephem-3- ylmethyl]pyridinium-4-caTboxylate (syn isomer) , mp. 150 to 155°C (dec,).

IR (nujol) 3300., 32 0 0, 1775, 16 6 0., 1610,1520 xat (13.) N-[7- (2-Carboxymethoxyimino-2- (5-amino-l ,2,4-20 thiadiazol-3-yl)acetamido>-3-cephem-3-ylmethyl]- 4'-carbamoylpyridinium-4-carboxylate (syn isomer), mp.175 to 180cC (dec.).

IR (Nujol) : 33SO., 3200, 1775, 1680., 1615, 1565, .1525 cm"1 25 NMR (DMS0-d6~D20, 6) : 3.23,3.55 (2H:, ABq,, J-18HZ), 4.67 (2H, 5), 5.10 (IH, <*., J«5Hz) ,. 5.-35 , 5 . 72 (2H, ABq, J-15Hz) , .80 (IH., d, J»5Hz) , 8,43 (2H, d, J-6Hz), 9.38 (2H, d, J=6Hz) 50 (12) N-[7-{2-Methoxycarbonylmethoxyimino-2-(5-amino-1,2 ,4- thiadiazol- 3-yl) acetamido }-3-.cephem-3-ylmethy1]pyridinium-4-carboxylate (syn isomer), mp.165 - 170°C (dec.).

IR (Nujol) : 3300-3150, 1760, 1670, 1620, 25 1520 cm"1 (13) N- [7-{ 2- (1-Methyl-1-carboxyethoxyimino) -2-(5-amino-1,2 ,4-thiadiazol-3-yl)acetamido) - 3-cephem-3-ylmethyljpyridinium-4-carboxylate (syn isomer), white powder, mp. 176 to 180°C (dec.).

IR (Nujol) : 3400-3150, 1770, 16 70., 162.0, 1520 cm'1 (14 ) N- [7- { 2- (1 -Methyl-l~ethoxycaxhonylethoxyi-mino) -2-(5-amino-1,2,4-thia diazol-3-yl)ace tamido}-3-cephem- 3- ylme thyl ] pyri dinium-4 - carb oxyl ate (syn isomer), white powder* mp. 164 to 168 °C (dec.).

IR (Nujol) : 3350-3150, 1770, 1720, 1670, 1620, 1520 cm"1 .15 ) N-[7-{2-(1-Methyl-l-t-butoxycarbonylethoxyimino)-^ 2- (5-amino-l ,2,4-thiadiazol-3-yl)acetamido)-3- cephem-3-ylmethyl]pyridinium-4-.carboxylate (syn isomer), mp. 17.6 to 180°C (-dec,)- IR (Nujol) 3300, 3200, 1780, 1730, 1680, 1620, 1520 cm"1 (16 ) N-(7-(2-(2-Cyclopen ten-l-y 1—oxy imino)-2— (5-amino-l, 2,4-thiadiazol-3-yl)acetamido)-3-cephem-3-ylmetbyl )—4 carbamoyl-pyridinlunt-4-carboxylate (syn isomer). mp 155 to 160 eC (DEC.) IR (Nujol): 3300, 3150, 1770, JL675, 1-610, .1560, 1520 cm~l HMR (LHSO-dg, £ ): 2-0-2.4 (4H, a), 3-17-3. 67 (2E, m), 5.08 (IH, d, z)+ 5.23-6.30(6H, m)* 8.27 (2E* broad s), 8.57 (2E, d* JaTEz)* 9.53(XE, d, 9.70(2H, At J~7Hz) (17) N— (7- (2- (1—Methyl-l-carboxyethoxyimi.no )-2- (5-amino-1,2,4- thiadiazol-3-yl )acetamido)—3-cepheiB-3-ylmethyl )— 4'—carbamoyl— pyridinium—4—carboxylate (syn isomer) mp 18 0 to 185 °C (DEC. ) IR (Nujol): 3300, 1770, 1680, 1620, 1560, 1520 cm-1 -78" 1 96 4 4 8 (18) 7' [2-8thoxyimino-2-(5-amino-l,2 ,4-thiadiazol-3-yl) acetamido] -3- (1-pyri dini ome thyl) -3-cephem-4-carboxylate (syn isomer) , mp. 155 to 165cC (dec,).

IR (Nujol) : 3400-3130, 1770, 1660, 1610, 1530 an"1 (19) [2-Propoxyimino-2- (5-amino-l.,2 ,4-thiadiazol-3-yi) acetamido] -3- (1-pyridiaioaethyl)-3-cephem-4-carboxylate (syn isomer), mp. 230 to 240°C (dec,). IR (Nujol) ; 3400-3200, 1770, 1670-1600, 153 Oof1 C20 ) 7 - [ 2 - Me thoxylmino-2 - (5 - amino-1,2,4- thiadiazol - 3 -y 1)acetamido] - 3 - (1 -PTridinicmeuhyi)-3-cephem-4— - carboxylate (syn isomer)., mp. 250 to 260eC (dec.). XR (Nujol) : 3400-3100, 1770, 1650, 1610, 1520 cm"1 (2i) 7- [2-15oproporyimin0-2- (5-a.mino-l,2,4-thiadiazol- 3-yl)ace tami do ]-3-(1-pyri diniomethyl)-3 -cephem- 4-carboxylate (syn isomer), mp, 160 to 165°C (-decO-IR (Nujol) 3270., 3180, .1770., 2.660., 1610, 1523 cm"1 79 (22) 7-[2-Allyloxyimino-2-(5-amino-l,2,4-thiadiazol-3 yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), mp 160 to 165°C (dec.) IR (Nujol) : 3290, 3180, 1770, 1660, 1610, 1525 cm"1 (23) 7-[2-(2-Propynyloxyimino)-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyTidiniomethyl) 3-cephem-4-carboxylate (syn isomer), mp 145 to 150°C (dec.).

IR (Nujol) : 3250, 2100, 1770, 1660, 1630, 1610, 1525 cm"1 (24) 7-[2-Hydroxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), mp 170 to 175°C (dec.) IR (Nujol) : 3350, 3200, 1780, 1620, 1530, 1490 cm"1 (25) 7-[2-Methylthiomethoxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl) 3-cephem-4-carboxylate (syn isomer), mp 195 to 205°C (dec.).

IR (Nujol) ; 3350-3150, 1770, 1670, 1620* 1520, 1150 cm"1 (-26) 7- [2-Trityloxyimino-2- (5-amino-l,2 ,4-thiadia20l-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4 carboxylate (syn isomer), mp 165 to 1706C (dec.) IR (Nujol) : 3450, 1780, 1670, 1620, 1530, 1490 cm"1 (2 7) 7-[2-(2,2,2-Trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn 80 isomer), mp 150 to 155°C (dec.).

IR (Nujol) : 3300, 1780, 1675, 1630, 1530 cm (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 to 165°C (dec.).

IR (Nujol) : 3300, 3200, 1780, 1680, 1620, 1570, 1530 cm"1 NMR (DMS0-d6+D20, 6) : 1.33 (3H, t, J«7Hz), 3.33, 3.67 (2H, ABq, J«18Hz), 4.35 (2H, q, J=7Hz), 5.30 (IH, d, J«4Hz), 5.47, 5.67 (2H, ABq, J=14Hz), 5.90 (IH, 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-th.iadiazol-3-yl) acetamido]-3- (1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), mp 140 to 145°C (dec.).

IR (Nujol) : 3350, 1780, 1670, 1620, 1530, 1490 cm"1 (30) 7-[2-Methoxyimino-2-(5-amino-l,2,4-thiadiazol-3 yl)acetamido]-3-(4-carbamoyl-l-pyridiniomethyl) 3-cephem-4-carboxylate (syn isomer), mp 165 to 170°C (dec,).

IR (Nujol) : 3350, 3200, 1780, 1690, 1610, 1570, 1530 cm"1 NMR (D20, 6) : 3.33, 3.67 (2H, ABq, J=18Hz), 4.07 (3H, s), 5.30 (IH, d, J=4Hz), 5.47, 5.67 (2H, ABq, J«14Hz), 5.90 (IH, d, J=4Hz) , 8.40 (2H, d, J«=7Hz) , 9.17 (2H, d, J=7Hz) 1 96 4 81 (31) 7-[2-Propoxyimino-2-(5- amino-1,2,4-thiadiazol-3-yl)acetamido]- 3-(4-carbamoyl-l-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), mp 170 to 175°C (dec.).

IR (Nujol) : 3350, 3200, 1780, 1690, 1610, 1570, 1530 cm"1 NMR (D20, 6) : 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 (IH, d, J-4Hz) , 5.47, 5. 70 (2H, ABq, J-14Hz) , 5.92 (IH,, d, J-4Hz), 8.42 (2H, d, J=7Hz), 9.17 (2H, d, J=7Hz) (32) 7-[2-Isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-l-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), mp 155 to 160°C (dec.).

IR (Nujol) : 3350, 3220, 1780, 1680, 1615, 1570, 1530 cm"1 NMR (DMS0-d6+D20, 6) : 1.22 (6H, d, J»6Hz) , 3.17, 3.48 (2H, ABq, J=18Hz), 4.1-4.6 (IH, m), 5.03 (.IH, d, J«5Hz), 5.25 , 5.63 (2H, ABq, J-14HZ), 5,70 (IH, d, J-SHz), 8.40 (2H, d, J=6Hz), 9,45 (2H, d, J=6Hz) (33) 7-[2-Allyloxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3r(4-carbamoyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomeT), mp 161 to 165°C (dec.).

IR (Nujol) : 3400-3150, 1770, 1670, 1610, 1560, 1520 cm"1 NMR (DMS0-d6+D20, 6) : 3.09, 3.50 (2H, ABq, J-18Hz), 4.5-4.7 (2H, m) , 4.9-5.4 (4H, m), 5.06 (IH, d, J«5Hz), 5.6-6.1 (IH, m) , 5.71 (IH, d, J«5Hz) , 8.43 (2H, d, J«6Hz), 9.50 s 82 (2H, d, J»6Hz) (34) 7-[2-(2,2,2-Trifluoroethoxyimino)-2-(5-amino- 1,2,4-thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-1-pyridiniomethyl)-3-cephem-4-carboxylate Csyn isomer), mp 160 to 165°C (dec.).

IR CNujol) : 3300, 3150, 1780, 1680, 1610, 1580, 1520 cm'1 NMR CD2°» 6) : 3.30, 3.67 C2H, ABq, J»17Hz), 4.73, 4.97 C2H, ABq, J«=8Hz) , 5.30 CIH, d, J=4Hz) , 5.47, 5. 67 C-2H, ABq, J=14Hz), 5,92 CIH, d, Jc4Hz), 8.40 C2H, d, J=7Hz), 9.20 C2H, d, J=7Hz) C35) 7-[2-Methylthiomethoxyimino-2-C5-amino-l,2,4- -thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-l-pyridiniomethyl)-3-cephem-4-carboxylate Csyn isomer), mp 160 to 165°C (dec.).

IR CNujol) : 3300, 3150, 1770, 1680, 1610, 1560, 1520 cm"1 NMR CDMS0-d6+D20, 6) ; 2.23 (3H, s), 3.15, 3.67 (2H, ABq, J«=18Hz) , 5.17 (IH, d, J=5Hz) , 5.32 (2H, s), 5.00-5.57 C2H, m), 5.80 CIH, d, J«5Hz), 8.68 (2H, d, J=6Hz), 9.50 (2H, d, J-6Hz) C36) 7- [2- C2-Propynyloxyimino)-2- C5-amiTio-l,2 ,4-thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-l-pyridiniomethyl)-3-cephem-4-carboxylate Csyn isomer), mp 155 to 160°C Cdec.).

IR CNujol) : 3400, 3250, 3150, 2120, 1770, 1685, 1610, 1560, 1525 cm"1 NMR CDMS0-d6+D20, 6) : 3.23, 3.58 C2H, ABq, J=18Hz), 3.45 CIH, t, J=2Hz), 4.80 C2H, d, J«=2Hz) , 5.13 CIH, d, J«=5Hz) , 5.35, 5.72 83 1 (2H, ABq, J-14HZ), 5.78 (IH, d, J=5Hz), 8.47 (2H, d, J"7Hz), 9.50 (2H, d, J=7Hz) Example 8 .5 7- [2-Cyclopentyloxyimino-2- (5-amino-l ,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 according to similar manners to those- of Examples 10 5 and 6 to give sodium 7-{2-cyclopentyloxyimino-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-carboxylate (syn isomer), mp 169 to 174°C (dec.)« IR (Nujol) : 3600"- 3100, 1760, 1690, 1665, 15 1640, 1610, 1520, 1005 cm"1 NMR (D20+NaHC03, 6) : 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 (IH, m) , 5.22 (IH, d, J«=5Hz) , 5.80 (IH, d, J-5Hz) Example 9 The following compounds were obtained according to similar manners to those of Examples 5, 6 and 8. (1) Disodium 7- [2-methoxyimino-2- (5-amino-l.,2,4-25 thiadiazol-3-yl)acetamido]-3-(2-methyl-5-oxo-6- oxido-2,5-dihydro-l,2,4-1 ria z in-3-y1)thi ome thy1-3-cephem-4-carboxylate (syn isomer), mp 220 to 225°C (dec.).

IR (Nujol) : 3400-3150, 1760, 1660, 1640-1560, 30 1520, 1040 cm'1 NMR (D20, 6) : 3.64 (3H, s), 3.48, 3.78 (2H, ABq, J=18Hz), 4.08 (3H, s), 4.00-4.56 (2H, m), 5.20 (IH, d, J=5Hz), 5.82 (IH, d, Jc5Hz) V w 84 (2) Disodium 7-[2-ethoxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]- 3-(2-methyl-5-oxo- 6 - oxi do - 2,5 - dihydro-1,2,4 -1 ri az in - 3 - y 1) thi ome thyl -3-cephem-4-carboxylate (syn isomer), mp 255 to _5 265°C (dec.).

IR (Nujol) : 3400-3150, 1760, 1660, 1600, 1500, 1400, 1030 cm"1 NMR (D20, 6) : 1.35 (3H, t, J«7Hz), 3.42, 3.80 (2H, ABq, J-18HZ), 3.65 (3H, s), 4.07, 4.43 10 (2H, ABq, J-13Hz), 4.38 (2H, q, J«7Hz), .22 (IH, d, J«5Hz), 5.83 (IH, d, J=5Hz) (3) 7-[2r (2-Cyclopenten-l-yloxyimino)-2-(S-amino-l^^-thiadiazol-S-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), mp 158 to 164°C (dec.).

IR (Nujol) : 3450-3150, 1770, 1680, 1630, 1510, 1260, 1180, 1100, 1030, 20 1010 cm"1 (4) 7-[2-Isopropoxyimino-2-(5-amino-l,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), mp 160 to 167cC (dec.).

IR (Nujol) : 3400, 3280, 3180, 1780, 1770, 1630, 1515, 1410, 1240, 1009 cm"1 (5) 7-[2-(2-Propyny!oxyimino)-2-(5-amino-l ,2.,4- thiadiazol-3-yl)acetamido]-3-(2-methyl-5-oxo-6- hydroxy-2,5-dihydro-l,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 161 to 166°C (dec.).

IR (Nujol) : 3260, 3180, 1770, 1670, 1620, 35 1520, 1335 cm"1 1 96 4 85 (6) 7- [2-Allyloxyimino-2- (5-amino-l ,2,4-thiadiazol-3-y1)ace tami do]- 3-(2-methyl- 5-oxo-6-hydroxy- 2,5-dihydro-1,2,4-tTiazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 169 to 173°C 5 (dec.).

IR (Nujol) : 3360, 3210, 1775, 1670, 1625, 1560, 1520, 1250, 1175, 1100, 1020 cm"1 86 A $ ' ^ 3 Example 10 To a solution of N-[7-{2-t-butoxycarbonylmethoxyimino- 2-(5- amino-1,2,4-1hi adiaz o1-3-y1)acetami do}-3-cep hem- 3-ylmethyl]pyridinium-4-carboxylate (syn isomer)(1.8 g) 5 in formic acid. CIS ml) was added conc. hydrochloric acid (0.5 ml) and the mixture was stirred foT one hour at room temperature. The solvent was distilled off under reduced pressure and the residue was pulverized with acetone, collected by filtration, washed with 10 acetone and diisopropyl ether to give a powder. The powder was. dissolved in wateT (3 ml) and subjected to column chromatography on a non ionic adsorption resin Diaion HP 20 (Trademark, prepared by Mitsubishi Chemical Industries) (50 ml) . After the column was -washed with 15 water (5 00 ml), the elution was carried out with 40% aqueous methanol. The eluates contain in gan abject compound aiexe - r.oll -ecte.d,.. evaporated to remove methanol under reduced pressure and lyophilized to give white powder of N-[7-{2-caTboxymethoxyimino-2-(5-amino-l,2-,4-20 thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]- pyridinium-4-carboxylate (syn isomer)(800 mg), mp, 150 to 155°C (dec.).

I.R. (Nujol) : 3350., 3200, 17.80, 1.680, 1530 cm*1 N.M.R. (D20+NaHC0-, o) .: 3.27 and 3.63 (2H, ABq, .

J*18Hz), 4,70 (2H, s) , 5.30 (IH, d, J«4Hz), 5,40 and 5,60 (2H, ABq, J«14Hz), 5-93 (IH, d, J«4Hz), 8.0-9.1 (5H, m) Example 12 h2 s" C-C07^o COO' \ CH3 .CH3 O-C-COOC-CH, .to, CH- J N.

Ho S . -co: \ CH, \ I o O-C-COOH ■ii- coo .87 To a cold, mixture of trifluoroacetic acid (22 ml) and anisole (4.4 ml) was added N- [7-{2-(1-methyl-1-t-butoxycarbonylethoxyimino)- 2-(5-amino-l ,2,4-thiadiazol - 3 - yl) ace tami do } - 3- cephem - 3 - ylmethyl ] -pyridinium-4- carb oxy late (3.18 g) and the mixture was s-tirred for 40 minutes at Toom temperature.. The mixture was evaporated, to remove trifluoroacetic acid and the residue was triturated with isopropyl ether to give- a yellowish powder. The powdeT was dissolved, in an aqueous sodium bicarbonate, adjusted to pH 1 with 6N hydrochloric acid, and washed with ethyl acetate.. The aqueous solution was subjected to a column chromato graphy on a non ionic adsorption resin,. Diaion HP-20 C14-0 ml)After the column was washed with water, the elution was carried out with 5% and 10$ aqueous isopropyl alcohol. The eluates containing an object compound were collected, evaporated "to remove isopropyl. alcohol under reduced pressure and lyophilized to give N-[7-■^-(l-methyl-l-carboxyethoxyimino) -2-(5-amino-l,2,4-thiadiazol-3-yl) acetamido }-3-cephem-3-ylme thyl]pyridini um-4-carboxylate (syn isomer) (2.20 g), white powder., mp. 176 to 180°C (dec.).

IR (Nujol) : 3400-3150, 1770, 1670, 1620, 1520 cm"1 NMR (DMSO-d6+D20, 6) : 1.48 (6H, s), 3,10, 3.62 (2Kf ABq, J-l-8Hz) , 5.12 (IH, d, J-5Hz), 5.45 (2H, m), 5.78 (IH, d, J»5Hz), 8.13 (2H, m) , 8.58 (IH, m) , -9.38 (2H, m) Example 12 The following compounds were prepared according to the similar manners to those of Examples 10 and •88" (1) N - [7- {2- (1-Carboxyethoxyimino) -2- (5-amino-l f 2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]- 4'-5 carbamoylpyridinium-4-carbo.xy.late (syn isomer) , mp. 170 to 175DC (dec.).

I.R. (Nujol) : 3300, 3160, .1770, 1680, 1610, 1560, 1520 cm"1 (2) N-[7-{2-(1-Carboxyethoxyimino)-2-(5-amino-l ,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium 4-carboxylate (syn isomer), mp. 175 to 180°C (dec-).

I.R. (Nujol) : 3300., 3200, 1775, 167.0., 1620,, 1520 an"1 N.M..R. (D20+NaHC03.,6) : 1-50 (3H, d, J«7Hz), .3.25 and 3.67 (2H, ABq, J»18Hz) , 4.40-4.90 (IH, m), 5.32 (IH, d., J«5Hz), 20 5.42 and 5.60 (2H, ABq, J«15Hz), 5.83- 6.00 (IH, m), 7.9-9.1 (5H, m) (3) N-[7-{2-Carboxymethoxy imino-2-(5-amino-l,2,4- thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-caTbamoylpyridinium-4-carboxylate (syn isomer), 25 mp.■175 to 180°C (dec.).

IR (Nujol) : 3350, 3200, 1775, 1680, 1615, 1565,, 1525 cm"1 (4 ) H-[ 7—£2- (1—Methyl-l—carboxyethoxyimino )-2- (5-amiao-1» 2 f 4-thiacLiazol—3-yl )acetamido]-3-cephem-3-ylmethyl] -30 4'—carbamoylpyridiniuiD-4—carboxylate (syn isomer) , mp. 180 to 185°C (dec.).

IH (Nujol); 3300, 1770, 1680, 1620, 2560, 1520 cm"1 89 Example 13 A mixture of 7-[2-trityloxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer)(5.55 g) and concentrated hydrochloric acid (2.3 ml) in formic acid (60 ml) was stirred for two hours at ambient temperature.

After an insoluble material was filtered off, the filtrate was evaporated to dryness and the residue was pulverized with acetone and collected by filtration. The powder was dissolved in water (13 ml) and subjected to column chromatography on a non-ionic adsorption resin Diaion HP20 (Trademark, prepared by Mitsubishi Chemical Industries) (100 ml), using water as an eluent. The eluates containing an object compoimd were collected and lyophilized to give yellowish white powder of 7-[2-hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (675 mg), mp 170 to 175°C (dec.).

NMR (DMS0-d5+D20, 6) : 3.14, 3.54 (2H, ABq, J=18Hz), 5.08 (IH, d, J=5Hz), 5.28, 5.62 (2H, ABq., J=12Hz) , 5.86 (IH, d, J=5Hz), 7.96-8.24 (2H, m), 8.40-8.68 (IH, m), 9.16-9.42 (2H, m) IR (Nujol) : 3350, 3200, 1780, 1620, 1530 1490 cm"1 Example 14 HC1 COOH SCN® N—t—C-CONH- C- CONH- COOH 90 To a cold solution of phosphorus.- pentachloride (20.8 g) in methylene chloride (375 ml) was added 2-(2-cyclopenten-l-yloxyimino)-2-(5-amino-l,2,4-th.iadiazol-3-yl)acetic acid (syn isomer)(25.4 g) at -18°C and the mixture was stirred for 40 minutes at -12 to -10°C.

To the reaction mixture was added diisopropyl ether (1.2 Jl ) below -10°C under stirring, which 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. On the other hand, a mixture of 1-[(7-amino-4-carboxy-3-cephem-3-yl)-methyl]pyridinium chloride hydrochloride dihydrate (30.77 g) and trimethylsilylacetamide (154.5 g) in methylene chloride (800 ml) was warmed at 35°C to make a solution, which was cooled to -18°C. To the cold solution were added the precipitates prepared above and the mixture was stirred for 30 minutes at -12 to -10°C. A solution of sodium bicarbonate (26 g) in water (400 ml) was added to the reaction mixture and the aqueous layer was separated out, 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 acidic alumina (117 g). To the eluate (1.2 I) were added potassium thiocyanate (56.2 g) and sodium chloride (171.5 g) and then the mixture was adjusted to pH 2.6 with IN hydrochloric acid under cooling in an ice-bath. After an insoluble material was filtered off, sodium chloride (171.5 g) was added to the filtrate and the solution was adjusted to pH 1.6 with IN hydrochloric acid under stirring and cooling in an ice-bath. The resulting precipitates were filtered, washed with cold water (2 x 150 ml) and dried to give l-[[7-{2-(2-cyclopenten-l-yloxyimino)-2-(5-amino-1,2,4-thiadiazol- 91 3-yl) ace tami do)-4-carboxy-3-cephem- 3-yl] methyl] -pyridinium thiocyanate (syn isomer)(28.1 g), mp 151 to 156°C (dec.).

IR (Nujol) : 2050, 1780, 1670, 1630, 1610, 1530 cm"1 NMR (DMS0-d6+D20, 6) : 1.6-2.7 (4H, m) , 3.33, 3.66 (2H, ABq, J=l8Hz), 5.20 (IH, d, J=5Hz), 4.9-6.3 (5H, m) , 5.86 (IH, d, J«=5Hz) , 8.2 (2H, m), 8.7 (IH, m) , 9.15 (2H, m) Example 15 1-[[7-{2-(2-Cyclopenten-l-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido)-4-carboxy-3-cephem-3-yl]methyl]pyridinium iodide (syn isomer) was obtained according to a similar manner to that of Example 14 by using sodium iodide instead of potassium thiocyanate. IR (Nujol) : 3400-3100, 1775, 1670, 1620, 1520 cm"1 NMR (DMS0-d6+D20, 6) : 1.6-2.8 (4H, m), 3.35, 3.80 (2H, ABq, J«=l9Hz), 5.31 (IH, d, J«5Hz) , 5.93 (IH, d, J»5Hz), 5.0-6.4 (5H, m), 8.28 (2H, m), 8.74 (IH, m) , 9.15 (2H, m) Example 16 To a solution of 1-[[7-{2-(2-cyclopenten-l-yloxyimino)-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido}- 4-carboxy-3-cephem-3-yl]methyl]pyridinium thiocyanate (syn isomer)(11.7 g) in dimethylformamide. (30 ml) was added a solution of lithium chloride (1.7 g) in methanol (20 ml) under stirring, which was continued for 10 minutes at ambient temperature. An insoluble material was filtered, washed with dimethylformamide (6 ml) and then the filtrate and the washings were combined.

The combined solution was added to acetone (300 ml) under stirring, which was continued for five minutes 92 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-l,2,4-thiadiazol-3-yl)acetamido)-4-carboxy-3-cephem-3-yl]methyl]pyridinium chloride (syn isomer)(11. 0 g).

IR (Nujol) : 3400-3100, 1780, 1660, 1630, 1530 cm"1 NMR (DMSO-dg, 6) ; 1.6-2.6 (4H, m), 3.39, 3.61 (2H, ABq, J-18HZ), 5.19 (IH, d, J«5Hz), 4.9-5.6 (2H, m), 5.64 (IH, broad s), 5.81 (IH, dd, J«5 and 8Hz), 5.7-6.2 (2H, m) , 8.20 (2H, m), 8.64 (IH, m), 9.22 (2H, m), 9.48 (IH, d, Jb8Hz) 93 Example 17 To a solution of sodium iodide (10 g) and pyridine (1.28 g) in formamide (8 ml) was added sodium 7-[2-ethoxyimino-2-(5-amino-l,2,4-thiadiazol -3-yl)acetamido]-cephalospo- ranate (syn isomer) (4.0 g) at 75°C under stirring, * * which-was continued for 1.5 hours at 80 to 85°C. The mixture, was "cooled to ambient temparature and poured into ethanol (100 ml). A resulting precipitate was collected by filtration and an additional one was • obtained from the filtrate by an addition of diisopropyl ether (100 ml)♦ These precipitates were dissolved in water (50 ml) 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 a non-ionic adsorption resin Diaion HP-20 (Trademark, prepared by Mitsubishi Chemical Industries) (160 ml).

After the column was washed with water, tJie elution was carried out with 30 % aqueous methanol- The eluates containing an object compound were collected, evaporated to remove methanol under reduced pressure and lyophilized to give white powder of 7-[2-ethoxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-(1— pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (1.52 g), mp. 155 to 165°C (dec)- IR (Nujol): 3400-3150, 1770, 1660, 1610, 1530 cnf1.

ExampTe 18 CPurification of the object compound) A powder CO.2 g) of 7-[2-eth.oxyimi.no-2-(5-amino*-1,2,4-thiadiazol-3-yl)acetamido]-3-Cl-pyridiniomethyl)-3-cephem-4-carboxylate Csyn isomer) was dissolved in water CO.8 ml) and dropped acetone Q..6 ml) thereto under stirring at ambient temperature. After few minutes, the stirring was stopped and the solution was stood for 1.5 hours at ambient temperature to crystallize. The resulting colorless needles were filtered, washed with 90% aqueous acetone Cl ml x 2) and acetone (l.ml x 3) and dried for 9 hours under reduced pressure to give colorless needles of 7-[2-ethoxyimino-2-C5-amino-1,2,4-thiadiazol-3-yl)acetamido] 3-Cl-pyridiniomethyl)-3-cephem-4-carboxylate acetone adduct monohydrate Csyn isomer)C120 mg), mp >1S5°C Cdec.).

IR CNujol) : 3430-3120, 1760, 1700, 1680, 1615, 1530 cm'1 NMR CD20, 6) : 1.32 C3H, t, J=7Hz), 2.26 C6H, s), 3.20 and 3.72 C2H, ABq, J=17Hz), 4.37 C2H, q, J= 7Hz), 5.30 CIH, d, J=5Hz), 5.35 and 5.66 C2H, ABq, J=14Hz), 5.91 CIH, d, J=5Hz), 8.12 C2H, m), 8.61 CIH, m), 8.98 C2H, m) Analysis for C^gH^gN^Oj^ • C^HgO-^O C H N H20 Calcd : 46.72 4.81 17.34 3.18 Found : 46.79 4.79 16.72 3.24 Example 19 CPurification of the object compound) 2-Ethoxyimino-2-C5-amino-1,2,4-thiadiazol-3-yl)-acetic acid Csyn isomer) CH.4 g) and 1-[(7-amino-4-carboxy-3-cephem-3-yl)methyl]pyridinium chloride hydrochloride dihydrate C24 g) were reacted according to a similar manner to that of Example 1. 196 4 95 - To the reaction mixture was added water (300 ml) and the mixture was adjusted to pH 1.5 with an aqueous solution of sodium hydroxide and subjected to column chromatography on a non-ionic adsorption resin Diaion 5 HP-20 (960 ml). After the column was washed with water (3.6 &) and eluted with 30% aqueous methanol (1,26 A). The.eluates were collected and concentrated under reduced pressure to a volume of 110 ml. The solution was subjected to column chromatography on 10 acidic alumina (120 g) and eluted with water. The eluates containing 7-[2-ethoxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer)(310 ml) were collected and acetone (1.1 A) was added thereto with 15 stirring at ambient temperature for 5 minutes. The mixture was stirred for 1.5 hours under ice-cooling and precipitates were collected by filtration, in turn washed with 90% aqueous solution of acetone (80 ml) and acetone (240 ml), and then dried under reduced 20 pressure to give crystals (20 g) of 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate acetone adduct (syn isomer). The crystals were dissolved in water (40 ml) and the solution was passed through a column 25 packed with acidic alumina (40 g). The elution was carried out with water and the eluates (140 ml) were collected. To the solution was added acetone (300 ml) at ambient temperature under stirring, which was stopped in a minute. The mixture was stood for 20 30 minutes at ambient temperature and for 1.5 hours in a refrigerator. The resulting colorless needles were filtered, washed with 901 aqueous acetone (25 ml x 3) and acetone (25 ml x 3) and dried for 3.5 hours under reduced pressure to give pure colorless needles 35 of 7-[2-ethoxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)- 1 r 4. 4 3 acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate acetone adduct (syn isomer)(14.3 g), mp > 15 7 0 C.

^ Example 20 (Purification of the object compound) A solution of 7-[2-ethoxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate acetone adduct (syn isomer)(1,0 g) in water (1 ml) was stood on for 5 days in a freezer 10 at -20°C. A mixture of ice and precipitates was stood on at ambient temperature until the ice was melted. The resulting precipitates were collected by filtration, washed with water (Q.3 ml) and dried in vacuo to give 7-[2-ethoxyimino-2-(5-amino-l,2,4-thiadiazol-15 3-yl)acetamido]-3-(l-pyridiniomethyl)-3-cephem-4- carboxylate (syn isomer)(0.52 g) as colorless needles, mp 165 to 170°C (dec.).

IR (Nujol) : 3450-3200, 3070, 1765, 1665, 1630, 1600, 1530, 1485 cm"1 20 NMR (D20, <5) : 1.32 (3H, t, J=7Hz), 3.20 and 3.72 (2H, ABq, J=17Hz), 4.33 (2H, q, J=7Hz), 5.27 (IH, d, J=5Hz), 5.34 and 5.65 (2H, ABq, J=14Hz), 5.89 (IH, d, J=5Hz), 8.10 (2H, m), 8.60 (IH, m), 8.97 (2H, m) Example 21(Purification of the object compound) To a solution of 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate acetone adduct (syn isomer)(40 30 g) in water (50 ml) was added a small amount of colorless needles of 7-[2-ethoxyimino-2-(5-amino-l,2,4-thiadiazol- 3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) and the mixture was stirred for one hour in an ice bath. 35 The resulting precipitates were collected by filtration,

Claims (3)

1. % - • 1i -97- washed with cold water (33 mi) and dried in vacuo for 10 hours to give 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3 - (1-pyridiniomethyl)-3-cephem-4-carboxylate dihydrate (syn isomer)(24.7 g), 5 as colorless needles, mp 170 to 175°C (dec.)* Water content (K.F. method) Calcd : 6.72%, Found : 6.20% 10 Example 22 (Purification of the object compound) A powder of 7-[2-methoxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (7.7 g) was dissolved in water (15.4 ml) and the solution was allowed to stand 15 overnight in a refrigerator. Precipitates were filtered in turn washed 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 7-[2-methoxyimino-2-(5-amino-l,2,4-thiadiazol-3-20 yl)aceta,mido]-3-(1-pyridiniomethyl)-3-cephem-4- carboxylate (syn isomer) (4.2 g), mp 165 to 170°C (dec.) IR (Nujol): 3300, 3200, 1765, 1670, 1630,1605, 1550-1520 cm"*l 25 NMR ©20, 8 ): 3.24, 3.70 (2H, ABq, J=18Hz), 4.06 (3H, s), 5.28 (IH, d, J=5Hz), 5.36, 5.60 (2H, ABq, J=14Hz), 5.87 (IH, d, J=5Hz), 8.06 (2H, m), 8.54 (IH, m), 8.95 (2H, m) 30 35 - 98- i o / /] -I o I / ^ M u What we claim is: Cephem compounds of the formula: R1-^- E- \ >' CONH / OV N s . 0-R' CH2R" wherein Rl is amino or a protected amino group; R^ is hydrogen, lower alkyl which may be substituted with suitable substituent

2. Syn isomer of a compound of claim 1.

3. A compound of claim 2, wherein N rr- 1 - 1 // ™ R -# N £rouP is R-\S S ^ A compound of claim 3, wherein Ri is amino; 2 R is hydrogen, lower alkyl which may be substituted with 1 to 3 substituent(s) selected from the group consisting of halogen, lower alkylthio, carboxy, protected carboxy and aryl, lower alkenyl, lower alkynyl, cyclo(lower)alkyl, cyclo(lower)alkenyl, -99- or tetrahydrofuryl substituted with an oxo group. A compound of claim 4, wherein ? > R~ is hydrogen, methyl, ethyl, propyl, isopropyl, 2,2,-2-trifluoroethyl, methylthiomethyl, carboxymethyl, 1-methyl-1 -carboxyethyl, 1-carboxyethyl, methoxycarbonyl-methyl, ethoxycarbonylmethyl, 1-me thyl-1-ethoxycarbonyl-ethyl, t-butoxycarbonylmethyl, 1-t-butoxycarbonylethyl, 1-me thyl-1-1-butoxycarbonyle thyl, 1-benzyloxycarb onylethyl trityl, allyl, 2-propynyl, cyclopentyl, 2-cyclopenten-1-yl 2-cyclohexen-l-yl or 2-oxotetrahydrofuran-3-yl. A compound of claim 5, wherein R is a group of the formula: - O-x wherein X is hydrogen or carbamoyl and R4 is -COO'. A compound of claim 6, which is selected from the group consisting of: 7-[2-hydroxyimino-2 -(5-amino-l,2,4-thiadiazol-3-yl)-ace tami do]- 3-(1-pyri dini ome thyl)- 3-cephem-4 -carboxy1ate (syn isomer), 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-ace tami do]- 3-(1-pyridiniome thyl)-3-cephem-4-carboxylate (syn isomer), 7-[2-ethoxyimino-2 -(5 -amino-1,2,4-thiadiazol-3-yl)-acetamido]- 3-(1-pyridiniomethyl)- 3-cephem-4-carboxylate (syn isomer), 7- [2-propoxyimino-2-(5-amino-l,2 ,4-thiadiazol - 3-yl) acetamidq 3-(1-pyridiniomethyl) -3-cephem-4-carboxylate (syn isomer), 7 -[2-isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl) acetamido]- 3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), . 7-[2-methoxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)-acetamido]-3-(4-carbamoyl-l-pyri-diniomethyl)-3-cephem- 4-carboxylate (syn isomer), 7 -[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-ace tami do]-3-(4-carbamoyl-1-pyri dini ome thyl)- 3-cephem-4-carboxylate (syn isomer), f v;' : - 100- 7-[2-propoxyimino-2-(5-amino-l,2 ,4-thiadiazol-3-yl)acetamido]- 3-(4-carbamoyl-l-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer], 7-[2-isopropoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido|-3-C4~carbamoyl~l-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), 7-[2-(2,2,2-trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), 7-[2-(2,2,2-trifluoroethoxyimino)- 2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-l-pyridiniomethyl) -3-cephem-4-carboxylate (syn isomer), 7-[2-methylthiomethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]- 3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), 7-[2-methylthiomethoxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-l-pyridiniomethyl) -3-cephem-4-carboxylate (syn isomer), 7-[2-carboxymethoxyimino-2-(5-amino-l,2,4-thiadiazol- 3-yl) acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), 7-[2-carboxymethoxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-l-pyridiniomethyl) - 3-cephem-4-carboxylate (syn isomer), 7-[2-(1-methyl-l-carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]- 3-(1-pyridinio-methyl)-3-cephem-4-carboxylate (syn isomer), 7-[2-(1-methyl-l-carboxyethoxyimino)- 2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-(4-carbamoyl--. 1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), 7-[2-(1-carboxyethoxyimino)-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]- 3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), 7-[2-(1-carboxye thoxyimino)-2-(5-amino-l,2,4- aoi- 1S6448 thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-l-pyridiniomethyl) -3-cephem-4-carboxylate (syn isomer)t ' 7- l2-allyloxyimino-2-(5-amino-l,2,4-thiadiazol-5 3-yl)acetamido]-3-(l-pyridiniomethyl)-3-cephem-4- carboxylate (syn isomer), 7- [2-allyloxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), 7- [2-(2-propynyloxyimino)2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), 7- {2-(2-propynyloxyimino)-2-(5-amino-l,2,4-thiadiazol -3-yl)acetamido]-3-(4-carbamoyl-1-15 pyridiniomethyl) - 3-cephem-4-carboxylate (syn isomer), 7- [2-cyclopentyloxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn ist?mer) , 7- {2-cyclopentyloxyimino-2-(3-amino-1,2,4-2 0 thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-1- pyridiniomethyl)-3-cephem-4-carboxyl£te (syn isomer), 7- {2- (2-cyclopenten-l-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl) -3-cephem-4-carboxylate (syn isomer), 25 Its hydroiodide and hydrochloride, and 7- [2-(2-cyclopenten-l-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-l-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), A compound of claim 5, wherein 30 R3 is 2-methyl-5-oxo-6-hydroxy-2,5-dihydro-l,2,4- triazinylthio and R is carDoxy. A compound of claim 8, which is selected from the group consisting of: 35 disodium 7-[2-methoxyimino-2-(5 - amino-1,2,4- USEPWtt - ao2- 1 thiadiazol-3-yl)acetamido]-3-(2-methyl-5-oxo-6-oxido-2,5-dihydro-l,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer), disodium 7-[2-ethoxyimino-2-(5-amino-l,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), 7-[2-allyloxyimino-2-(5-amino-l,2,4-thiadiazol-3-yl)acetamido]-3-(2-methyl-5-oxo-6-hydroxy-2,5-dihydro-l,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), 7-[2-isopropoxyimino-2-(5-amino-l,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), 7-[2-(2-propynyloxyimino)-2-(5-amino-l,2,4-thiadiazol- 3-yl) acetamido] - 3-(2-methyl-5-oxo-6-hydroxy-2,5-dihydro-l,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer), sodium 7-[2-cyclopentyloxyimino-2-(5-amino-l,2,4-thiadiazol- 3-yl)acetamido]- 3-(2-methyl-5-oxo-6-hydroxy-2,5-dihydro-l,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) and 7-{2-(2-cyclopenten-l-yloxyimino)-2-(5-amino--1,2,4-thiadiazol-3-yl)acetamido]-3-(2-methyl-5-oxo-6-hydroxy-2,5-dihydro-l,2,4-triazin-3-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer) A process for preparing cephem compounds of the formula: 0-R R 103- <^0,5 wherein is amino or a protected amino group; Rz is hydrogen lower alkyl which may be substituted with suitable substituent(s), (as hereinbefore defined), lower alkenyl, lower alkynyl, cyclo(lower)- alkyl, cyclo(lower)alkenyl, or 0 containing 5-membered heterocyclic group substituted with oxo group (s) ; >3 _ .V. ^ R" is a group of the formula: v_/ wherein X is hydrogen or carbamoyl; and COO-: or R4 is R is 2-lower alkyl-5-oxo-6-hydroxy-2,5-dihydro-l,2,4-triazinylthio; and R4 is carboxy or protected carboxy, or pharmaceutically acceptable salts thereof, which comprises reacting a compound of the formula: 3 4 wherein 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 formula: C-COOH a N < 2 0-R 1 2 wherein R and R are each as defined above, or its reactive derivative at the carboxy 104- 196 4 J8 group or a salt thereof. A process for preparing cephem compounds of the formula: *-A ■:-C0NH-t— J- N 0 | 0-R2 R ch2R- 10 15 20 25 wherein is amino or a protected amino group; R^ is hydrogen lower alkyl which may be substituted with suitable substituent (s) , (as hereinbefore defined):,; lower alkenyl, lower alkynyl, cyclo(lower)-alkyl, cyclo (lower)alkenyl, or 0 containing 5-membered heterocyclic group substituted with oxo group(s); .— R3 is a group of the formula: V wherein X is hydrogen or carbamoyl; and R4 is -C00-; or R^ is 2-lower alkyl-S-oxo^-hydroxy^jS-dihydro-l^^-triazinylthio; and R4 is carboxy or protected carboxy, or pharmaceutically acceptable salts thereof, which comprises reacting a compound of the formula: 30 *1 -105- C- & x 1 2 wherein R and R are each as defined above; 3a R is a group which can be substituted with a group of the formula: R wherein R is as defined above; and R4a is carboxy when ' is a compound of the formula: W wherein X is as defined above; or 4 3. R . is carboxy or protected carboxy when R"^ is a compound of the formula: R^c-H 3c wherein R is 2-lower alkyl-S-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazinylthio; or a salt thereof, with a compound of the formula: R3b •T'L wherein R is as defined above, or its reactive derivative. A process for preparing a compound of the formula R1 -CH,R3 S 2b °' ' 0R R4 wherein R1 is amino or a protected amino group; 2h R is a carboxy(lower)alkyl; 3 + R is a group of the formula: - wherein X is hydrogen or carbamoyl; and 4 — R is -COO ; or , 3 R is 2-lower alkyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazinylthio; and 4 R is carboxy or protected carboxy; or pharmaceutically acceptable salts thereof which comprises subjecting a compound of the formula: _ -1Q6- N R \ S>^ C-CONH- N 5 OR 0' 2a .N r CH2R° 3 4 R and R are each as defined above 10 ,2a 15 wherein R , and R"°" is a protected carboxy (lower) alkyl, or a salt thereof, to elimination reaction of the protective group of carboxy. A process for preparing a compound of the formula C-CONH N II N S OH 20 25 30 wherein R1 is amino or a protected amino group; R3 is a group of the formula: -wherein X is hydrogen or carbamoyl; and R4 is -COO"; or 3 R is 2-lower alkyl-5-oxo-6-hydroxy-2,5-dihydro-1",2,4-triazinylthio; and 4 R is carboxy or protected caTboxy, or pharmaceutically acceptable salts thereof which comprises subjecting a compound of the formula: 35 •10 7- o .c a /on O u T T A wherein R , R and R are each as defined above 2c and R is a protective group of hydroxy, or a salt thereof, to elimination reaction of the protective group of hydroxy. A compound of the formula: I 0 [n wherein r! is amino or a protected amino group; is hydrogen, lower alkyl which may be substituted with suitable substituent^Cs) , (as hereinbefore defined) , lower alkenyl, lower alkynyl, cyclo(lower)-alkyl, cyclo(lower)alkenyl, or 0 containing 5-membered heterocyclic group substituted with oxo group(s); •t 1 R is lower alkanoyl(lower)alkanoyloxy, 4b and R is carboxy or protected carboxy, and a salt thereof. . -8 NOVI* - lo6- i 9 0 A •-! A process for preparing a compound of the formula: I wherein r1 is amino or a protected amino group; R^ is hydrogen, lower alkyl which may be substituted with suitable substituent(s), (as hereinbefore defined), lower alkenyl, lower alkynyl, cyclo(lower)-alkyl, cyclo(lower)alkenyl, or 0 containing 5-membered heterocyclic group substituted with oxo group(s); R"* is lower alkanoyl(lower)alkanoyloxy, 4b and R is carboxy or protected carboxy; or a salt thereof, which comprises a) reacting a compound of the formula: H2N-i |"S>1 N Y^-CH2R3d wherein R3^ and R4*5 are each as defined above, or its reactive derivative at the amino group or a salt thereof, with a compound of the formula: jf1 n 10 30 -109- 1 2 wherein R and R are each as defined above, or its reactive derivative at the carboxy grpup or a salt thereof, or b) subjecting a compound of the formula: C-CONH ii X-ii ch2r" 0R2a I«> wherein R , R and R are each as defined above 2a and R is a protected carboxy(lower)-alkyl, or a salt thereof, to elimination IS reaction of the protective group of carboxy, to give a compound of the formula: — C-CONH RX^ — CH„R3d 20 a 0R2b R4b wherein R1, R3d and R4^ are each as defined 9K 25 above and R is a carboxy(lower)alkyl, or a salt thereof. A compound of the formula: HOOC-CH-(CH2)3CONHy—S* ^ ijlH ~X- N CO COO NH-<^ 35 ** fl 10 20 * 1 - iio- ■ (i J * J x wherein X is hydrogen or carbamoyl, and a salt thereof. A process for preparing a compound of the formula hooc-gh-cch2)3conh- , m a — ch0iy 0^-^ r lrt2,\y CO NH ^ wherein X is hydrogen or carbamoyl, or a salt thereof, which comprises reacting a compound of the formula: 15 hooc-ch- (ch2) 3c0nh-| r^s > ip. q ch2r3e CO I C00H 3e wherein R is a group which can be substituted with a group of the formula wherein X is as defined above, or a salt thereof, with a compound of the formula: 25 wherein X is as defined above. a pharmaceutical antibacterial composition 30 comprising a compound of claim 1 in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient. a method for producing a pharmaceutical antibacterial composition which comprises mixing a compound of 35 claim 1 as an active ingredient with an inert carrier. Ill 1S6448 A compound as claimed in claim 1 substantially as herein described with reference to any one of the Examples. A process of claim 10, 11, 12 or 13 substantially as herein described with reference to any one of the Examples. A method for producing a pharmaceutical antibacterial composition as claimed in claim 19 substantially as herein described with reference to any one of the Examples. fiffllSWM, SON X CAREY JftrtOftNErS for thh applicants