GB2023583A

GB2023583A - 3,7-disubstituted-3-cephem-4- carboxylic Acid Compounds and Processes for the Preparation Thereof

Info

Publication number: GB2023583A
Application number: GB7905196A
Authority: GB
Original assignee: Fujisawa Pharmaceutical Co Ltd
Current assignee: Fujisawa Pharmaceutical Co Ltd
Priority date: 1978-02-15
Filing date: 1979-02-14
Publication date: 1980-01-03
Also published as: GB2023583B

Abstract

Compounds of the formula: <IMAGE> wherein R<1> is amino or a protected amino; R<3> is carboxy or a protected carboxy; R<2> is isobutyl and R<4> is acetoxy; or R<2> is cyclo(lower)alkyl or lower alkynyl and R<4> is lower alkanoyloxy; or R<2> is lower alkyl and R<4> is (C5-C6) alkanoyloxy; or R<2> is (C2-C6)alkyl, lower alkenyl, cyclo(lower)alkyl or lower alkynyl and R<4> is hydrogen, carbamoyloxy, thiadiazolylthio which may have a lower alkyl or triazolylthio; or R<2> is (C2-C5)alkyl, cyclo(lower)alkyl or lower alkynyl and R<4> is tetrazolylthio having a methyl; or R<2> is lower alkyl, lower alkenyl, cyclo(lower)alkyl or lower alkynyl and R<4> is aroyloxy which may have nitro or amino, cyclo(lower)alkanecarbonyloxy, carbamoyloxy having an aryl which may be substituted with halogen, ar(lower)alkanoyloxy, aryloxy(lower)alkanoyloxy having lower alkoxy, thenoyloxy, tetrazolylthio having a (C3-C6)alkyl or benzothiazolylthio; and pharmaceutically acceptable salts thereof, are made by standard methods. The compounds are antibacterial agents.

Description

SPECIFICATION 3,7-Disubstituted-3-Cephem-4-Carboxylic Acid Compounds and Processes for the Preparation Thereof The present invention relates to new 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and pharmaceutically acceptable salts thereof. More particularly, it relates to new 3,7-disubstituted-3cephem-4-carboxylic acid compounds and pharmaceutically acceptable salts thereof which have antibacterial activities and to processes for the preparation thereof, to pharmaceutical composition comprising the same, and to a method of using the same therapeutically in the treatment of infectious disease in human beings and animals.

Accordingly, it is one object of the present invention to provide 3,7-disubstituted-3-cephem-4- carboxylic acid compounds and pharmaceutically acceptable salts thereof, which are highly active against a number of pathogenic bacteria.

Another object of the present invention is to provide processes for the preparation of 3,7disubstituted-3-cephem-4-carboxylic acid compounds and pharmaceutically acceptable salts thereof.

A further object of the present invention is to provide pharmaceutical composition comprising, as active ingredients, said 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and pharmaceutically, acceptable salts thereof.

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

The object 3,7-disubstituted-3-cephem-4-carboxylic acid compounds are novel and can be represented by the following formula (I):

wherein R1 is amino or a protected amino; R3 is carboxy or a protected carboxy; R2 is isobutyl and R4 is acetoxy; or R2 is cyclo(lower)alkyl or lower alkynyl and R4 is lower alkanoyloxy; or R2 is lower alkyl and R4 is (C5-C6) alkanoyloxy; or R2 is (C2-C6)alkyl, lower alkenyl, cyclo(lower)alkyl or lower alkynyl and R4 is hydrogen, carbamoyloxy, thiadiazolylthio which may have a lower alkyl or triazolylthio; or R2 is (C,--C,)alkyl, cyclo(lower)alkyl or lower alkynyl and R4 is tetrazoEylthio having a methyl; or R2 is lower alkyl, lower alkenyl, cyclo(lower)alkyl or lower alkynyl and R4 is aroyloxy which may have nitro or amino, cyclo(lower)alkanecarbonyloxy, carbamoyloxy having an aryl which may be substituted with halogen, ar(lower)alkanoyloxy, aryloxy(lower)alkanoyloxy having lower alkoxy, thenoyloxy, tetrazolylthio having a (C3-C8)alkyl or benzothiazolylthio.

The object compound of the present invention (I) are novel compounds and can be prepared by the Processes 1 to 4 as mentioned below.

Process 1

or its reactive or its reactive or a salt thereof derivative at derivative at the amino group or the carboxy group a salt thereof or a salt thereof Process 2

c-con. Elimination of the amino protective group OR (la) or a salt thereof

H2N C-CONH I CH2' g4 Process 3 or a salt thereof

R1 NS Elimination of Rt X+CCOC ) the carboxy pro Y 11 tective group 0 (1)

or a salt thereof Process 4

RI~lc-m'MB CH2R4a Reduction oR2d R (10 or a salt thereof

or a salt thereof wherein R',R2,R3 and R4 are each as defined above, R1a is a protected amino, R3a is a protected carboxy, R2a is lower alkyl, lower alkenyl, cyclo(lower)alkyl or lower alkynyl, R48 is aroyloxy having nitro group(s) and R4b is aroyloxy having amino group(s).

Among the starting compounds some of the compound (III) is novel and can be prepared by the processes which are illustrated by the following scheme.

(1) CH3--CO-CC-Z cn-co-c-z N S Halogenation On ( & (y) H2N--CC-NHZ NC-z Y-cH2CO-C-Z S nzN- II N N N bR2 ORt (vr) (E) ,ll cCooll N c-coo ii H2NX Rìav N oR2 zR2 Amino-protecting agent (Ea) (Ea') (2) Rt COCOOH R(2fl2 c-cooll or a salt thereof N Rn loRZ (z) ( =)

wherein Ri, Ria and R2 are each as defined above, Z is a protected carboxy and Y is halogen.

Some of the other starting compound (II) is also novel and can be prepared by the processes as illubtrated below.

R5--Y CS, (xl) CS2 (Xl) (1) C6H13NH2C6H13NHCS-SH (X) or its salt X- N3 yN, c6N13nItcs-sR5 (xm)~ ,,n ( Cosh13 or a salt thereof

or a salt thereof or a salt thereof

or a salt thereof

R15 ) RNS,3 ottCH20H ottCH20R4 R3 (r) (2r) Oxidation R1asA yS Reduction oF tCH2oR4C R3 Elimination of the amino protective group RI s, HON - R4c 11$yc2 OR4c .R3 0-R4G (ism) (lib) wherein R1a and R3 are each as defined above, Y' is an acid residue, R5 is a lower alkyl, X is an alkali metal, R8 is a group which can be substituted by a group of the formula:

R7 is ( C3-C6) alkyl, and R4c is carbamoyl having an aryl which may be substituted with halogen, aryloxy (lower) alkanoyl having lower alkoxy, thenoyl, cyclo (lower) alkanecarbonyl, or aroyl having nitro.

Regarding the object compounds of the formulae (I), (Ib), (Id) and (If), and the starting compounds of the formulae (Ia), (Ic0, (Ie) (III), (IIIa), (IIIa'), (VII) and (VIII), it is to be understood that said object and starting compounds include tautomeric isomers relating to their thiazole groups. That is, in case that the group represented by the formula:

(wherein R1 is as defined above) in the formula of said object and starting compounds take the formula:

(A) (R1 is as defined above), said group of the formula:

can also be alternatively represented by its tautomeric formula:

(B) wherein Rib is imino or a protected imino). That is, both, of the said group (A) and (B) are in the state of equilibrium as so-called tautomeric forms which can be represented by the following equilibrium.

(wherein R1 and Rlb are each as defined above).

These types of tautomerism between 2-aminothiazole compounds and 2-iminothiazoiine compounds as stated above have been well known in the literature, and it is obvious to the person skilled in the art that both of the tautomeric isomers are equilibrated and easily convertible reciprocally, and accordingly it is to be understood that such isomers are included within the same category of the compound per se. Accordingly, the both of the tautomeric forms of the object compounds and the starting compounds are clearly included within the scope of the present invention. In the present specification, 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:

only for the convenient sake.

Furthermore, regarding the object compounds (I), (ib) (lid) and (If), and the starting compounds (lea) (it), (lye) (III), (Illa), (ills,) and (lV)-(VIl), it is to be understood that said object and starting compounds include syn isomer, anti isomer and a mixture thereof.For example, regarding the object compound (I), said syn isomer can be represented by the partial structure of the formula:

in its molecule, while the corresponding anti isomer is represented by the partial structure of the formula:

in its molecule, and in case that it is convenient for the explanation of this invention to express both of the syn isomer and anti isomer by one general formula, it is represented by the partial structure of the formula:

Regarding the other object compounds and starting compounds 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).

Suitable pharmaceutically acceptable salt of the object 3,7-disubstituted-3-cephem-4-carboxylic acid compounds (I) are conventional non-toxic salts and may include an inorganic salt, for example, 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 salt, etc.), ammonium salt etc., an organic salt, for example, an organic amine salt (e.g., trimethylamine salt, triethylamine salt, ethanolamine salt, diethanolamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.) etc., an organic acid salt (e.g., acetate, maleate, tartrate, methanesulfonate, banzenesulfonate, toluenesulfonate, etc.), an inorganic acid salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.), or a salt with an amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.), and the like.

In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention intend to include within the scope thereof are explained in details as follows.

The term "lower" is intended to mean 1 to 6 carbon atom(s), unless otherwise provided.

The term "(CaCb)" is intended to mean a to b carbon atom(s), for example, "(C2-C6)alkyl" means alkyl having 2 to 6 carbon atoms.

Suitable protected amino may include an acylamino and amino group substituted by a conventional protective group other than the acyl group such as ar(lower)alkyl (e.g., benzyl, trityl, etc.) and the like.

Suitable protected imino may include an acylamino and imino group substituted by a conventional protective group other than the acyl group such as ar(lower)alkyl (e.g., benzyl, trityl, etc.) and the like.

Suitable acyl moiety in the terms "acylimino", "acylamino" and "acyloxy" 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, hexanoyl, etc.); cyclo(lower)alkanecarbonyl having 4 to 7 carbon atoms (e.g., cyclopropanecarbonyl, cyclohexanecarbonyl, etc.), preferably one having 6 to 7 carbon atoms; lower alkoxycarbonyl having 2 to 7 carbon atoms (e.g., methoxycarbonyl, ethoxycarbonyi, propoxycarbonyl, 1 -cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tbutoxycarbonyl, pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, etc.); lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.); arenesulfonyl (e.g., benzenesulfonyl, tosyl, etc.); aroyl (e.g., benzoyl, toluoyl, naphthoyl, phthaloyl, indancarbonyl, etc.); ar(lower)alkanoyl (e.g., phenylacetyl, phenylpropionyl, etc.); ar(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, etc.); aryloxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, phenoxyhexanoyl, etc.); heterocyclicarbonyl (e.g., thenoyl, furoyl, nicotinoyl, etc.); and the like.

The acyl moiety as stated above may have 1 to 3 suitable substituent(s) such as halogen (e.g., chlorine, bromine, iodine or fluorine), hydroxy, cyano, nitro, amino, lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, etc.), preferably one having 1 to 2 carbon atom(s), lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, etc.), lower alkenyl (e.g., vinyl, allyl, etc.), aryl (e.g., phenyl, tolyl, etc.) which may be substituted with halogen or the like.

Preferable example of acyl having said substituent(s) may be halo(lower)alkanoyl [more preferably trihalo(lower)alkanoyl], N-aryl- or N-halogen substituted aryl-carbamoyl, aryloxy(lower)alkanoyl having lower alkoxy, or aroyl having nitro or amino.

Preferable example of acylamino may be lower alkanoylamino, ar(lower)alkanoylamino [more preferably phenyl(lower)alkanoylamino] or halo(lower)alkanoylamino [more preferably trihalo(lower)alkanoylamino].

Suitable protected carboxy may include esterified carboxy in which said ester moiety may be the ones such as lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyi esTer, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, 1 cyclopropylethyl ester, etc.), wherein lower alkyl moiety may preferably be 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(lower)alkyl ester (e.g., 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower alkanoyioxy(lower)alkyl ester (e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyioxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, etc.); lower alkanesulfonyl(lower)alkyl ester (e.g., mesylmethyl ester, 2mesylethyl ester etc.); ar(lower)alkyl ester, for example, mono or di- or tri-phenyl(lower)alkyl ester which may have one or more suitable substituent(s) (e.g., benzyl ester, 4-methoxy-benzyl ester, 4 nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4 dimethoxybenzyl ester, 4-hydroxy-3,5-ditertiarybutylbenzyl ester, etc.); aryl ester which may have one or more suitable substituent(s) (e.g., phenyl ester,- tolyl ester, tertiary-butylphenyl ester, xylyl ester, mesityi ester, cumenyl 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 7 carbon atoms, preferably one having 2 to 5 carbon atoms; lower alkanoyloxy(lower)alkoxycarbonyl having 3 to 13 carbon atoms (e.g., acetoxymethoxycarbonyl, pivaloyloxymethoxycarbonyl, hexanoyloxymethoxycarbonyl, etc.), preferably one having 6 to 8 carbon atoms; or ar(lower)alkoxycarbonyl having 8 to 20 carbon atoms (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, etc.), preferably one having 12 to 14 carbon atoms.

Suitable cyclo(lower)alkyi is one having 3 to 6 carbon atoms and may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, and preferably one having 5 to 6 carbon atoms.

Suitable lower alkynyl is one having 2 to 6 carbon atoms and may include ethynyl, 2-propynyl, 2butynyl, 3-pentynyl, 3-hexynyl and the like, and preferably one having 2 to 4 carbon atoms, and more preferably one having 2 to 3 carbon atoms.

Suitable lower alkanoyloxy is one having lower alkanoyl group as mentioned above and may include, for example, formyloxy, acetoxy, propionyloxy butyryloxy, isobutyryloxy, valeryloxy, succinyloxy, pivaloyloxy, hexanoyloxy and the like, preferably one having 2 to 6 carbon atoms.

Suitable lower alkyl may include one which may be branched, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.

Suitable lower alkenyl is one having 2 to 6 carbon atoms and may include, for example, vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl, 3-pentenyl and the like, and preferably one having 2 to 4 carbon atoms.

Suitable thiadiazolylthio may include, for example, 1 ,2,4-thiadiazolylthio, 1 ,3,4-thiadiazolylthio, 1 ,2,5-thiadiazolylthio and the like. Said thiadiazolylthio group may have a lower alkyl group as mentioned above.

Suitable triazolylthio may include, for example, 4H-1 ,2,4-triazolylthio, 1 H-l ,2,3-triazolylthio, 2H 1 ,2,3-triazolylthio and the like.

Suitable tetrazolylthio may include 1 H-tetrazolylthio or 2H-tetrazolylthio.

Suitable aroyloxy may include, for example, benzoyloxy, toluoyloxy, napthoyloxy, phthaloyloxy, indanecarbonyloxy and the like, which may have 1 to 3 nitro or amino group(s).

Suitable cyclo(lower)alkanecarbonyloxy is one having 4 to 7 carbon atoms and may include, for example, cyclopropanecarbonyloxy, cyclohexanecarbonyloxy and the like, preferably one having 6 to 7 carbon atoms.

Suitable aryl being the substituent of carbamoyloxy may include phenyl, tolyl and the like, which may be substituted with 1 to 3 halogen (e.g., chlorine, bromine, etc).

Suitable ar(lower)alkanoyloxy may preferably be phenyl(lower)alkanoyloxy and may include phenylacetoxy, phenylpropionyloxy and the like.

Suitable aryloxy(lower)alkanoyloxy may preferably be phonoxy(lower)alkanoyloxy and may include phenoxyacetoxy, phenoxypropionyloxy, phenoxyhexanoyloxy and the like, which have 1 to 3 lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tbutoxy, pentyloxy, hexyloxy, etc.) preferably one having 1 to 3 carbon atom(s).

Suitable halogen may include chlorine, bromine, fluorine and iodine.

Suitable acid residue may include aforesaid halogen, lower alkanesulfonyloxy (e.g., mesyloxy, ethanesulfonyloxy, etc.), arenesulfonyloxy (e.g., benzenesulfonyloxy, p-toluenesulfonyloxy, etc.) and the like.

Suitable alkali metal may include sodium, potassium, and the like.

Suitable group which can be substituted by a group of the formula:

may include azido, aforesaid halogen, acyloxy (preferably lower alkanoyloxy) and the like.

Suitable carbamoyl having an aryl which may be substituted with halogen, aryloxy(lower)alkanoyl having lower alkoxy, cyclo(lower)alkanecarbonyl and aroyl having nitro can be referred to the ones exemplified for acyl.

Among the suitable examples of each of the groups of the object compounds as explained and illustrated above, the preferred examples thereof are illustrated as follows: preferable example of R1 may be amino or acylamino [more preferably lower alkanoylamino or halo(lower)alkanoylamino]; and preferable example of R3 may be carboxy or ar(lower)alkoxycarbonyl [more preferably diphenyl(lower)alkoxycarbonyl].

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

Process 1 The object compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative 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 Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (II) with a carbonyl compound such as acetoacetic acid or the like; a silyl derivative formed by the reaction or the compound (II) with a silyl compound such as trimethylsilylacetamide, bis(trimethylsilyl)acetamide or the like; a derivative formed by reaction of the compound (II) with phosphorus trichloride or phosgene, and the like.

Suitable salt of the compounds (II) and (III) 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 (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, 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 acid chloride, an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorus acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2ethylbutyric acid or trichloroacetic acid, etc.) or aromatic carboxylic acid (e.g. benzoic acid, etc.); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazoje; or an activated ester (e.g., cyanomethyl ester, methoxymethyl ester, dimethylimino-methyl [(CH3)2N+=CH-] ester, vinyl ester, propargyl ester, 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, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8quinolyl thioester, etc.), or an ester with a N-hydroxy compound (e.g., N,N-dimethylhydroxylamine, 1 hydroxy-2-( 1 H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1 -hydroxy-6-chloro-1 Hbenzotriazole, etc.), and the like.These reactive derivatives can optionally be selected from them according to the kind of the compound (III) to be used.

The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,Ndimethylformamide, pyridine or any other organic solvents which do not adversely influence the reaction. These conventional solvents may also be used in a mixture thereof.

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 condensing agent such as N,N'dicyclohexylcarbodi mide; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N'-(4- diethylaminocyclohexyl)carbodiimide; N,N'-diethylcarbodiimide; N,N'-diisopropylcarbodiimide;N ethyl-N'-(3-dimethylaminopropyl)carbodiimide; N,N-carbonylbis-(2-methyl imidazole); pentamethyleneketene-N-cyclohexylamine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1 alkoxy-l -chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride; phosphorus trichloride; thionyl chloride; oxalyl chloride; triphenylphosphine; 2-ethyl-7hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intra-molecular salt; 1 (p-chlorobenzenesulfonyloxy)-6-chloro- 1 H-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride, etc.; or the like.

The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,Ndi(lower)alkylbenzylamine, or the like. 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 tha present reaction of the compound (II) with the corresponding syn isomer of the starting compound (III), for example, in the presence of a Vilsmeier reagent as mentioned above etc. and under around neutral condition.

Process 2: The object compound (lib) or a salt thereof can be prepared by subjecting the compound (lea) or a salt thereof to elimination reaction of the amino protective group.

Suitable salt of the compound (lea) may include a metal salt, ammonium salt, an organic amine salt and the like as aforementioned.

The present elimination reaction is carried out in accordance with a conventional method such as hydrolysis; reduction; a method by reacting the compound (Ia), wherein the protective group is acyl group, with iminohalogenating agent and then with iminoetherifying agent, and, if necessary, subjecting the resulting compound to hydrolysis; or the like.

The hydrolysis may include a method using an acid or base or hydrazine and the like. These methods may be selected depending on the kind of the protective groups to be eliniinated.

Among these methods, hydrolysis using an acid is one of the common and preferable method for eliminating the protective groups such as substituted or unsubstituted alkoxycarbonyl (e.g. tpentyloxycarbonyl, etc.), alkanoyl (e.g., formyl, etc.), cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl (e.g., benzyloxycarbonyl, substituted benzyloxycarbonyl, etc.) or the like. Suitable acid may include an organic or an inorganic acid, for example, formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluensulfonic acid, hydrochloric acid and the like, and preferable acid is, for example, formic acid, trifluoroacetic acid, hydrochloric acid, etc. The acid suitable for the reaction can be selected according to the kind of protective group to be eliminated. When the elimination reaction is conducted with the acid, it can be carried out in the presence or absence of a solvent. Suitable solvent may include an organic solvent, water or a mixed solvent thereof. When trifluoroacetic acid is used, the elimination reaction may preferably be carried out in the presence of anisole.

The hydrolysis using hydrazine is commonly applied for eliminating the protective group, for example, succinyl or phthaloyl.

The hydrolysis with a base is preferably applied for eliminating acyl group, for example, haloalkanoyl (e.g., trifluoroacetyl, etc.) etc. Suitable base may include an inorganic base or an organic base. The hydrolysis using a base is often carried out in water or a hydrophilic organic solvent or a mixed solvent thereof.

Among the protective groups, the acyl group can generally be eliminated by hydrolysis as mentioned above or by the other conventional hydrolysis. In case that the acyl group is halogen substituted-alkoxycarbonyl or 8-quinolyloxycarbonyl, they are eliminated by treating with a heavy metal such as copper, zinc or the like.

The reductive elimination is generally applied for eliminating the protective group, for example, haloalkoxycarbonyl (e.g. trichloroethoxycarbonyl, etc.), substituted or unsubstituted aralkoxycarbonyl (e.g., benzyloxycarbonyl, substituted benzyloxycarbonyl, etc.), 2-pyridylmethoxycarbonyl, etc. Suitable reduction may include, for example, reduction with an alkali metal borohydride (e.g., sodium borohydride, etc.) and the like.

Among the protective groups, the acyl group can be eliminated by treating with an iminohalogenating agent (e.g., phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, etc.) and an iminoetherifying agent such as lower alkanol (e.g., methanol, ethanol, etc.), if necessary, followed by hydrolysis. The reaction temperature is not critical and may suitably be selected in accordance with the kind of the amino protective group and the elimination method as mentioned above, and the present reaction is preferably carried out under a mild condition such as under cooling, at ambient temperature or slightly elevated temperature.

The present invention includes, within its scope, the case that the protected carboxy is transformed into the free carboxy group according to reaction conditions in the course of the reaction or in post-treatment.

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

The present elimination reaction is carried out in accordance with a conventional method such as hydrolysis or the like. The hydrolysis may include a method using an acid or base and the like. These methods may be selected depending on kind of the protective groups to be eliminated.

The hydrolysis using an acid is one of the most common and preferable methods for eliminating the protective groups such as ar(lower)alkyl [e.g., (mono- or di- or tri-)phenyl(lower)alkyl, substituted phenyl(lower)alkyl, etc lower alkyl, substituted lower alkyl, or the like. Suitable acid may include inorganic or organic acid, for example, formic acid, trifluoroacetic acid, benzenesulfonic acid, ptoluenesulfonic acid, hydrochloric acid, and the like. The present reaction may be carried out in the presence of anisole. The acid suitable for the reaction can be selected according to the protective group to be eliminated and other factors.The hydrolysis using an acid may be carried out in the presence of a solvent, such as an organic solvent, water or a mixed solvent thereof The reaction temperature is not critical and may be suitably selected in accordance with the kind of the protective group and the elimination method, and the present reaction is preferably carried out under a mild condition such as under cooling, at ambient temperature or slightly warming.

The present invention includes, within its scope, ihe case that the protected amino group is transformed into the free amino group auring the reaction or post-treating in the present reaction.

Process 4 The object compound (I,) or a salt thereof can be prepared by subjecting the compound (lye) or a salt thereof to reduction.

Suitable salt of the compound (le) can be referred to the ones exemplified for the compound (lea) The present reduction is carried out in accordance with a conventional method such as catalytic reduction or the like.

Suitable catalyst may include platinic oxide palladium on charcoal and the like.

Suitable solvent may include an alcohol (e.g., methanol, ethanol, etc.), tetrahydrofuran, or any other solvent which does not adversely affect the reaction.

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

The processes for preparing the starting compound (lib) are explained in details as follows.

1. The compound (XVII) can be prepared by reacting the compound (XVI) with acylating agent.

Suitable acylating agent may include a compound of the formula: R4d--OH(XXI) wherein R4d is aryloxy(lower)alkanoyl which may have lower alkoxy, thenoyl, cyclo(lower)alkanecarbonyl or aroyl having nitro, or its reactive derivative, and a compound of the formula: RB--N=C=O (XXII) where Ra is aryl which may be substituted with halogen.

Suitable reactive derivative of the compound (XXI) can be referred to the ones as exemplified for the compound (III).

Suitable aryl for R8 may include phenyl, tolyl, xylyl, mesityl, cumenyl, naphthyl and the like, wherein said aryl group may be substituted with 1 to 3 halogen (e.g., chlorine, bromine, iodine or fiuorine).

The present reaction is carried out according to a similar manner to that of Process 1.

In the formula of the compound (XVII), the structure of the following formula:

means a mixture of 3- and 2-cephem compounds.

2. The compound (XVIII) can be prepared by oxidizing the compound (XVII).

Suitable oxidizing agents may include conventional ones used for oxidation of sulfur atom at 1 st position of cephalosporin compound, for example, per acid (e.g., perbenzoic acid, 3-chloroperbenzoic acid), hydrogen peroxide/sodium tungstate, or the like.

The present reaction is usually carried out in a solvent such as ethyl acetate, tetrahydrofuran or any other solvent which does not adversely affect the reaction, and usually carried out under cooling or at ambient temperature.

3. The compound (XIX) can be prepared by reducing the compound (XVIII).

Suitable reducing agent may include conventional ones used for reduction of S-oxide, for example, phosphorus halide (e.g., phosphorus trichloride, phosphorus tribromide, etc.) or the like.

The reaction is preferably carried out in a solvent such as dimethylformamide or the like, and preferably carried out under cooling or at ambient temperature.

4. The compound (lib) can be prepared by subjecting the compound (XIX) to elimination reaction of the amino protective group.

The present elimination reaction is carried out according to a similar manner to that of Process 2.

In the aforementioned reactions and/or the post-treating of the reactions of the present invention, the aforementioned tautomeric isomers may occasionally be transformed into the other tautomeric isomers and such case is also included in the scope of the present invention.

In case that the object compound (I) is obtained in a form of the free acid at 4 position and/or in case that the object compound (I) has free amino group, it may be transformed into its pharmaceutically acceptable salt as aforementioned bv a conventional method.

The object compound (I) and pharmaceutically acceptable salt thereof of the present invention are all novel compounds which exhibit high antibacterial activity, inhibiting the growth of a wide variety of pathogenic microorganisms including Gram-positive and Gram-negative bacteria and are useful as antibacterial agents.

Now, in order to show the utility of the object compound (I), with regard to some representative compounds of this invention, there are shown the test data on the in vitro anti-bacterial activity in the following.

Test Compounds (1) 7-[2-(2-Propynyloxyimino)-2-(2-aminothiazol-4-yl)-acetamido]cephalosporanic acid (syn isomer).

(2) 7-[2-(2-Propynyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3- cephem-4-carboxylic acid (syn isomer).

(3) 7-[2-(2-Propynyloxyimino)-2-(2-a minothiazol-4-yl)acetamido]-3-( 1 H-l ,2,3-triazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

(4) 7-[2-Ethoxyimino-2-(2-aminothiazol-4yl)acetamido-3-( 1 ,3,4-thiadiazol-2-yl)thiomethyl-3- cephem-4-carboxylic acid (syn isomer).

(5) 7-[2-(2-Propynyloxyim ino)-2-(2-a minothiazol-4-yl-acetamido]-3-( 1 ,3,4-thiadiazol-2yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

(6) 7-[2-Allyloxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-( 1 ,3,4-thiadiazol-2-yI)thiomethyl-3- cephem-4-carboxylic acid (syn isomer).

(7 )-[2-Hexyloxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-( l-methyl-l Htetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

(8) 7-[2-lsopropoxyimino-2-(2-a m inothiazol-4-yl)-aceta mido]-3-( 1 -hexyl- 1 H-tetrazol-5 yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

Test Method In vitro antibacterial activity was determined by the two-fold agar-plate diiution method as described below.

One loopful of an overnight culture of each test strain in Trypticase-soy broth (108 viable cells per ml.) was streaked on heart infusion agar (HI-agar) containing graded concentrations of test compounds, and the minimal inhibitory concentration (MIC) was expressed in terms of Hg/ml. after incubation at 370C for 20 hours.

TEST RESULTS

MIC (pg/ml.) Test Compounds Test Bacteria (1) (2) (3) Pr. vulgaris 1 0.78 0.20 0.39 MIC (llg/ml) Test Compounds Test Bacteria (4) (5) (6) (7) (8) B. subtilis ATOC 6633 0.78 0.39 0.78 0.78 0.78 Test Results For therapeutic administration, the object compound (I) or pharmaceutically acceptable salts thereof of the present invention is used in the form of conventional pharmaceutical preparation which contains said compound, as an active ingredient, in admixture with a pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parental or external administration. The pharmaceutical preparations may be in solid form such as capsule, tablet, dragee, ointment or suppository, or in liquid form for injection such as solution, suspension, or emulsion.If needed, there may be included in the above preparations auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and the other commonly used additives.

While the dosage of the compounds may vary from and also depend upon the age, condition of the patient, a kind of disease, a kind of the compound (I) to be applied, etc., an average single dose or about 10 mg., 50 mg., 100 mg., 250 mg., 500 mg., and 1,000 mg. of the object compound (I) of the present invention has proved to be effective in treating diseases infected by pathogenic bacteria.

In general, daily dose between 1 mg/body and about 6,000 mg/body or even more may be administered to a patient.

The following preparations and examples are given for the purpose of illustrating the present invention:- Preparation 1 (1) ) Ethyl 2-(2-propynyloxyimino)-3-oxobutyrate (syn isomer) (71.2 g) was obtained by reacting ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer) (56.7 g) wlth 2propynyl bromide (43 g) in the presence of potassium carbonate (72.3 g) and N,N-dimethylformamide (280 ml.).

l.R. (Film): 3280,3220,2120,1735, 1670 cm-' (2) Ethyl 2-(2-propynyloxyimino)-3-oxo-4-chlorobutyrate (syn isomer) (61.6 g) was obtained by reacting ethyl 2-(2-propynyloxyimino)-3-oxobutyrate (syn isomer) (71.2 g) with sulfuryl chloride (50.2 g) in acetic acid (81 ml).

l.R. (Film): 3300,2130,1745,1720, 1675 cm-l (3) Ethyl 2-(2-propynyloxyimino)-2-(2aminothiazol-4-yl)acetate (syn isomer) (35.6 g) was obtained by reacting ethyl 2-(2-propynyloxyimino)-3-oxo-4-chlorobutyrate (syn isomer) (61 g) with thiourea (20 g) in the presence of sodium acetate trihydrate (35.8 g) water (150 ml) and ethanol (180 ml).

I.R. (Nujol): 3290,2220, 1729 cm-l (4) 2-(2-propynyloxyimino)-2-(2-aminothiazol-4-yl)acetic acid (syn isomer) (1.924g) was obtained by hydrolyzing ethyl 2-(2-propynyloxyimino)-2-(2-aminothioazol-4-yl)acetate (syn isomer) (2.8 g) in the presence of 1N aqueous soluition of sodium hydroxide (22.17 ml), methanol (23 ml) and tetrahydrofuran (20 ml).

I.R. (Nujol): 2190, 1740 cm-' Preparation 2 Formic acid (107 g) was added to acetic acid anhydride (239 g) under ice-cooling, and the mixture was stirred for 1 hour at 500C and then cooled to 200C. To the mixture was added 2-(2propynyloxyimino)-2-(2amino-thiazol-4-yl-acetic acid (syn isomer) (135 g), and the mixture was stirred for 3 hours at ambient temperature. To the mixture was added diisopropyl ether (400 ml) and then the precipitated crystals were collected by filtration, washed with diisopropyl ether and then dried to give 2-(2-propynyloxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (118.4 g).

I.R. (Nujol): 3250, 2310, 1685, 1600, 1560 cm-1 N.M.R. (d6-DMSO, S): 3.53 (1H, m), 4.87 (2H, d, (J=2Hz), 7.63 (1H, s), 8.61 (1H, s), 12.7 (1H, broad s).

Preparation 3 To a solution of 2-(2-formamidothiazol-4-yl)-glyoxylic acid (30 g) and sodium bicarbonate (12.6 g) in water (1300 ml) was added allyloxyamine hydrochloride (19.8 g), and the mixture was stirred for 7 hours at ambient temperature at pH 6. To the reaction mixture was added ethyl acetate (500 ml).

After the mixture was adjusted to pH 1.9 with 10% hydrochloric acid, the ethyl acetate layer was separated. The ethyl acetate layer was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and then the solvent was distilled off. The residue was pulverized in diisopropyl ether, collected by filtration and then dried to give 2-allyloxyamino-2-(2-formamido-thiazol-4-yl)acetic acid (syn isomer) (25.3 g).

l.R. (Nujol): 3110,1730,1660, I540cm1 N.M.R. (d6-DMSO, ô): 4.70 (2H, m), 5.13-5.60 (2H, m), 5.73-6.27 (1 H, m), 7.57 (1H, s) 8.35 (1 H, s) Preparation 4 (1) Sulfuryl chloride (35.2 g) was added all at once to the stirred solution of ethyl 2-ethoxyimino3-oxobutyrate (syn isomer) (48.9 g) in acetic acid (49 ml) at room temperature, and stirred at the same temperature for an hour. After adding the resultant solution into water (200 ml), the solution was extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride, neutralized with an aqueous solution of sodium bicarbonate and washed with water.

The solution was dried over magnesium sulfate and concentrated under reduced pressure to give ethyl 2-ethoxy-imino-3-oxo-4-chlorobutyrate (syn isomer) (53.8 g), pale yellow oil.

(2) A mixture of ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate (syn isomer) (38.7 g), thiourea (13.2 g), sodium acetate (14.3 g), methanol (95 ml) and water (95 ml) was stirred at 480C for 40 minutes.

After the resultant solution was adjusted to pH 6.5 with an aqueous solution of sodium bicarbonate, the appeared precipitates were collected by filtration and washed with diisopropyl ether to give ethyl 2-ethoxyimino-2-(2-aminothiazol-4-yl)acetate (syn isomer) (14.7 g), mp 130 to 131 C.

I.R. (Nujol): 3450, 3275, 3125, 1715, 1620 cm-1 (3) Ethyl 2-ethoxyimino-2-(2-aminothiazol-4-yl)acetate (syn isomer) (5 g) was added to a mixture of 1 N sodium hydroxide (45.9 ml) and ethanol (30 ml) and stirred at room temperature for 5 hours.

After removing ethanol from the resultant solution under reduced pressure, the residue was dissolved in water (60 ml) and adjusted to pH 2.0 with 10% hydrochloric acid. The solution was subjected to salting-out, and the precipitates were collected by filtration and dried to give 2-ethoxyimino-2-(2aminothiazol-4-yl)acetic acid (syn isomer) (2.9 g).

I.R. (Nujol): 3625, 3225 (shoulder), 3100, 1650, 1615 cm-' N.M.R. (dó-DMSO, b): 1.20 (3H, t, J=7Hz), 4.09 (2H, q, J=7Hz), 6.82 (1 H, s), (2H, broad s) (4) 2-Ethoxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer) (100 g), formic acid (85.5 g) and acetic anhydride (190.1 g) were treated in a similar manner to that of Preparation 2 to give 2ethoxyimino-2-(2formamidothiazol-4-yl)acetic acid (syn isomer) (99.1 g).

I.R. (Nujol): 3200, 3140, 3050, 1700 cm-1 N.M.R. (d6-DMSO, S): 1.18 (3K, t, J=6Hz), 4.22 (2H, q, J=6Kz), 7.56 (1 H, s), 8.56 (1H, s), 12.62 (1H, broad s) Preparation 5 The following compounds were obtained according to similar manners to those of Preparations 1 to 4.

(1) 2-lsopropoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer), mp. 168 to 1690C (dec.).

I.R. (Nujol) : 3200, 3130, 1710, 1600, 1560 cm-1 (2) 2-Butoxyimino-2-(2-formamidothiazol-4-yl)-acetic acid (syn isomer).

I.R. (Nujol): 3350, 3160, 3050, 1700, 1680, 1570 cm-1 (3) 2-Hexyloxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer), mp. 115 to 11 60C (dec.).

I.R. (Nujol): 3170, 3070, 1720, 1700 1660 cm-1 N.M.R. (d6-DMSO, S): 0.6-2.1 (11H, m), 4.15 (2H, t, J=6Hz), 7.53 (1H, s), 8.56 (1H,s), 12.69 (1H, s) (4) 2-Pentyloxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer), mp 1 760C (dec.) I.R. (Nujol): 3160, 1655, 1620, 1460 cm-1 N.M.R. (d6-DMSO, S): 7.20 (2H, s), 6.82 (1H, s),4.07 (2H, t, J=6Kz), 0.6-2.2 (9H, m) (5) 2-Propoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer), mp. 1 640C (dec.).

I.R. (Nujol): 3200, 3120, 3050, 1700, 1550 cm-1 (6) 2-Pentoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer), mp. 1 250C (dec.).

I.R. (Nujol): 3200, 3140, 1700, 1565 cm-1 (7) 2-Allyloxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer), mp 1 870C (dec.).

I.R. (Nujol): 3350, 1630, 1580, 1460 cm-1 (8) 2-Hexyloxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer), mp 1 740C (dec.).

I.R. (Nujol): 1660, 1625, 1425 cm-1 (9) 2-lsopropoxyimino2-(2-aminothiazol-4-yl)acetic acid (syn isomer), mp 151 C (dec.).

(10) 2-lsobutoxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer) mp. 122 to 1240C.

(11) 2-Cyclohexyloxyimino-2-(2-aminothiazol-4-yl)aceticacid (syn isomer), mp. 1480C (dec.).

(12) 2-Propoxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer), mp 161 C (dec.).

(13) 2-lsobutoxyimino-2-(2-formamidothiazol-4-yl)-acetic acid (syn isomer), mp 1 630C (dec.).

Preparation 6 (1) Water (500 ml.) was added to hexylamine (490.0 g.) and a solution of sodium hydroxide (193.6 g.) in water (700 ml.) was added thereto under ice-cooling and stirring. Carbon disulfide (367.8 g) was added dropwise thereto over 2 hours at 2 to 10 C and them methyl iodide (687.3 g) was added dropwise thereto over 1 hour at O to 50C. The resulting mixture was stirred for 30 minutes at the same temperature and for 2 hours at ambient temperature. The reaction mixture was extracted with diethyl ether (1.5 1). The extract was washed with a saturated aqueous solution of sodium chloride (300 ml) dried over magnesium sulfate and concentrated to give an oil of methyl N-hexyldithiocarbamate (825.5 9).

l.R. (Film): 3225, 2960, 2935, 2860 cm-1 N.M.R. (CDCI3,8): 0.86 (3H, t, J=5.0Hz), 1.1 01 .90(8K, m), 2.58 (3H, s), 3.72 (2H, m) (2) Sodium azide (155.9 g) and water (0.8 1) were added under stirring to a solution of methyl Nhexyldithiocarbamate (430 g) in ethanol (1.7 1) and the resulting mixture was refluxed for 3.5 hours at 900 C. Ethanol was distilled off from the reaction mixture and the residue was washed with diethyl ether (11), adjusted to pH 2.0 with conc. hydrochloric acid and extracted with diethy! ether (1 I). The extract was washed with water, dried over magnesium sulfate and concentrated to give an oil of 1hexyl-1 Htetrazol-5-thiol (431.3 g).

I.R. (Film) : 3110, 2960, 2930, 2860 cm-l N.M.R. (CDCl3, S): 0.91 (3H, t, J=5.OHz). 1.10~1.65 (6H, m), 1.97 (2H, m), 4.33 (2H, t, JH=7.0Hz).

(3) To 7-aminocephalosporanic acid (150.0 g) was added 0.2 M phosphate buffer solution (3 1), which was prepared by dissolving sodium biphosphate dihydrate (62.1 g) and disodium hydrogen phosphate (25.5 g) in water (3 1) and the resulting mixture was adjusted to pH 6.5 with 2N aqueous solution of sodium carbonate. To the mixture was added 1-hexyl-1 H-tetrazole-5-thiol (154.6 g) and the resulting mixture was stirred for 2 hours at 60 to 650C and at pH 6.0 to 6.5 with bubbling of nitrogen gas. The reaction mixture was adjusted to pH 3.5 with conc. hydrochloric acid under ice-cooling.

Precipitates were collected by filtration and washed with water, and methanol (4 i) and conc.

hydrochloric acid (400 ml) were added thereto. The mixture was stirred for 2 hours and an insoluble material was filtered off. The filtrate was treated with an activated charcoal and adjusted to pH. 3.5 with 28% aqueous solution of ammonia. Precipitates were collected by filtration, in turn washed with water, acetone and diethyl ether and dried to give powder of 7-amino-3-(1-hexyl-1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (116.38 g).

I.R. (Nujol): 1803,1620,1350cm-1 N.M.R. (d6-DMSO, S): 0.95 (3H, t, J=6.5Hz), 1.26 (6H, m), 1.80 (2H, m), 3.65 (2H, ABq, J=1 8Hz), 4.00-4.50 (4H, m), 4.79 (1H, d, J=6.0Hz), 4.95 (1H, d, J=6.0Hz).

Preparation 7 7Aminocephalosporanic acid (283.0 g) and 1-propyl-1 Htetrazole-5-thiol (225.0 g) were treated in 0.2 M phosphate buffer soiution (5.5 1) in a similar manner to that of Preparation 6-(3) to give 7 amino-3-( 1 -propyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (125.0 g).

I.R. (Nujol): 3300, 1795, 1610 cm-1 N.M.R. (d6-DMSO, S): 0.91 (3H, t, J=7.5Hz), 1.60~2.28 (2H, m), 3.63 (2H, ABq, J=18.0Hz), 3.98~4.58 (4H, m), 5.08 (1 H, d, J=5.0Hz), 5.49 (1 H, d, J=5.0Hz).

Preparation 8 (1) 3-Chlorophenylisocyanate (3.7 g) was added at ambient temperature to a solution of benzhydryl 7-(2-phenylacetamido)-3hydroxymethyl-3-cephem-4-carboxylate (10.3 g) in a mixture of tetrahydrofuran (200 ml) and triethylamine (2.4 g), and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 ml), and the solution was in turn washed with 10% hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride to give a solution containing a mixture of benzhydryl 7-(2-phenylacetamldo)-3-[n-(3-chlorophenyl)-carbamoyloxymethyl]-3- cephem-4-carboxylate and benzhydryl 7-(2-phenylacetamido-3-[N-(3-chlorophenyl)- carba moyloxymethyl]-2-cephem-4-carboxylate.

(2) To the above-obtained ethyl acetate solution was added dropwise at 7 to 1 00C a solution of 3-chloro-perbenzoic acid (5.2 g) in ethyl acetate, and the mixture was stirred for 1 hour at the same temperature. Precipitates were collected by filtration, washed with diethyl ether and dried to give benzhydryl 7-(2-phenylacetamido)-3-[N-(3-chlorophenyl)carbamoyloxy-methyl]-3-cephem-4- carboxylate-1-oxide (7.7 g).

I.R. (Nujol): 3280, 1790, 1700, 1650, 1600, 1530 cm-1 (3) Phosphorus trichloride (3.2 g) was added at -400C to a stirred solution of benzhydryl 7-(2phenyl-acetamido)-3-[N-(3-chlorophenyl)carbamoyloxymethyl]-3-cephem-4-carboxylate-1-oxide (7.6 g) in dimethylformamide (50 ml) and the mixture was stirred for 1 hour at -20 to -400C. The reaction mixture was poured into cooled water. Precipitates were collected by filtration, washed with water and dried to give benzhydryl 7-(2-phenylacetamido)-3-[N-(3-chlorophenyl)-carbamoyloxymethyl]-3- cephem-4-carboxylate (5.0 g).

I.R. (Nujol): 3280, 3190, 1780, 1730, 1710, 1660, 1620, 1600, 1540 cm-1 N.M.R. (d6-DMSO, b): 3.56 (2H, s), 3.64 (2H, s), 4.86 (2H, ABq, J=1 2Hz), 5.14 (1K, d, J=5Hz), 5.76 (1H, d,d, J=5 and 8Hz), 6.95 (1H, s), 7.00~7.70 (19H, m), 9.10(1H, d, J=8Hz), 10.00 (1 H, s) (4) Pyridene (1.9 g) was added to a solution of phosphorus pentachloride (4.93 g) in methylene chloride (50 ml) at 50C and the suspension was stirred for 30 minutes at ambient temperature.To the reaction mixture was added benzyhydryl 7-(2-phenylacetamido)-3-[N-(3chlorophenyl)carbamoyloxymethyl]-3-cephem-4-carboxylate (5.0 g) at 50C and stirred for 1.5 hours at 5 to 7 C to give a homogeneous solution. To the above solution cooled to -300C was added methanol (8 ml). After the solution was stirred for 1 hour at -10 to -200C, water (5 ml) was added and continued to stir for 30 minutes at O to 50C. After removing the solvent under reduced pressure, water (80 ml) and diethyl ether (100 ml) were added to the residue, and the aqueous layer containing oil was separated. The aqueous solution containing oil was adjusted to pH 8.0 with 20% aqueous solution of sodium carbonate and extracted with ethyl acetate.The extracts were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was pulverized with diisopropyl ether to give benzhydryl 7-amino-3-[N-(3chlorophenyl)carbamoyloxymethyl]-3-cephem-4-carboxylate (2.2 g).

I.R. (Nujol): 3410, 3360, 1760, 1700, 1650, 1595, 1520 cm-1 N.M.R. (d6-DMSO, S): 3.60 (2H, broad s), 4.80 (1H, d, J=5Hz), 4.83 (2H, ABq, J=13Hz). 5.05 (1H, d, J=5Hz), 6.93 (1H, s), 6.9-0~7.70 (14H, m), 9.97 (1H, s) Preparation 9 (1) Benzhydryl 7-(2-phenylacetamido)-3-hydroxymethyl-3-cephem-4-carboxylate 910.3 q) and 2 (4-methoxyphenoxy)acetyl chloride (7.4 g) were reacted according to a similar manner to that of Preparation 8 (1) to give a solution containing a mixture of benzhydryl 7-(2-phenylacetamido)-3-[2-(4methoxyphenoxy)acetoxymethyl]-3-cephem4-carboxylate and benzhydryl 7-(2-phenylacetamido)-3 [2-(4-methoxyphenoxy)-acetoxymethyl]-2-cephem-4-carboxylate.

(2) The above-obtained solution was reacted with 3-chloroperbenzoic acid (4.7 g) according to a similar manner to that of Preparation 8-(2) to give benzhydryl 7-(2-phenyZacetamido)-3-[2-(4- methoxyphenoxy)acetoxymethyl]-3-cephem-4-carboxylate- 1-oxide (7.1 g).

I.R. (Nujol): 3270, 1780, 1760, 1720, 1650, 1520, 1500 cm-1 N.M.R. (d6-DMSO, S): 3.63 (2H, s), 3.67 (3H, s), 3.75 (2H, ABq, J=1 9Hz), 4.65 (2H, s), 4.90 (1 H, d, J=5Kz), 4.97 (2H, ABq, J=13Hz), 5.93 (1H, d, d, J=5 and 8Hz), 6.85 (4H, s), 6.96 (1K, s), s),7.00~7.70 (15H, m), 8.41 (1H, d, J=8Hz).

(3) Benzhydryl 7-(2-phenylacetamido)-3-[2-(4-methoxyphenoxy)acetoxymethylj-3- cephem-4-carboxylate-1 -oxide (6.9 g) and phosphorus trichloride (2.7 g) were reacted according to a similar manner to that of Preparation 8-(3) to give benzhydryl 7-(2-phenylacecamido-3-[2-(4methoxyphenoxy)acetoxymethyl]-3-cephem-4-carboxylate (6.1 g).

I.R. (Nujol): 3300,1775,1740,1730, 1650 cm~' N.M.R. (d6-DMSO, #) : 3.50 (4H, broad s),3.63 (3H, s), 4.62 (2H, s),4.83 (2H, ABq, J=13Hz), 5.07 (1H, d, J=5Hz), 5.72 (1H, d,d, J=5 and 8Hz), 6.77 (4H, s), 6.85 (1K, 5), s),6.70~7.60 (15H, m), 9.00 (1H, d, J=8Hz).

(4) Benzhydryl 7-(2-phenylacetamido)-3-[2-(4-methoxyphenoxy)acetoxymethyl]-3-cephem-4carboxylate (6.0 g), phosphorus pentachloride (5.65 g), pyridine (2.2 g) and methanol (7.3 ml) were reacted according to a similar manner to that of Preparation 8-(4) to give benzhydryl 7-amino-3-[2-(4 methoxyphenoxy)acetoxymethyl]-3-cephem-4-carboxylate (4.6 9).

N.M.R. (d6-DMSO, S): 3.52 (2H, broad s),3.68 (3H, s), 4.69 (2H, s), 4.60~5.10 (4H, m), 6.89 (4H, s), 6.96 (1H, s), 7.00~7.70 (10H, m) Preparation 10 The following compounds were obtained according to a similar manner to that of Preparation 8.

(1) Benzhydryl 7-amino-3-(2-thenoyl)oxymethyl-3-cephem-4-carboxylate.

I.R. (Nujol): 3400~3300, 1770, 1710, 1610, 1520 cm-1 N.M.R. (d6-DMSO, S): 3.68 (2H, broad s), 4.90 (1H, d, J=5Hz), 5.03 (2H, ABq, J=13Hz), 5.12 (1H, d, J=5Hz).

6.97 (1K, 5), s), 7.17~7.67 (11H, m), 7.73~8.1 (2H, m) (2) Benzhydryl 7-amino-3-cyclohexanecarbonyloxyrmethyl-3-cephem-4-carboxylate.

I.R. (Nujol): 3200, 1800, 1730, 1620 cm-1 N.M.R. (d6-DMSO, S): 0.83~2.0 (10H, m), 3.07~3.40 (1H, m), 3.58 (2H, broad s), 4.66~5.33 (4H, m), 6.93 (1H, s), 7.0~7.58 (10H, m) (3) Benzhydryl 7-amino-3-(N-phenylcarba moyloxymethyl)-3-cephem-4-carboxylate.

I.R. (Nujol): 3420, 3380, 1770, 1725, 1660, 1600, 1530 cm-1 N.M.R. (d6-DMSO, S): 3.65 (2H, broad s), 4.83 (2H, ABq, J=13Hz), 4.90 (1H, d, J=5Hz), 5.10 (1K, d, J=5Hz), 7.00 (1 H, s), 6.83~7.73 (15H, m), 9.78 (1 H, s).

(4) Benzhydryl 7-amino-3-(4-nitrobenzoyloxymethyl)-3-cephem-4-ca rboxylate hydrochloride.

I.R. (Nujol): 3400, 3350, 1770, 1720, 1630, 1600, 1540 cm-1 N.M.R. (d6-DMSO, S): 3.74 (2H, broad s), 4.72~5.32 (4H, m), 6.92 (1H, s), 7.0~7.64 (10H, m), 8.12 (2H, d, J=9Hz), 8.32 (2H, d, J=9Hz).

Example 1 2-Ethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (3.0 9) and dry ethyl acetate (40 ml) were added at O to 5 C with stirring to a suspension of Vilsmeier reagent prepared from dry dimethylformamide (1.0 g) and phosphorus oxychloride (2.1 g) in dry ethyl acetate (4.0 ml) by conventional method, and the resulting mixture was stirred for 30 minutes at the same temperature.

The solution was added at -1 0C with stirring to a solution of 7-amino-3-(1,3,4-thiadiazol-2- yl)thiomethyl-3-cephem-4-carboxylic acid (3.7 g), trimethylsilylacetamide (10.3 9) and bis(trimethyisilyl)acetamide (6.8 9) in dry ethyl acetate (80 ml), and the mixture was stirred for 1.5 hours at the same temperature. After addition of water (50 ml) to the reaction mixture, an insoluble material was filtered off, and ethyl acetate layer in the filtrate was separated and extracted with an aqueous solution of sodium bicarbonate (50 ml). The aqueous extract was washed with ethyl acetate and acidified to pH 2.0 with conc. hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give powder of 7-[2-ethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3 (1,3,4-thiadiazol2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.3 9).

I.R. (Nujol): 3250, 1780, 1680 cm-1 N.M.R. (d6-DMSO, S): 1.31 (3H, t, J=7.0Hz), 3.77 (2H, m), 4.28 (2H, q, J=7.0Hz), 4.43 (2H, ABq, J=13.0Hz), 5.18 (1 h, d, J=5.4Hz), 5.84 (1H, d,d J=-5.4 and 9.8Hz), 7.42 (1H, s), 8.53 (1 H, s), 9.57 (1 H, s), 9.66 (1H, d, J=9.8 Hz).

Example 2 Phosphorus oxychloride (0.96 g) was added at a time to a suspension of 2-(2-propynyloxyimino) 2-(2-aminothiazol-4-yl)acetic acid (syn isomer) (1.13 g) in dry tetrahydrofuran (10 ml) at 20C and the mixture was stirred for 15 minutes at 2 to 40C. Trimethylsilylacetamide (1.0 g) was added dropwise thereto and the resulting mixture was stirred for 20 minutes at 2 to 60C. Phosphorus oxychloride (0.96 g) was added thereto and the mixture was stirred for 20 minutes. Dry dimethylformamide (0.45 g) was added thereto at a time at 4 to 6 C and the mixture was stirred for 1 hour to give a clear solution. On the other hand, trimethylsilylacetamide (4.6 g) was added to a stirred suspension of 7-amino-3-(1,3,4thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.65 g) in dry ethyl acetate (20 ml) and the solution was stirred for 30 minutes at 40 C.To this solution was added the above-obtained tetrahydrofuran solution at a time at -300C, and the resulting mixture was stirred for 1 hour at -5 to -200C. To the reaction mixture were added water (30 ml) and ethyl acetate (20 ml). An organic layer was separated and extracted with an aqueous solution of sodium bicarbonate. The extract was adjusted to pH 3.0 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water to give 7-[2-(2-propynyl)oxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-( 1 ,3,4-thiadiazol-2- yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.4 g).

I.R. (Nujol): 3300, 1780, 1680 cm-1 N.M.R. (de-DMSO, S): 3.43 (1 H, m), 3.67 (2H, broad s), 4.42 (2H, ABq, J=13Hz), 4.68 (2H, broad s), 5.13 (1 H, d, J=5Kz), 5.77 (1H, d,d, J=5 and 8Hz), 6.77 (1H, s), 7.18 (2H, broad s), 9.50 (1 H, s), 9.60 (1H, d, J=8Hz).

Example 3 The Vilsmeier reagent was prepared from dry dimethylformamide (1.0 g), dry ethyl acetate (4 ml) and phosphorus oxychloride (2.1 g) by the conventional method. Dry ethyl acetate (45 ml) and 2methoxy-imino-2-(2formamidothiazol-4-yl)acetic acid (syn isomer) (2.85 g) were added thereto. This solution was added at -10 C to a stirred solution, which was prepared by stirring for 1 hour at 40 C a mixture of 7-amino-3-(1-hexyl-1Htetrazol-5-yl)thiomethyl3-cephem-4-carboxylic acid (4.5 g), trimethylsilylacetamide (10.4 g) and dry ethyl acetate (90 ml), and the resulting mixture was stirred for 1.5 hours at -5 to - 10 C. Water (50 ml) was added to the reaction mixture and the ethyl acetate layer was separated. Water (40 ml) was added thereto and the mixture was adjusted to pH 7.0 witha saturated aqueous solution of sodium bicarbonate.The aqueous layer was separated, washed with ethyl acetate and adjusted to pH 2.5 to 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried under reduced pressure to give powder of 7-[2-methoxy-imino-2-(2forma midothiazol-4-yl)acetamido]-3-( 1 -hexyl- 1 Htetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (6.18 g).

I.R. (Nujol): 3250,1777,1680 cm~' N.M.R. (d6-DMSC,S): 0.85 (3H, t, J=5.5Hz), 1.65 (6H, m), 2.78 (2H, m), 3.72 (2H, m), 3.93 (3H, s), 4.07-4.59 (4H, m), 5.17 (1 H, d, J=5.0Kz), 5.83 (1 H, d,d, J=5.0, 8.2Hz), 7.46 (1H, s), 9.56 (1H, s), 9.70 (1 H, d, J=8.2Hz).

Example 4 Phosphorus oxychloride (0.92 g) was added dropwise over 3 minutes at -5 to -1 00C to a solution of dimethylformamide (0.44 g) in ethyl acetate (2 ml). Ethyl acetate (20 ml) was added thereto and after 10, minutes, 2-isopropoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetatic acid (syn isomer) (1.29 g), was added thereto at -5 to -10 C. The mixture was stirred for 10 minutes to give a clear solution. On the other hand, 7-amino-3-carbamoyloxymethyl3-cephem-4-carboxylic acid (1.37 g) was dissolved under stirring in a solution of sodium bicarbonate (1.68 g) in water (30 ml), and then acetone (20 ml) was added thereto. To the solution was added dropwise with stirring the ethyl acetate solution obtained above at 0 to 50C and at pH 6.5 to 7.5.After stirring for 20 minutes at the same temperature, the aqueous layer was separated and acetone was distilled off. The remaining aqueous layer was adjusted to pH 3.0 with 10% hydrochloric acid under ice-cooling and stirring. Precipitates were collected by filtration, washed with water and dried to give 7-[2-isopropoxyimino-2-(2-formamido-1,3thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (1.5 g).

i.R. (Nujol): 3450, 3250, 1780, 1710, 1690, 1650 cm-1 N.M.R. (d6-DMSO, S): 9.63 (1H, d, J=8Hz), 8.53 (1H, s), 7.43 (1H, s) 6.60 (1H, s), 5.83 (1H, dd, J=5, 8Hz), 5.20 (1H, d, J=5Hz), 4.77 (2H, ABq, J=14Hz), 4.40 (1H, m), 3.57 (2H, broads), 1.27 (6H, d, J=6Hz) Example 5 Water (0.05 g) was added to a suspension of 2-allyloxyimino-2-(2amino-1 ,3-thiazol4-yl)acetic acid (syn isomer) (1.0 g) in tetrahydrofuran (10 ml). Phosphorus oxychloride (0.84 g) was added thereto at 0 to 50C and the mixture was stirred for 20 minutes at the same temperature.

Trimethylsilylacetamide (0.66 g) was added thereto, the mixture was stirred for 20 minutes at the same temperature, phosphorus oxychloride (0.84 g) was added thereto, the resulting mixture was stirred for 20 minutes at 0 to 50C, dimethylformamide (0.45 g) was added thereto and the resulting mixture was stirred for 1 hour at the same temperature. The resulting solution was added dropwise at -5 to 50C and pH 7.0 to 8.0 to a solution, which was prepared by adding acetone (15 ml) and tetrahydrofuran (15 ml) to a solution of 7-amino-3-(1 ,3,4-thiadiazol-2-yl)thiomethyl3-cephem-4- carboxylic acid (1.45 g) in a mixture of sodium bicarbonate (0.42 g) and water (10 ml). The resulting mixture was stirred for 2 hours under ice-cooling keeping the pH of the mixture at 7.0 to 8.0 and then adjusted to pH 7.5.An insoluble material was filtered off and the filtrate was washed with ethyl acetate. The aqueous layer was adjusted to pH 6.0 and organic solvent in the aqueous layer was distilled off under reduced pressure. The remaining aqueous layer was adjusted to pH 4.0 and an insoluble material was filtered off. The filtrate was adjusted to pH 3.0 and precipitates were collected by filtration and dried to give 7-[2-allyloxyimino-2-(2-amino-1 ,3-thiazol-4-yl)acetamido]-3-( 1 ,3,4- thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.5 g).

I.R. (Nujol) 3350, 1780, 1680, 1630 cm-' N.M.R. (d8-DMSO, d) 9.63 (1 H, d, J=8Hz), 9.57 (1 H, s), 7.23 (2H, m), 6.77 (1 H, s), 6.10(1H, m), 5.83 (1H, dd, J=5, 8Hz), 5.43 (1 H, m), 5.25 (1 H, m), 5.17 (1K, d, J=5Kz), 4.61(2K, m), 4.47 (2H, ABq, J=1 4Hz), 3.72 (2H, m) Example 6 Water (0.1 ml) was added to a suspension of 2-hexyloxyimino-2-(2-amino-1 ,3-thiazol-4-yl)acetic acid (syn isomer) (2.0 g) in tetrahydrofuran (20 ml).Phosphorus oxychloride (1.4 g) was added thereto at 0 to 50C and the mixture was stirred for 20 minutes at the same temperature.

Trimethylsilylacetamide (1.3 g) was added thereto, the mixture was stirred for 20 minutes at the same temperature, phosphorus oxychloride (1.4 g) was added thereto, the resulting mixture was stirred for 20 minutes at 0 to 5 C, dimethylformamide (0.75 g) was added thereto and the resulting mixture was stirred for 1 hour at the same temperature. The resulting solution was at a time added at -200C to a solution of 7-amino-3-(1 H- 1 ,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (3.3 g) in a mixture of tetrahydrofuran (30 ml) and trimethylsiiylacetamide (6.8 g). The resulting mixture was stirred for 1.5 hours at the same temperature.The reaction mixture was post-treated according to similar manners to those of the aforementioned Examples to give 7-[2-hexyloxyimino-2-(2-amino-1 3- thiazol-4-yl)acetamido]-3-( 1 H-1,2,3-triazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.5g).

I.R. (Nujol 3100,1780, 1630 cm-l N.M.R. (d6-DMSO, b) 10.17(1H, d, J=8Hz), 8.17 (2H, m), 7.97 (1H, s), 7.25 (1H, m), 6.70 (1H, s), 5.73 (1H, dd, J=5, 8Hz), 5.13 (1 H, d, J=5Hz), 3.97 (2H, m), 3.60 (2H, m), 1.25 (8H, m), 0.83 (3H, m) Example 7 2-(2-Propynyl)oxyimino-2-(2-amino-l ,3-thiazol-4-yi)acetic acid (syn isomer) (1.2 g) was suspended in tetrahydrofuran (15 ml). Phosphorus oxychloride (1.... g) was added thereto at 0 to 5 C and the mixture was stirred for 20 minutes at the same temperature.Trimethylsilylacetamide (0.5 g) was added thereto, the mixture was stirred for 20 minutes at the same temperature, phosphorus oxychloride (1.0 g) was added thereto, the resulting mixture was stirred for 20 minutes at 0 to 5 C, dimethylformamide (0.5 g) was added thereto and the resulting mixture was stirred for 1 hour at the same temperature. The resulting solution was added dropwise at -5 to 5 C and pH 6.5 to 8.5 to a solution, which was prepared by adding acetone (10 ml) and tetrahydrofuran (10 ml) to a solution of 7amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (1.9 g) in a mixture of sodium bicarbonate (0.4 g) and water (15 ml).

The resulting mixture was stirred for 2 hours under ice-cooling keeping the pH of the mixture at 7.0 to 8.0 and then adjusted to pH 7.5. An insoluble material was filtered off and the filtrate was washed with ethyl acetate. The aqueous layer was adjusted to pH 6.0 and organic solvent in the aqueous layer was distilled off under reduced pressure. The remaining aqueous layer was adjusted to pH 4.0 and an insoluble material was filtered off. The filtrate was adjusted to pH 3.0 and precipitates were collected by filtration and dried to give 7-[2-(2-propynyl)oxyimino-2-(2-amino-1 3- thiazol-4-yl)acetamido]-3-carba moyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (2.2 g).

I.R. (Nujol): 3300, 1770, 1720, 1640 cm-' N.M.R. (d6-DMSO, Us): 9.63 (1H, d, J=8Hz). 7.27 (2H, m), 6.80 (1H, s),6.58 (2H, m), 5.77 (1 H; dd, J=5, 8Hz), 5.15 (1 H, d, J=5Kz), 4.76 (2H, ABq, J=12Hz), 4.73 (2H, s),3.50 (2H, m), 3.45 (1 H, m) Example 8 Phosphorus oxychloride (0.92 g) was added dropwise over 3 minutes at -5 to -1 00C to a solution of dimethylformamide (0.44 g) in ethyl acetate (2 ml).Ethyl acetate (20 ml) was added thereto and after 10 minutes, 2-isopropoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetic acid (syn isomer) (1.29 g) was added thereto at-5 to -1 00C. The mixture was stirred for 10 minutes to give a clear solution. On the other hand, 7-amino-3-(1-methyl-1 H-tetrazol-5-yl)-thiomethyl-3-cephem-4carboxylic acid (1.64 g) was dissolved under stirring in a soiution of sodium bicarbonate (1.68 g) in water (30 ml), and then acetone (20 ml) was added thereto. To the solution was added dropwise with stirring the ethyl acetate solution obtained above at 0 to 50C and at pH 6.5 to 7.5. After stirring for 20 minutes at the same temperature, the aqueous layer was separated and acetone was distilled off.The remaining aqueous layer was adjusted to pH 3.0 with 10% hydrochloric acid under ice-cooling and stirring. Precipitates were collected by filtration, washed with water and dried to give 7-[2isopropoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) 1.7 g).

I.R. (Nujol): 3500, 3300, 1780, 1730, 1680 cm-' N.M.R. (d8-DMSO, 8): 9.62 (1H, d, J=8Hz), 8.53 (1H, s), 7.40 (1H, s), 5.83 (1 H, dd, J=5, 8Hz), 5.17 (1K, d, J=5Hz), 4.1 7 (2H, m), 3.97 (3H, s), 3.73 (2H, broad s), 1.27 (6H, d, J=6Hz) Example 9 Phosphorus oxychloride (0.51 g) was added dropwise over 5 minutes at 50C to a solution of dimethylformamide (0.24 g) in dry ethyl acetate (1 ml).After precipitation of crystals, the mixture was stirred for 30 minutes at 1 OOC, to which were added dry ethyl acetate (9 ml) and at a time 2-methoxy imino-2-[2-(2,2,2-trifluoroacetamido)-l ,3-thiazol-4-yl]acetic acid (syn isomer) (0.89 g) at-10 C. The resulting mixture was stirred for 30 minutes at -10 to -50C. The resulting solution was added dropwise at -1 50C over 5 minutes to a solution of 7-amino-3-benzoyloxymethyl-3-cephem-4carboxylic acid (1.0 g) and trimethylsilylacetamide (3.2 g) in dry ethyl acetate (10 ml), after which the resulting mixture was stirred for 1 hour at 100 to-15 C. To the reaction mixture was added water (10 ml) and the ethyl acetate layer was separated.The aqueous layer was further extracted with ethyl acetate (10 ml). The ethyl acetate layers were combined together and water (20 ml) was added thereto. The resulting mixture was adjusted to about pH 6 with sodium bicarbonate. The aqueous layer was separated and ethyl acetate (25 ml) was added thereto. The mixture was adjusted to pH 2.5 under ice-cooling and stirring with 10% hydrochloric acid. The ethyl acetate layer was separated and the aqueous layer was further extracted witn ethyl acetate (15 ml and 10 ml).The ethyl acetate layers were combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with an activated charcoal and evaporated under reduced pressure to give crystals, which was dried under reduced pressure to give 7-[2-methoxyimino-2-{2-(2,2,2trifluoroacetamido)- 1,3-thiazol-4-yl}acetamido]-3-benzoyloxymethyl-3-cephem-4-carbxylic acid (syn isomer) (1.15 g).

I.R. (Nujol): 3250, 1790, 1730, 1650 cm-' N.M.R. (d6-DMSO, S): 9.95 (1H, d, J=8Hz), 7.92-8.16 (2H, m),7.4-7.84 (3H, m), 7.6 (1 H, s), 5.92 (1 H, dd, J=5, 8Hz), 5.26 (1H, d, J=5Hz), 5.18 (2H, ABq, J=13Hz), 3.96 (3H, s), 3.76 (2H, broad s).

Example 10 Phosphorus oxychloride (0.56 g) was at a time added under 50C to a mixture of 2-methoxyimino 2-(2-amino-1 ,3-thiazol-4-yl)acetic acid (syn isomer (0.6 g) and dry ethyl acetate (6 ml), and the mixture was stirred for 20 minutes at 4 to 60C. Bis(trimethylsilyl)acetamide (0.3 g) was at a time added thereto at the same temperature and the mixture was stirred for 10 minutes at the same temperature. To the resulting mixture was at a time added phosphorus oxychloride (0.56 g) and the mixture was stirred for 30 minutes at the same temperature, to which was added dropwise dimethylformamide (0.24 g) and the resulting mixture was stirred for 30 minutes at 4 to 60C.Thus obtained solution was at a time added with stirring at-15 C to a solution of 7-amino-3-(4nitrobenzoyl)oxymethyl-3-cephem-4-carboxylic acid (1.1 g) and trimethylsilylacetamide (3.5 g) in dry ethyl acetate (20 ml), and the resulting mixture was stirred for 2 hours at -5 to-10 C. The reaction mixture was adjusted to pH 7-7.5 with a saturated aqueous solution of sodium bicarbonate under OOC, stirred for 1 hour at pH 7 under 50C, adjusted to pH 2.5 and filtered. The organic layer in the filtrate was separated, and water (20 ml) was added thereto. The mixture was adjusted to pH 6.5 with sodium bicarbonate. The aqueous layer was separated and washed with diethyl ether. Remaining solvent in the aqueous layer was removed by passing nitrogen gas, and the aqueous layer was adjusted to pH 2.5 with 10% hydrochloric acid under ice-cooling.Precipitates were collected by filtration, washed with water and dried to give pale yellow powder of 7-[2-methoxyimino-2-(2-amino-1 3- thiazol-4-yl)acetamido]3-(4-nitrobenzoyl)oxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.7 g), mp 151 to 163 C (dec.).

I.R. (Nujol) 3250-3350, 2500-2600, 1780, 1725, 1680, 1650, 1600, 1535, 1350 cm-1 N.M.R. (d6-DMSO, S): 9.68 (1H, d, J=8hz), 8.5 (4H, m), 7.28 (2H, s), 6.80 (1H, s), 5.88 (1H, dd, J=5,8Hz), 5.24 (1H, d, J=6Hz), 5.20 (2H, ABq, J=13Hz), 3.82 (3H, s), 3.72 (2H, ABq, J=1 8Hz).

Example 11 The following compounds were obtained according to similar manners to those of Examples 1 to 10.

(1) 7-[2-Isopropoxylmino-2-(2-formsmidothiazol-4-yl)-acetamido]-3-(1,3,4-thiadiazol-2yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300, 3050, 1777, 1727, 1672 cm-1 N.M.R. (d6-DMSO, S): 1.28 (6H, d, J=6Hz), 3.75 (2H, broad s), 4.43 (3H, m). 4.8~5.6 (1 H), 5.90 (1 H, d,d, J=5 and 8Hz), 7.45 (1H, s), 8.58 (1H, broad s), 9.60 (1H, s), 9.77 (1H, d, J=8Hz), 12.80 91H, broad s).

(2) 7-[2-pentyloxyimino-2-(2-formamidothlazol-4-yl)-acetamido]-3-(1,3,4-thiadiazol-2yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) : 3300, 3250, 1785, 1680 cm-1 N.M.R. (d6-DMSO, b): 0.6~1.9 (9H, m), 3.72 (2H, broad s),4.11 (2H, t, J=6Hz), 4.47 (2H, ABq J=13Hz), 5.18 (1H, d, J=5Hz), 5.82 (1 H, d,d, J=5 and 8Hz), 7.41 (1H, 5), 8.53 (1H, s), 9.57 (1H, s), 9.64 (1H, d, J=8Hz), 12.65 (1H, s) (3) 7-[2-Butoxyimino-2-(2-formamidothiazol-4-yl)-acetamido]-3-(1-methyl-1H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300, 2500~2600, 1775, 1710, 1690, 1670, 1645 cm-1 N.M.R. (d6-DMSO. d): 0.90 (3H, m), 1.2~1.8 (4H, m), 3.70 (2H, ABq, J=18Hz), 3.94 (3H, s), 4.12 (2H, m), 4.32 (2H, ABq J=13Hz), 5.16 (1H, d, J=5Hz), 5.80 (1H, d,d, J=6 and 8Hz), 7.37 91H, s), 8.50 (1H, s), 9.62 (1 H, d, J=8Hz), 12.6 (1 H, s).

(4) 7-[2-(2-propynyloxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3240, 2110, 1770, 1665 cm-1 N.M.R. (d6-DMSO, S): 3.49 (1 H, m), 3.70 (2H, m), 3.96 (3H, s), 4.33 (2H, ABq, J=15.0Hz), 4.76 (2H, m), 5.14 (1H, d, J=5.0Hz), 5.80 (1 H, d,d, J=5.0 and 8.0Hz), 7.44 (1H, s), 8.53 (1 H, s), 9.74 (1 H, d, J=8.0Hz).

(5) 7-[2-Methoxyimino-2-(2-formamidothlazol-4-yl)-acetamido]-3-(1-propyl-1H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) : 3180, 1775, 1665 cm-1 N.M.R. (d6-DMSO, S): 0.85 (3H, t, J=8.0Hz), 1.82 (2H, m), 3.69 (2H, m), 3.88 (3H, s), 4.06~4.68 (4H, m), 5.13 (1 H, d), J=5.0Hz), 5.81 (1H, d,d, J=5.0 and 8.0 Hz), 7.42 (1 H, s), 8.52 (1 H, s), 9.65 (1H, d, J=8.0Hz).

(6) 7[2-Allyloxyimino-2-(2-formamidothiazol-4-yl)-acetamido]-3-(1-propyl-1Htetrazol-5yl)thiomethyl3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3180, 1775, 1670 cm-1 N.M.R. (d6-DMSO, S): 0.87 (3H, t, J=8.0Hz), 1.65 (2H, m), 3.73 (2H, ABq, J=16.0Hz), 4.00~4.53 (4H, m), 4.69 (2H, d, J=5.0Hz), 5.00~5.68 (3H, m), 5.68~6.36 (2H, m), 7.45 (1H, s), 8.56 (1H, s,), 9.72 (1H, d, J=8.0Hz).

(7) 7-[2-(2-Propynyloxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-propyl-1H-tetrazol5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3270, 2125, 1780, 1680 cm-1 N.M.R. (d6-DMSO, S): 0.87 (3H, t, J=8.0Hz). 1.84 (2H, m). 3.50 (1H, m0, 3.73 (2H, broad s), 4.03~4.59 (4H, m), 4.78 (2H, m), 5.17 (1 H, d, J=5.0Hz), 5.84 (1 H, d,d, J=5.0 and 8.0Hz). 7.47 (1 H, s), 8.56 (1H, s). 9.76 (1H, d, J=8.0Hz).

(8) 7-[2-Isopropoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-hexyl-1H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3175, 1780, 1670 cm-1 N.M.R. (d6-DMSO, S): 0.66 (3H, t, J=5.0Hz), 1.05~1.57 (6H, m), 1.92 (2H, m), 3.77 (2H, m), 4.10~4.72 (5H, m).

5.24 (1H, d, J=5.0Hz), 5.90 (1H, d,d, J=5.0 and 8.4Hz), 7.43 (1H, s0, 8.56 (1H, s), 9.64 (1H, d, J=8.4Hz).

(9) 7-[2-Hexyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-hexyl-1H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxyiic acid (syn isomer).

I.R. (Nujol) : 3175, 1785, 1642 cm-1 N.M.R. (d6-DMOS, #) : 0.86 (6H, m), 1.00~1.57 (12H, m). 1.57~2.07 (4H, m), 3.75 (2H, m), 3.97~4.60 (8H, m), 5.18 (1 H, d, J=5.2Hz), 5.85 (1 H, d,d, J=5.2 and 8.4Hz), 7.41 (1H, 5), 8.56 (1 H, s),9.65 (1 H, d, J=8.4Hz).

(10) 7-[2-Allyloxyimino-2-(2-formamidothloazol-4-yl)-acetamido]-3-(1-hexyl-1H-tetrazol-5yl)thiomethyl3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3180, 1780, 1680 cm-1 N.M.R. (d6-DMSO, d): 0.84~1.97 (11H, m). 3.68 (2H, ABq, J=18Hz), 4.30 (4H, m), 4.64 (2H, m). 5.00~5.46 (3H, m), 5.56~6.24 (2H, m), 7.37 (1H, s), 8.48 (1H, s), 9.67 (1H, d, J=8Hz).

(11) Benzhydryl 7-[2-methoxyimino-2-92-aminothiazol-4-yl)acetamido]-3cyclohexaneca rbonyloxymethyl-3-cephem-4ca rboxylate (syn isomer).

I.R. (KBr): 3300, 1780, 1730, 1690, 1630 cm-1 N.M.R. (d6-DMSO, #) : 1.0~2.10 (10H, m), 3.13 (1H, m), 3.60 (2H, broad s), 3.93 (3H, s), 4.93 92H, ABq, J=13Hz), 5.22 (1H, d, J=5Hz), 5.83 (1 H, d,d, J=5 and 8Hz), 6.87 (1 H, s), 6.96 (1 h, s), 7.17~7.67 (10H, m), 9.70 (1H, d, J=8Hz).

(12) Benzyhydryl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(4- methoxyphenoxy)acetoxymethyl]-3-cephem-4-carboxylate (syn isomer).

I.R. (Nujol): 3300, 1780, 1725, 1680, 1620, 1530, 1510 cm-1 N.M.R (d6-DMSO, #) : 3.58 92h, broad s), 3.70 (3H, s), 3.87 (3H, s), 4.70 (2H, s), 4.91 (2H, ABq, J=14Hz), 5.22 (1H, d, J-5Hz), 5.92 (1H, d,d, J=5 and 8Hz), 6.78 (1H, s), 6.88 (4H, s), 6.95 (1H, s, 7.04~7.64 (10H, m), 9.64 (1H, d, J=8Hz).

(13) Benzyhydryl 7-[2-methoxylmino-2-(2-aminothiazol-4-yl)acetamido]-3-pivaloyloxymethyl-3cephem-4-carboxylate (syn isomer).

I.R. (Nujol): 3300, 1780, 1725, 1680, 1620, 1530 cm1 N.M.R. (d6-DMSO, S): 1.13 (9H, s), 3.62 (2H, broad s), 3.88 (3H, s),4.86 (2H, ABq, J=14Hz), 5.26 (1H, d, J=5Hz), 5.96 (1H, dd, J=5 and 8Hz), 6.80 (1H, s), 6.98 (1H, s,), 7.12~7.68 (10H, m), 9.73 (1H, d, J=8Hz).

(14) Benzhydryl 7-[2-methoxyimino-2(2-aminothiazol-4-yl)acetamido]-3-(2-thenoyl)oxymethyl3-cephem-4-carboxylate (syn lsomer).

I.R. (Nujol): 3300, 1780, 1710, 1670, 1610, 1510 cm-1 N.M.R. (d6-DMSO, S): 3.73 (2H, broad s), 3.87 (3H, s), 5.03 (2H, ABq, J=13Hz), 5.27 (1 H, d, J=5Hz), 5.93 (1 H, dd, J=5 and 8Hz), 6.77 (1H, s), 6.97 (1H, s), 7.1~7.67 (11H, m), 7.77~8.1 (2H, m), 9.67 (1 H, d, J=8Hz).

(15) benzhydryl 7-[2-methoxyimino-2-(2-aminothiazol4-yl)acetamido]-3-(N-(3chlorophenyl)carbamoyloxymethyl]-3-cephem-4-carboxylate (syn isomer).

I.R. (Nujol): 3300, 1770, 1720, 1670, 1600, 1530 cm-1 N.M.R. (d6-DMSO, S): 3.70 (2H, broad s), 3.90 (3H, s), 4.90 (2H, ABq, J=13Hz), 5.27 (1 H, d, J=5Hz), 5.93 (1H, d,d, J=5 and 8Hz), 6.80 (1 H, s) 6.97 (1H, s), 6.87~7.77 (14H, m), 9.60 (1H, d, J=8Hz), 10.00 (1H,s).

(16) Benzhydryl 7-[2-methoxylmino-2-92-aminothiazol-4-yl)acetamido]-3-(Nphenylcarba moyloxymethyl)-3-cephem4-carboxylate (syn isomer).

I.R. (Nujol): 3300, 1780, 1720, 1675, 1600, 1530, 1500 cm-1 N.M.R. (d6-DMSO, S): 3.63 (2H, broad s), 3.80 (3H, s), 4.80 (2H, ABq, J=13Hz), 5.20 (1 H, d, J=5Hz), 5.86 (1H, d,d, J=5 and 8Hz), 6.73 (1 H, s), 6.93 (1 H, s), 6.83~7.67 (15H, m), 9.57 (1H, d, J=8Hz), 9.73 (1H, s).

(17) 7-[2-(2-Propynyloxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4)thiadiazol-2yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3250, 1780, 1690, 1660, 1620, 1550, 1530 cm1 N.M.R. (d6-DMSO, S): 3.44 (1H, m), 3.68 (2H, ABq, J=18Hz), 4.44 (2H, ABq, J=13Hz), 4.74 (2H, m), 5.16 (1H, d, J=5Hz), 5.80 (1H, d,d J=5 and 8Hz), 7.44 (1H, s), 8.50 (1H, s), 9.76 (1H, d, J=8Hz), 12.66 (1 H, broad sj.

(18) 7-[2-Ethoxylmino-2-92-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl3cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) : 3300, 1775, 1660 cm-1 (19) 7-[2-Isopropoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1,3,4-thiadiazol-2yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3325, 1774, 1656 cm-1 (20) 7-[2-Pentyloxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1,3,4-thiadiazol-2yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3350, 3200, 1775, 1675 cm~1 (21) 7-[2-Butoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1 1-methyl-i H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3350, 3250, 2550~2600, 1780, 1700, 1670, 1630 cm-1 (22) 7-[2-(2-Propynyloxyimino)-2-(2-aminothiazol-4-yl)-acetamido]-3-(1-methyl-1H-tetrazol-5yl)thiomethyl 3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3280, 2130, 1765, 1690, 1630 cm-1 (23) 7-[2-Methoxyimino-2-92-aminothiazol-4-yl)acetamido]-3-(1-propyl-1H-tetrazol-5yl)thiomethyl-3cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3350, 1780, 1670, 1630 cm-1 (24) 7-[2-Allyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-91-propyl-1H-tetrazol-5yl)thiomethyl3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3340, 3230, 1780, 1680, 1630 cm-1 (25) 7-[2-(2-Propynyloxyimino)-2-(2-aminothiazol-4-yl)-acetamido]-3-(1-propyl-1H-tetrazol5-yl-thiomethyl-3-cephem-4-carboxylic acid (syn Isomer).

I.R. (Nujol): 3330. 2150, 1770, 1677, 1635 cm-1 (26) 7-[2-Methoxyimino-2-92-aminothiazol-4-yl)-acetamido]-3-91-hexyl-1H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

i.R. (Nujol): 3350, 3230, 1777, 1675, 1627 cm-1 (27) 7-[2-Isopropoxyimino-2-(2-aminothiazol-4-yl-)acetamido]-3-91-hexyl-1H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3320, 1780, 1675, 1630 cm1 (28) 7-[2-Hexyloxyimino-2-(2-aminothiazol-4-yl)-aceta mido]-3-( 1 -hexyl- 1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3350, 3230, 1765, 1670, 1615 cm-1 (29) 7-[2-Allyloxyimino-2-(2-a m i noth iazcl4-yl)-aceta mido] -3-( 1 -hexyl-1 H-tetrazoi-5yl)thiomethyl-3-cephem-4-carboxylic acid hydrochlorids (syn isomer).

I.R. (Nujol): 3240, 1780, 1720, 1675 cm-1 (30) 7-[2-methoxyimino-2-92-aminothiazol-4-yl)acetamldo]-3-[n-(3 chlorophenyl)carbamoyloxymethyl]-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3320, 1780, 1710, 1680, 1800, 1540 cm-1 (31) 7-[2-methoxylmino-2-(2-aminothiazol-4-yl)acetamido]-3-cyclohexanecarbonyloxymethyl-3cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300, 1780, 1730, 1670 cm-1 (32) 7-[2-Methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(4 methoxyphenoxy)acetoxymethyl]-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300, 1780, 1730, 1680, 1635 cm-1 (33) 7-[2-methoxyimino-2-(2-aminothlazol-4-yl)~acetamido]-3-pivaloyloxymethyl-3-cephem-4carboxylic acid (syn isomer).

I.R. (Nujol): 3300, 1780, 1720, 1670, 1540 cm-1 (34) 7-[2-Methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(2-thenoyl)oxymethyl-3-cephem- 4-carboxylic acid (syn isomer).

I.R. (Nujol) : 3250, 1780, 1710, 1680, 1635, 1530 cm-1 (35) benzhydryl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-94nitrobenzoyloxymethyl)-3-cephem-4-carboxylate (syn isomer).

I.R. (Nujol): 3300, 1780, 1720, 1670, 1600 1520 cm-1 N.M.R. (d6-DMSO, S): 3.43 (2H, broad s), 3.92 (3H, s), 5.08 (2H, ABq, J=1 3 Hz), 5.2 (1H, d, J=5Hz), 6.00 (1H, d,d, J=5 and 8Hz), 6.83 (1H, s), 7.00 (1K, 5), s), 7.10~7.80 (10H, m), 8.15 (2H, d, J=9Hz), 8.38 (2H, d, J-9Hz), 9.73 (1H, d, J=8Hz).

(36) Benzhydryl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(4am inobenzoyloxymethyl)-3-cephem-4-ca rboxylate (syn isomer).

I.R. (Nujol): 3280, 1780, 1710, 1670, 1605, 1520 cm-1 (37) 7-[2-Methoxyimino-2-(2-aminothiazol-4-yl)acetamldo]-3-(4-aminobenzoyloxymethyl)-3cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3350, 1780, 1680, 1605, 1540 cm-1 (38) 7-[2-Methoxylmino-2-(2-aminothiazol-4-yl)acetamido]-3-(N-phenylcarbamoyloxymethyl)3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300, 1780, 1710, 1670, 1600 cm-1 (39) 7-[2-lsobutoxyimino-2-(2-amino- 1 ,3-thiazol-4-yl)-acetamido]cephalosporanic acid (syn isomer).

I.R. (Nujol): 3400-320, 1780, 1740, 1660, 1630, 1540 cm-1 N.M.R. (d6-C!MSO, S): 9.56 (1H, d, J=8Hz), 6.72 (1H, s), 5.78 (1H, dd, J=5.8Hz), 5.14 (1H, d, J=5Hz), 4.83 (2H, ABq, J=14Hz), 3.82 (2H, d, J=7Hz). 3.54 (2H, ABq, J=17Hz), 2.02 (3H, s), 1.98 (1 H, m), 0.88 (6H, d, J=7Hz) (40) 7-[2-Cyclohexyloxylmino-2-(2-amino-1,3-thiazol-4-yl)acetamido]cephalosporanic acid (syn isomer).

I.R. (Nujol): 3400-3200, 1780, 1740, 1670, 1630, 1530 cm-1 N.M.R. (d6-DMSO, S) 9.46 (1 H, d, J=8Hz). 6.72 (1H, s), 5.76 (1H, dd, J=5,8Hz), 5.10 (1H, d, J=5Hz), 4.84 (2H, ABq. J=13Hz), 4.00 (1H, m), 3.50 (2H, broad s). 2.00 (3H, s), 1.00-2.00 (10H, m).

(41) 7-[2-(2-Propynyl)oxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]cephalosporanic acid (syn isomer).

I.R. (Nujol) 3310, 1780, 1740, 1670 cm-1 N.M.R. (d6-DMSO, S): 9.72 (1H, d, J=8Hz). 7.3 (2H, m), 6.83 (1H, s), 5.83 (1H, dd, J=5.8Hz). 5.20 (1H, d, J=5Hz), 4.87 (2H ; Abq, J=13Hz), 4.77 (2H, d, J=2Hz), 3.60 (2H, m), 3.50 (1H, m). 2.11 (3H, s).

(42) 7-[2-Propoxyimino-2-(2-amino-1,3-thiazol-4-yl)-acetamido]-3-(1-methyl-1H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3400-3200, 1780, 1670, 1630, 1535 cm-1 N.M.R. (d6-DMOS, #) 9.57 (1H, d, J-8Hz), 6.72 (1H, s), 5.77 (1H, dd, J=5, 8Hz), 5.13 (1H, d, J=5Hz), 4.30 (2H, ABq, J=14Hz). 4.02 (2H, t, J=7Hz), 3.93 (3H, s), 3.69 (2H, ABq, J=18Hz), 1.64 (2H, m), 0.90 (3H, t, J=7Hz).

(43) 7-[2-Pentyloxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5yl)-thiomethyl-3-cephem-4carboxylic acid (syn isomer).

I.R. (Nujol) 3300, 1770, 1660, 1630 cm1 N.M.R. (d6-DMSO, S): 9.52 (1H, d, J=8Hz), 7.20 (2H, m), 6.68 (1H, s), 5.74 (1H, dd, J=4 8Hz), 5.10 (1H, d, J=4Hz), 4.30 (2H, ABq, J=13Hz), 4.02 (2H, t, J=6Hz), 3.90 (3H, s), 3.66 (2H, ABq, J=18Hz), 1.60 (2H, m), 1.30 (4H, m), 0.82 (3H, t, J=6Hz).

(44) 7-[2-Hexyloxylmino-2-(2-amino-1,3-thiazol-4-yl)-acetamido]-3-(1-methyl-1H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3350, 3250, 1780, 1670, 1630 cm1 N.M.R. (d6-DMSO. #) : 10.25 (1H, d, J=5Hz), 7.25 (2H, m), 6.73 (1H, s), 5.77 (1H, dd, J=5.8Hz), 5.13 (1H, d, J=5Hz), 4.17 (2H, m). 3.91 (3H, s), 3.67 (2H, m), 1.33 (8H, m), 0.83 (3H, m).

(45) 7-[2-Ethoxyimino-2-92-formamido-1,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3500, 3300, 1780, 1710, 1660 cm-1 N.M.R. (d6-DMSO, S): 9.67 (1H, d, J=8Hz), 8.53 (1H, s), 7.43 (1H, s), 6.58 (1H, s), 5.87 (1H, dd, J=5.8Hz), 5.23 (1H, d, J=5Hz), 4.80 92H, ABq, J=13Hz), 4.23 (2H, q, J=7Hz), 3.57 (2h, broad s), 1.3 (3H, t, J=7Hz).

(46) 7-[2-Ethoxyimino-2-(2-amino1,3-thiazol-4-yl)-acetamido]-3-carbamoyloxymethyl-3cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3300, 3200, 1780, 1720. 1660 cm-1 N.M.R. (d6-DMSO, S): 9.58 (1H, d, J=8Hz), 7.33 (1H, broad s), 6.77 (1H, s), 6.58 (1H, s), 5.83 (1H, dd, J=4, 8Hz), 6.20 (1H, d, J=4Hz), 4.77 (2H, ABq, J=12Hz), 4.16 (2H, q, J=7Hz0, 3.53 (2H, broad s), 1.23 (3H, t, J=7Hz).

(47) 7-[2-Propoxylmino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3 carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3250, 3200, 1780, 1700, 1660, 1525 cm-1 N.M.R. (d6-DMSO, S) 9.62 (1 H, d, J=8Hz), 8.50 (1H, s), 7.43 (1H, s), 6.57 (2H, broad s), 5.84 (1K, dd, J=5, 8Hz), 5.18 (1K, d, J=5Hz), 4.58 (2H, ABq, J=13Hz), 4.08 (2H, t, J=7Hz), 3.54 (2H, ABq, J=1 8Hz), 1.68 (2H, m), 0.92 (3H, t, J=7Hz).

(48) 7-[2-Isobutoxyimino-2-92-formaido-1,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3450, 3300, 1780, 1710, 1680, 1610 cm-1 N.M.R. (d6-DMSO, S) 9.6 (1H, d, J=8Hz), 8.5 (1H, s). 7.18 (1H, s), 6.6 (2H, broad s), 5.8 (1H, dd, J=5, 8Hz), 5.15 (1 H, d, J=5Hz), 4.76 (2H, ABq, J=13Hz), 3.84 (2H, d), J=6Hz), 3.5 (2H, ABq, J=1 8Hz), 2.04 (1 H, m), 0.88 (6H, d, J=6Hz).

(49) 7-[2-Isobutoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3cephem-4-carboxylic acid (syn isomer) i.R. (Nujol) 3300, 1770, 1730, 1660 cm-1 N.M.R. (d6-DMSO, S) 9.55 (1 H, d, J=9Hz), 7.27 (2H, broad s), 6.73 (1H, s), 6.60 (1H, broad s), 5.83 (1H, dd, J=5, 9Hz), 5.20 (1H, d, J=5Hz), 4.80 (2H, ABq, J=12Hz), 3.87 (2H, d, J=7Hz), 3.53 (2H, ABq, J=1 8Hz), 0.90 (6H, d, J=7Hz).

(50) 7-[2-Allyloxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3cephem-4-carboxylic acid (syn isomer.

I.R. (Nujol) 3300, 1770, 1720, 1660, 1630 cm-1 N.M.R. (d6-DMSO, S) 9.82 (1 H, d, J=8Hz), 7.20 (2H, m), 6.92 (1 H, s), 6.7 (2H, m), 6.0 (1 H, m), 5.80 (1 H, dd, J=5, 8Hz), 5.40 (1H, m), 5.22 (1 H, m) ; 5.13 (1H, d, J=5Hz, 4.70 (2H, ABq, J=1 4Hz), 4.65 (2H, m), 3.50 (2H, ABq, J=1 6Hz).

(51) 7-[2-propoxyimino-2-92-amino-1,3-thiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3400-3200, 1780, 1670, 1625, 1540 cm-1 N.M.R. (d6-DMSO, S) 9.50 (1K, s), 9.50 (1 H, d, J=8Hz), 6.68 (1 H, s), 5.74 (1H, dd, J=5.8Hz), 5.12 (1H, d, J=5Hz). 4.40 (2H, ABq, J=14Hz), 3.98 (2K, t, J=7Hz). 3.66 (2H, ABq, J=17Hz), 1.62 (2H, m), 0.87 (3H, t, J=7Hz).

(52) 7-[2-Ethoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1H-1,2,3-triazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3500, 3200, 1780, 1670, 1620 cm-1 N.M.R. (d6-DMSO, S) 9.64 (1H, d, J=8Hz), 8.5 (1H, s), 7.9 (1H, s), 7.4 (1H, s), 5.76 (1H, dd, J=4,8Hz), 5.14 (1H, d, J=4Hz), 4.1 (2H, q, J=7Hz), 3.92 (2H, ABq, J=13Hz), 3.58 (2H, ABq. J=18Hz), 1.26 (6H, t, J=7Hz).

(53) 7-[2-Ethoxyimino-2-(2-amino- 1 ,3-thiazol-4-yi)-acetamido]-3-( 1 H-1,2,3-triazol-5- yl)thiomethyi-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3350, 3150, 1770, 1670 cm-1 N.M.R. (d6-DMSO, S) 9.56 (1H, d, J=SHz), 7.92 (1H, s), 7.28 (1H, m), 6.75 (1H, s), 5.75 (1H, dd, J=5, 9Hz), 5.06 (1H, d, J=5Hz), 4.05 (2H, q, J=7Hz), 3.9 (2H, m), 3.64 (2H, ABq, J=17Hz). 1.24 (3H, t, J=7Hz).

(54) 7-[2-Propoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1H-1,2,3-triazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3300-3100, 1780, 1680, 1650, 1550 cm-1 N.M.R. (d6-DMSO, S) 9.62 (1H, d, J=8Hz), 8.50 (1H, s), 7.92 (1H, s), 7.38 (1H, s), 5.78 (1H, dd, J=5, 8Hz), 5.15 (1H, d, J=5Hz), 4.20-3.70 (4H, m), 3.65 (2H, ABq, J=17Hz), 1.66 (1 H, m), 0.90 (3H, t, J=7 Hz).

(55) 7-[2-Propoxyimino-2-(2-amino-l ,3-thiazol-4-yl)-acetamido]-3-( 1 H-1,2,3-triazol-5- yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3400-3100, 1770, 1670, 1630, 1530 cm-1 N.M.R. (d6-DMSO, S) 9.58 (1H, d, J=8Hz), 7.97 (1H, s), 6.77 (1H, s), 5.78 (1H, dd, J=5, 8Hz), 5.18(1H, d, J=5Hz), 4.23-3.76 (4H, m), 3.67 (2H, broad s), 1.67 (2H, m), 0.93 (3H, t, J=7Hz).

(56) 7-[2-lsopropoxyimino-2- (2-amino-1 ,3-thiazol-4-yl)acetamido]-3-(1 1 H-1 ,2,3-triazol-5- yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3300, 3150, 1780, 1670, 1640 cm-1 N.M.R. (d6-DMSO, S) 9.50 (1H, d, J=9Hz), 7.97 (1H, s), 6.73 (1H, s), 5.77 (1H, dd, J=5, 9Hz), 5.17 (1H, d, J=5Hz), 4.33 (1H, m), 4.0 (2H, ABq, J=13Hz). 3.67 (2H, ABq, J=18Hz). 1.23 (6H, d, J=6Hz).

(57) 7-[2-Isobutoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1H-1,2,3-triazole-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol 3470, 3320, 3200,3 160, 1770, 1660 cm-1 N.M.R. (d6DMSO, S) 9.57 (1 H, d, J=9Hz),7.97 (1H, s), 7.22 (2H, broad s), 6.75 (1H, s). 5.77 (1H, dd, J=5, 9Hz), 5.18 (1H, d, J=5Hz), 4.03 (2H, ABq, J=12Hz), 3.88 (2H, d, J=6Hz), 3.70 (2H, ABq, J=1 8Hz), 2.0 (1 H, m), 0.92 (6H, d, J=6Hz).

(58) 7-[2-(2-Propynyl)oxyimino-2-(2-amino-1,3-thiaozl-4-yl)acetamido]-3-(1H-1,2,3-triazol-5yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3320, 3150, 1770, 1670, 1630 cm-1 N.M.R. (d6-DMSO, #) 9.67 (1H, d, J=8Hz), 7.98 (1H, s), 6.83 (1H, s), 5.75 (1H, dd, J=4,8Hz), 5.18 (1H, d, J=4Hz). 4.77 (2H, m), 4.0 (2H, ABq, J=13Hz), 3.70 (2H, ABq, J=1 8Hz), 3.48 (1H, m).

(59) 7-[2-Isopropoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300,3200, 1780, 1720, 1640 cm-1 (60) 7-[2-Propoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem 4-carboxylic acid hydrochloride (syn isomer) I.R. (Nujol) 3350, 3200, 1770, 1720, 1665, 1630, 1550, cm-1 (61) 7-[2-Isopropoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-91-methyl-1H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3330, 3250, 1780, 1680 cm-1 (62) 7-[2-methoxyimino-2-[2-(2,2,2-trifluoroacetamido)-1,3-thiazol-4-yl)acetamido]-3-(4nitrobenzoyl)oxymethyl-3-cephem-4-carboxylic acid (syn isomer), pale yellow powder.

I.R. (Nujol) 3200, 2500-2600, 1785, 1720, 1680, 1650, 1600, 1525, 1355 cm-1 N.M.R. (d6-DMSO, S) 9.80 (1H, d, J=8Hz), 8.4 (4H, m), 7.60 (1H, s), 5.78 (1H, dd, J=5,8Hz). 5.25 (1 H, d, J=5Hz). 5.15 (2H, ABq. J=13Hz), 3.94 (3H, s), 3.75 (2H, Abq. J=18Hz).

(63) 7-[2-Methoxyimino-2-92-amino-1,3-thiazol-4-yl)acetamido]-3-benzoyloxymethyl-3cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3300, 1780, 1720, 1680 cm-1 N.M.R. (d6-DMSO, S) 9.63 (1H, d, J=8Hz), 7.87-8.1 (2H, m), 7.48-7.75 (3H, m), 6.75 (1H, s), 5.83 (1H, dd, J=5,8Hz), 5.19 (1H, d, J=5Hz), 5.15 (2H, ABq, J=13Hz), 3.83 (3H, s),3.72 (2H, broad s).

(64) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-phenylacetoxymethyl-3cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3350, 3300, 1780, 1710, 1660, 1542, 1535, 1460, 1400, 1380, 1320, 1280, 1260, 1240, 1130, 1115, 1065, 1042, 965, 720 cm-1 N.M.R. (d6-DMSO, S) 7.33 (5H, s), 7.23 (2H, broad s), 6.78 (1H, s), 5.81 (1H, dd, J=4, 8Hz), 5.18 (1H, d, J=4Hz).

4.78 and 5.06 (2H, ABq, J=8Hz), 3.9 (3H, s), 3.73 (2H, s), 3.5 (2H, broad s).

(65) 7[2-Methoxylmino-2-(2-amino-1,3-thiazol-4-yl)acetsmido]-3-hexanoyloxymethyl-3cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3350,3300,1780,1700, 1660,1535,1460,1400, 1375,1340,1315,1280, 1255, 1045 cm-1 N.M.R. (d6-DMSO, S) 9.63 (1 H, d, J=8Hz), 7.24 (2H, broad s), 6.76 (1H, s), 5.81(1K, dd, J=4, 8Hz), 5.17 (1K, d), J=4Hz), 4.75 and 5.03 (2H, ABq, J=12Hz), 3.84 (3H, s), 3.45 and 3.67 (2H, ABq, J=1 8Hz), 2.32 (2H, t, J=8Hz), 1-1.7 (6H, m), 0.85 (3H, t, J=3Hz).

(66) 7-[2-Methoxyimino-2-(2-formamido-1,3-thiazol-4-yl)-acetamido]-3-(2benzothlazoyl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3200, 1780, 1680, 1620, 1545, 1460, 1435, 1385, 1040, 1000 cm-1 N.M.R. (d6-DMSO, S) 9.7 (1 H, d, J=8Hz), 8.53 (1 H, s), 7.68-8.16 (2H, m), 7.16-7.66 (3H, m), 5.83 (1H, dd, J=5.8Hz), 5.18 (1H, d, J=5Hz), 4.23 and 4.81 (2H, ABq, J=15Hz), 3.93 (3H, s), 3.73 (2H, broad s).

(67) 7-[2-Propoxyimino-2-92-formamldothiazol-4-yl)-acetamido]-3-methyl-3-cephem-4carboxylic acid (syn isomer).

I.R. (Nujol): 3450, 3300, 1775, 1725, 1680, 1655, 1620, 1590, 1555 cm-1 N.M.R. (d6-DMSO, #) 0.88 (3H, t, J=7Hz), 1.67 (2H, m), 2.00 (3H, s), 3.43 (2H, ABq, J=14Hz), 4.03 (2H, t, J=7Hz), 5.10 (1H, d, J=5Hz), 5.75 (1H, d,d, J=5 and 8Hz), 7.40 (1H, s). 8.53 (1 H, s), 9.60 (1 H, d, J=8Hz), 12.7 (1 H, broad s) (68) 7-[2-Hexyloxyimino-2-(2-formamidothlazol-4-yl)-acetamido]-3-methyl-3-cephem-4carboxylic acid (syn isomer).

I.R. (Nujol): 3310, 3230, 3080, 1780, 1690, 1660 cm-1 N.M.R. (d6-DMSO, S): 0.6-2.2 (11 H, m), 2.05 (3H, s), 3.64 (2H, ABq, J=19Hz), 4.12 (2H, t, J=6Hz), 5.13 (1H, d, J=5Hz), 5.74 (1H, d,d, J=5 and 8Hz), 7.41 (1H, s). 8.52 (1H, s), 9.57 (1H, d, J=8Hz), 12.69 (1 H, broad s).

(69) 7-[2-Propoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-methyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3300, 1775, 1655, 1635, 1545 cm-1 (70) 7-[2-Hexyloxyimino-2-(2-aminothiazol-4-yl)aceta mido]-3-methyl-3-cephem-4-ca rboxylic acid (syn isomer).

I.R. (Nujol): 3420, 3170, 3070, 1765, 1720, 1670, 1630 cm-1 Example 12 Conc. hydrochloric acid (0.85 g) was added under ice-cooling to a stirred solution of 7-[2ethoxyimino-2-(2-formamidothiazol-4-yl)aamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4carboxylic acid (syn isomer) (2.3 g) in a mixture of a methanol (23 ml) and tetrahydrofuran (23 mull, and the mixture was stirred for 2.5 hours at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate (pH 7.0). The aqueous solution was washed with ethyl acetate and adjusted to pH 3.5 with conc.

hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give powderr of 7-[2-ethoxyimino-2-(2-aminothiazol-4-ylacetamldo]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3cephem-4-carboxylic acid (syn isomer) 1.865 g).

l.R. (Nujol): 3300, 1775, 1660 cm- N.M.R. (d6-DMSO, S): 1.67 (3H, t, J=7.6 Hz), 3.75 (2H, m), 4.16 (2H, q, J=7.6Hz), 4.48 (2H, ABq, J=13.6Hz), 5.18 (1K, d, J=5.2Hz), 5.83 (1H, d,d, J=5.2 and 8.0Hz), 6.79 (1H, s), 7.38 (2H, broad s), 9.63 (1H, s), 9.63 (1H, d, J=8.0Hz).

Example 13 Conc. hydrochloric acid (2.1 g) was added under ice-cooling and stirring to a solution of 7-[2 methoxy-imino-2-(2-formamidothiazol-4-yl)acetamido]-3-( 1 -hexyl- 1 H-tetrazol- 5-yl)thiomethyl-3-.

cephem-4-carboxylic acid (syn isomer) (6.0 g) in methanol (60 ml), and the mixture was stirred for 4 hours at ambient temperature. The solvent was removed from the reaction mixture and ethyl acetate (50 g) was added thereto. The mixture was adjusted to pH 7.0 under stirring with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was separated, washed with ethyl acetate and adjusted to pH 3.5 with conc. hydrochloric acid. Precipitates were collected by filtration, washed with water and dried under reduced pressure to give powder of 7-[2-methoxyimino-2-(2-aminothiazol-4yl)acetamido]-3-(1-hexyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (4.62 si.

I.R. (Nujol): 3350,3230, 1777, 1675, 1627 cm-t N.M.R. (d6-DMSO, S): 0.82 (3H, t, J=5.0Hz), 1.23 (6H, m), 1.80 (2H, m), 3.69 (2H, m), 3.85 (3H, s), 4.05~4.63 (4H, m), 5.12 (1H, d, J=5.0Hz), 5.75 (1H, d,d, J=5.0, 8.6Hz), 6.76 (1 H, s), 7.23 (2H, broad s), 9.59 (1H, d, J=8.6Hz) Example 14 Conc. hydrochloric acid (1 ml) was added to a solution of 7-[2-isopropoxyimino-2-(2-formamido 1 ,3-thiazol-4-yl)acetamido]-3-carba moyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (1.3 g) in a mixture of tetrahydrofuran (10 ml) and methanol (10 ml).The mixture was stirred for 3.5 hours at ambient temperature and then concentrated to dryness. Water was added to the residue and to the mixture was added sodium bicarbonate to give a solution. The solution was adjusted to pH 3.0 with conc. hydrochloric acid under ice-cooling. Precipitates were collected by filtration, washed with water and dried to give 7[2-isopropoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-carbamoyl- oxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.25 g).

I.R. (Nujol) 3300, 3200, 1780, 1720, 1640 cm-1 N.M.R. (d6DMSO, S) 9.48 (1 H, d, J=8Hz), 7.24 (2H, broad s), 6.7 (1 H, s), 6.54 (1H, s), 5.75 (1 H, dd, J=5, 8Hz), 5.16 (1H, d, J=5Kz), 4.72 (2H, ABq, J=13Hz), 4.3 (1H, m), 3.5 (2H, broad s), 1.22 (6H, d, J=6Hz) Example 15 7-[2-Propoxyimino-2-(2-formamido-1,3-thiaszol-4-yl)acetamido]-3-carbamoyloxymethyl-3cephem-4-carboxylic acid (syn isomer) (0.5 g) was suspended in methanol (15 ml). To the suspension was added conc. hydrochloric acid (0.2 ml) and the mixture was stirred for 2 hours at ambient temperature. The reaction mixture was concentrated and the residue was washed with tetrahydrofuran, collected by filtration and dried to give 7-[2-propoxyimino-2-(2-amino-1 ,3-thiazol-4- yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer) (0.4 g).

I.R. (Nujol) 3350, 3200, 1770, 1720, 1665, 1630, 1550 cm-1 N.M.R. (d6-DMSO, S) 9.82 (1 H, d, J=8Hz), 6.98 (1 H, s), 5.80 (1 H, dd, J=5,8Hz), 5.22 (1H, d, J=5Hz), 4.80 (2H, ABq, J=14Hz), 4.15 (2H, t, J=7Hz), 3.58 (2H, broad s), 1.72 (2H, m), 0.92 (3H, t, J=7Hz) Example 16 Conc. hydrochloric acid (1 ml) was added to a solution of 7-[2-isopropoxyimino-2-(2-formamido- 1 ,3-thiazol-4-y)aceta mido]-3-( 1-methyl-1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.5 g) in a mixture of tetrahydrofuran (12 ml) and methanol (12 ml). The mixture was stirred for 3.5 hours at ambient temperature and then concentrated to dryness. Water was added to the residue and to the mixture was added sodium bicarbonate to give a solution.The solution was adjusted to pH 3.0 with conc. hydrochloric acid under ice-cooling. Precipitates were collected by filtration, washed with water and dried to give 7-[2-isopropoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3- (1-methyl-1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.8 g).

I.R. (Nujol) 3330, 3250, 1780, 1680 cm-1 N.M.R. (d8-DMSO, S) 9.50 (1H, d, J=8Hz), 6.70 (1H, s), 5.83 (1H, dd, J=5, 8Hz), 5.17 (1K, d, J=5Hz), 4.33 (2H, broad s),3.97 (3H, s). s), 3.71 (2H, broad s), 1.25 (6H, d, J=6Hz) Example 17 A solution of 7-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)- 1,3-thiazol-4-yl iacetamido]-3- benzoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (1.1 g) in acetone (4 ml) was added at ambient temperature to a solution of sodium acetate trihydrate (2.4 g) in water (10 ml), and the mixture was allowed to stand for 3 days at ambient temperature.Acetone was distilled off under reduced pressure and water (10 ml) was added thereto. The resulting mixture was adjusted to pH 2.5 with 10% hydrochloric acid under ice-cooling. Precipitates were collected by filtration, washed with water and dried under reduced pressure to give 7-[2-methoxyimino-2-(2-amino-1 ,3-thiazol-4- yl)acetamido]-3-benzoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.62 g).

I.R. (Nujol) 3300, 1780, 1720, 1680 cm1 N.M.R. (d6-DMSO, S) 9.63 (1H, d, J=8Hz), 7.87-8.1 (2H, m), 7.48-7.75 (3H, m), 6.75 (1H, s), 5.83 (1H, dd, J=5.8Hz), 5.19 (1H, d, J=5Hz), 5.15 (2H, ABq, J=13Hz), 3.83 (3H, s),3.72 (2H, broad s) Example 18 The following compounds were obtained according to similar manners to those of Examples 12 to 17.

(1) 7-[2-Isopropoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2 yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3325, 1774, 1656 cm-1 N.M.R. (d6-DMSO, S) 1.22 (6H, d, J=6Hz), 3.70 (2H, broad s), 4.37 (3H, m), 5.15 (1 H, d, J=5Hz), 5.77 (1H, d,d, J=5 and 8Hz), 6.70 (1H, s), 7.20 (2H, m), 9.50 (1H, d, J=8Hz), 9.55 (1H, s) (2) 7-[2-Pentyloxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3350, 3200, 1775, 1675 cm-1 N.M.R. (d6-DMSO, S) 0.62~2.0 (9H, m), 3.72 (2H, broad s),4.06 (2H, t, J=6Hz), 4.45 (2H, ABq, J=13Hz), 5.17 (1H, d, J=5Hz), 5.78 (1H, d,d, J=5 and 8Hz), 6.73 (1H, s), 7.2 (2H, s), 9.5 (1H, d, J=8Hz), 9.55 (1H, s0.

(3) 7-[2 Butoxyimino-2-(2-a minothiazol-4-yl)acetamido]-3-(1 i-methyl- 1 H-tetrazol-5- yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3350, 3250, 2550~2600, 1780, 1700, 1670, 1630 cm-1 N.M.R. (d6-DMSO, S) 1.0 (3H, m), 1.2~1.7 (4H, m), 3.77 (2H, ABq. J=19Hz), 3.95 (3H, s), 4.15 (2H, m), 4.33 (2H, ABq, J=13Hz), 5.20 (1H, d, J=5Hz), 5.82 (1H, dd, J=5,8Hz), 6.73 (1H, s), 9.56 (1H, d, J=8Hz) (4) 7-[2-(2Propynyloxyimino)-2-(2-aminothiazol-4-yl)-acetamido]-3-91-methyl-1H-tetrazol-5yi)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3280, 2130, 1765, 1690, 1630 cm-1 N.M.R. (d6-DMSO, #) 3.45 (1H, m). 3.70 (2H, m), 3.96 (3H, s), 4.33 (2H, ABq, J=16Hz), 4.71 (2H, m). 5.14 (1H, d, J=5.0Hz), 5.79 (1H, dd, J=5.0 and 8.0Hz). 6.79 (1H, s), 7.65 (2H, broad s), 9.33 (1H, d, J=8.0Hz) (5) 7-[2-Methoxyim ino-2-92-aminothiazol-4-yl)acetamido]-3-(1 -propyl- 1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3350, 1780, 1670, 1630 cm-1 N.M.R. (d6-DMSO, S) 0.87 (3H, t, J=7.0Hz), 1.84 (2H, m), 3.73 (2H, broad s), 3.89 (3H, s), 4.06~4.72 (4H, m), 5.14 (1H, d, J=5.0Hz), 5.80 (1H, d,d, J=5.0 and 8.0Hz). 6.78 (1H, s), 7.23 (2H, broad s), 9.59 (1H, d, J=8.0Hz) (6) 7-[2-Allyloxyimino-2-(2-a minothiazol-4-yl)acetamido]-3-( 1 -propyl- 1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3340, 3230, 1780, 1680, 1630 cm1 N.M.R. (d6-DMSO, S) 0.86 (3H, t, J=7.0Hz), 1.83 (2H, m), 3.71 (2H, broad s),4 .05~4.80 (6H, m), 5.01~5.53 (3H, m), 5.63~6.42 (2H, m), 6.75 (1H, s), 7.20 (2H, broad s), 9.59 (1H, d, J=8.2Hz) (7) 7-[2-(2-Propynyloxyimino)-2-(aminothiazol-4-yl)-acetamidoj-3-( 1 -propyl- 1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3330, 2150, 1770, 1677, 1635 cm-1 N.M.R. (d6-UMSO, S) 0.88 (3H, t, J=7.0Hz), 1.84 (2H, m), 3.49 (1H, m), 3.73 (2H, m), 3.91~4.60 (4H, m). 4.75 (2H, m). 5.17 (1H, d, J=5.0 Hz), 5.80 (1H, d,d J=5.0 and 8.0 Hz). 6.86 (1H, s). 9.72 (1H, d, J=8.0Hz) (8) 7-[2-Isopropoxyimino-2-(2aminothiazol-4-yl)-acetamido]-3-(1-hexyl-1H)-tetrazol 5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3320, 1780, 1675, 1630 cm-1 N.M.R. (d6-DMSO, S) 0,84 (3H, t, J=6.l0Hz), 1.00~1.50 (12H, ml, 1.80 (2H, m), 3.72 (2H, ABq, J=17.0Hz).

4.10~4.60 (5H, m). 5.15 (1H, d, J=5.0 Hz), 5.81 (1H, d,d, J=5.0, 8.0Hz), 6.77 1H, s), 9.59 (1H, d, J=8.0Hz) (9) 7-[2-Hexyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-hexyl-1H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3350, 3230, 1765, 1670, 1615 cm-1 N.M.R. (d8-DMSO, S) 0.84 (6H, m), 1.26 (12H, m), 1.70 (4H, m), 3.20~4.60 (8H, m), 5.40 1H, d, J=5.0Hz), 5.68 (1H, d,d, J=5.0, 8.0Hz), 6.72 (1H, s), 7.23 (2H, broad s), 9.49 (1H, d, J=8.0Hz) (10) 7-[2-Allyloxyimino-2(2-aminothiazol-4-yl)-acetamido]-3-( -hexyl- H-tetrazol-5 yl)thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer).

I.R. (Nujol) 3240, 1780, 1720, 1675 cm-1 N.M.R. (d6-DMSO, S) 0.63~2.13 (11H, m), 3.73 (2H, ABq, J=18Hz), 4.08~4.90 (6H, m), 5.10~6.30 (5H, m).

6.94 (1H, s), 7.93 (2H, broad s), 9.80 (1H, d, J=8Hz) (11) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(4-nitrobenzoyl-oxymethyl3-cephem-4-carboxylic acid (syn isomer), pale yellow powder, mp 151 to 1 630C (dec.).

I.R. (Nujol) 3250-3350, 2500-2600, 1780, 1725, 1680, 1650, 1600, 1535, 1350 cm-1 N.M.R. (d6-DMSO, S) 9.68 (1H, d, J=8Hz), 8.5 (4H, m), 7.28 (2H, s), 6.80 (1H, s), 5.88 (1H, dd, J=5,8Hz), 5.24 (1H, d, J=5Hz), 5.20 (2H, ABq, J=1 3Hz, 3.82 (3H, s), 3.72 (2H, ABq, J=18Hz) (12) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-phenylacetoxymethyl-3cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol 3350, 3300, 1780, 1710, 1660, 1542, 1535, 1460, 1400,1 380, 1320, 1280, 1260, 1240,1130,1115,1065, 1042,965,720cm1 N.M.R. (d6-DMSO, S) 7.33 (5H, s), 7.23 (2H, broad s), 6.78 (1 H, s), 5.81 (1H, dd, J=4, 8Hz), 5.16 (1 H, d, J=4Hz), 4.78 and 5.06 (2H, ABq, J=8Hz), 3.9 (3H, s), 3.73 (2H, s),3.5 (2H, broad s) (13) 7-[2-Methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-hexanoyloxymethyl-3cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3350,3300,1780,1700, 1660,1535,1460,1400, 1375,1340,1315,1280, 1255, 1045 cm-1 N.M.R. (d6-DMSO, S) 9.63 (1 H, d, J=8Hz), 7.24 (2H, broad s), 6.76 (1H, s), 5.81 (1H, dd, J=4.8Hz), 5.17 (1 K, d, J=4Hz), 4.75 and 5.03 (2H, ABq, J=12Hz), 3.84 (3H, s), 3.45 and 3.67 (2H, ABq, J=18Hz), 2.32 (2H, t, J=8Hz), 1-1.7 (6H, m), 0.85 (3H, t, J=3Hz) Furthermore, according to similar manners to those of Examples 12 to 17, the object compounds of Examples 2 and 5-7 and the compounds of Examples 11 11(11)-11 1(16), 11 (30)-(44), 11(46), 11(49)-11(51), 11(53), 11(55)-11(58) and 11(69)-11(70)were also obtained.

Example 19 Trifluoroacetic acid (10.1 g) was added under ice-cooling to a stirred solution of benzhydryl 7-[2 methoxyimino-2-(2-a m inothiazol-4-yl)acetamido]-3-(N-phenylcarbamoyloxymethyl-3-cephem-4- carboxylate (syn isomer) )3.1 g) and anisole (3.8 9) in methylene chloride (30 ml), and the mixture was stirred for 30 minutes at ambient temperature. After removing methylene chloride from the reaction mixture, diethyl ether was added thereto. Precipitates were collected by filtration. Water and ethyl acetate were added to the precipitates, and the mixture was adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate. The separated aqueous solution was adjusted to pH 6.0 with 10% hydrochloric acid, washed with ethyl acetate and evaporated to remove organic solvent.The aqueous solution was adjusted to pH 3.0 with 10% hydrochloric acid under ice-cooling, and precipitates were collected by filtration and dried to give 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetaMido]-3-(N- phenylcarbamoyloxymethyl)-3-cephem-4-carboxylic acid (syn isomer) (1.35 9).

I.R. (Nujol) 3300 1780, 1710, 1670, 1600 cm-1 N.M.R. (d6-DMSO, S) 3.67 (2H, broad s). 3.91 (3H, s). 4.98 (2H, ABq, J=13Hz), 5.23 (1H, d, J=5Hz), 5.83 (1H, d,d, J=5 and 8Hz), 6.83 (1H, s), 6.97~7.67 (5H, m), 9.67 (J1/2H, d, J=8Hz), 9.8 (1H, s) Example 20 The following compounds were obtained according to a similar manner to that of Example 19 (1) 7-[2-Methoxyimino-2-(2-aminothiazol-4-yl)aceta mido]-3-[N-(3 chlorophenyl)carbamoyloxymethyl)-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3320, 1780, 1710, 1680, 1600, 1540 cm-1 N.M.R. (d6-DMSO, #) 3.67 (2H, broad s), 3.90 (3H, s), 4.95 (2H, ABq, J=13Hz), 5.20 (1H, d, J=5Hz), 5.81 (1H, d,d, J=5 and 8Hz), 6.78 (1H, s), 6.83~7.76 (4H, m), 9.63 (1H, d, J=8Hz), 10.1 (1H, s) (2) 7-[2-Methoxylmino-2-(2-aminothiazol-4-yl)acetamido]-3-cyclohexanecarbonyloxymethyl-3cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3300, 1780, 1730, 1670 cm-1 N.M.R. (d6-DMSO, #) 1.0~2.03 (10H, m), 3.53 (2H, broad s), 3.83 (1H, m), 3.87 (3H, s), 4.88 (2H, ABq, J=13Hz), 5.18 (1H, d, J=5Hz), 5.82 (1H, d,d, J=5 and 8Hz), 6.77 (1H, s), 7.28 (2H, broad s), 9.62 (1H, d, J=8hz) (3) 7-[2-Methoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-[2-(4methoxyphenoxylacetoxymethyl]-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol) 3300, 1780, 1730, 1680, 1635 cm-1 N.M.R. (d6-DMSO, S) 3.52 (2H, ABq, J=17Hz), 3.68 (3H, s), 3.93 (3H, s), 4.74 (2H, s),4.96 (2H, ABq, J=1 3Hz), 5.14 (1H, d, J=5Hz), 5.78 (1H, d,d, J=5 and 8Hz), 6.90 (1H, s), 6.88 (4H, s), 9.80 (1H, d, J=8Hz) (4) 7-[2-Methoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-plyaloyloxymethyl-3-cephem-4carboxylic acid (syn isomer) I.R. (Nujol) 3300, 1780, 1720, 1670, 1540 cm-1 N.M.R. (d6-DMSO, S) 1.06 (9H, s), 3.50 (2H, broad s), 3.80 (3H, s), 4.83 (2H, ABq, J=13Hz), 5.13 (1H, d, J=5Hz), 5.76 (1H, d,d J=5 and 8Hz), 6.75 (1H, s), 9.58 (1H, d, J=8Hz) (5) 7-[2-methoxyimino-2-92-aminothiazol-4-yl)acetamido]-3-(2-thenoyl-oxymethyl-3-cephem-4carboxylic acid (syn isomer).

I.R. (Nujol) 3250, 1780, 1710, 1680, 1635, 1530 cm-1 N.M.R. (d6-DMSO, #) 3.70 (2H, broad s), 3.92 (3H, s), 5.15 (2H, ABq, J=13Hz), 5.22 (1H, d, J=5Hz), 5.83 (1H, d,d, J=5 and 8Hz), 6.85 (1H, s), 7.27 (1 H, m), 7.83~8.12 (2H, m), 9.72 (1 H, d, J=8Hz) (6) 7-[2-Methoxyimino-2-(2-aminothiazol-4-yl)-acetmaido]-3-(4-aminobenzoyloxy, ethyl)-3cephem-4-carboxylic acid (syn isomer).

!.R. (Nujol) 3350, 1780, 1680, 1605, 1540 cm-1 N.M.R. (d6-DMSO, S) 3.72 (2H, broad s), 3.87 (3H, s), 5.08 (2H, ABq, J=13Hz, 5.20 1H, d, J=5Hz), 5.83 (1H, d,d, J=5 and 8Hz), 6.77 (1H, s), 6.88 (2H, d, J=9Hz), 7.80 (2H, d, J=9Hz), 9.67 (1H, d, J=8Hz) Furthermore, according to a slmilar manner to that of Example 19, the object compounds of Examples 1-10 and the compounds of Examples 11(1)-11(10), 11(17)-11(34) and 11(37)11(70)were also obtained.

Example 21 Platinic oxide (0.4 9) was added to a solution of benzhydryl 7-[2-methoxyimino-2-(2 aminothiazol-4-yl)-acetamido]-3-(4-nitrobenzoyloxymethyl-3-cephem-4-carboxylate (syn isomer) (4.3 g), in a mixture of ethanol (50 ml) and tetrahydrofuran (50 ml) and, the suspension was subjected to catalytic reduction at ambient temperature under ordinary pressure for 3 hours. After removing the catalyst from the resultant mixture by filtration, the filtrate was evaporated under reduced pressure.

The residue was dissolved in ethyl acetate and the solution was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was pulverized with diethyl ether to give benzhydryl 7-[2-methoxylmino-2-(2-aminothiazol-4-yl)- acetamido]-3-(4-aminobenzoyl-oxymethyl)-3-cephem-4-carboxylate (syn isomer) (3.0 g).

I.R. (Nujol) 3280,1780,1710,1670, 1605, 1520cm1 N.M.R. (d6-DMSO, S) 3.76 (2H, broad s), 3.88 (3H, s), 5.02 (2H, ABq, J=13Hz), 5.26 (1H, d, J=5Hz), 5.96 (1H, d,d, J=5 and 8Hz), 6.82 (1H, s), 6.90 (2H, d, J=9Hz), 6.98 (1H, s), 7.04~7.66 (10H, m), 7.82 (2H, d, J=9Kz), 9.72 (1 H, d, J=8Hz)

Claims

Claims 1. 3,7-Disubstituted-3-cephem-4-carboxylic acid compounds of the formula:

wherein R1 is amino or a protected amino; R3 is carboxy or a protected carboxy; R2 is isobutyl and R4 is acetoxy; or R2 is cyclo(lower)alkyl or lower alkynyl and R4 is lower alkanoyloxy; or R2 is lower alkyl and R4 is (C5-C6) alkanoyloxy; or R2 is (C2-C6)alkyl, lower alkenyl cyclo(lower)alkyl or lower alkynyl and R4 is hydrogen, carbamoyloxy, thiadiazolylthio which may have a lower alkyl or triazolylthio; or R2 is C2-C6 alkyl, cyclo(lower)alkyl or lower alkynyi and R4 is tetrazolylthio having a methyl: or R2 is lower alkyl, lower alkenyl, cyclo(lower)alkyl or lower alkynyl and R4 is aroyloxy which may have nitro or amino, cyclo(lower)alkanecarbonyloxy, carbamoloxy having an aryl which may be substituted with halogen, ar(lower)alkanoyloxy, aryloxy(lower)alkanoyloxy having lower alkoxy, thenoyloxy, tetrazolylthio having a (C3-C6)alkyl or benzothiazolylthio; and pharmaceutically acceptable salts thereof.
2. Syn isomer-of a compound of claim 1.
3. A compound of claim 2, which is a compound of the formula:

and pharmaceutically acceptable salts thereof.
4. A compound of claim 3, wherein R1 is amino or acylamino and R3 is carboxy or esterified carboy.
5. A compound of claim 4, wherein R1 is amino; lower alkanoylamino or halo(lcwer)alkunoylamino; R3 is carboxy or ar(lower)alkoxycarbonyl; R2 is isobutyl and R4 is acetoxy; or R2 is cyclo(lower)alkyl or lower alkynyl and R4 is lower alkanoyloxy; or R2 is lower alkyl and R4 is (C5-C6) alkanoyloxy; or R2 is (C2-C6) alkyl, lower alkenyl or lower alkynyl and R4 is hydrogen, carbamoyloxy, thiadiazolylthio or triazolylthio; or R2 is (C2-C6) alkyl or lower alknynyl and R4 is tetrazolylthio having a methyl; or R2 is lower alkyl, lower alkenyl or lower alkynyl and R4 is aroyloxy which may have nitro or amino, cyclo(lower)alkanecarbonyloxy, carbamoyloxy, having an aryl which may be substituted with halogen, ar(lower)alkanoyloxy, aryloxy(lower)alkanoyloxy having lower alkoxy, thenoyloxy, tetrazolylthio having a (C3-C8) alkyl or benzothiazolylthio.
6. A compound of claim 5, which is 7-[2-isobutoxyimino-2-(2-aminothiazol-4 yl)acetamido]cephalosporanic acid (syn isomer).
7. A compound of claim 5, wherein R1 is amino, R3 is carboxy, R2 is cyclo(lower)alkyl or lower alkyl and R4 is lower alkanoyloxy.
8. A compound of claim 7, wherein R2 is cyclohexyl or 2-propynyl and R4 is acetoxy.
9. A compound of claim 8, which is 7-[2-cyclohexyloxy-imino-2-(2-aminothiazol-4yl)acetamido]cephalosporanic acid (syn isomer).
10. A compound of claim 8, which is 7-[2-(2-propynyloxyimino)-2-(2-aminothiazol-4yl)acetamido]-cephalosphoranic acid (syn isomer).
11. A compound of claim 5, wherein R1 is amino, R3 is carboxy or ar(lower)alkoxycarbonyl, R2 is lower alkyl and R4 is (C-C6)alkanoyloxy.
12. A compound of claim 11, wherein R3 is carboxy or diphenyl(lower)alkoxycarbonyl.
13. A compound of claim 12, wherein R3 is carboxy or benzhydryloxycarbonyl, R2 is methyl and R4 is pivaloyloxy or hexanoloxy.
14. A compound of claim 13, which is 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3- pivaloyloxymethyl-3-cephem-4-carboxylicd acid (syn isomer).
1 5. A compound of claim 13, which is 7-[2-methoxy-imino-2-(2-aminothiazol-4-yl)acetamidoj- 3-hexanoyloxy-methyl-3-cephem-4-carboxylic acid (syn isomer).
1 6. A compound of claim 5, whorein R1 is amino or lower alkanoylamino, R3 is carboxy, R2 is (C2-C6)alkyl, lower alkenyl or lower alkynyl and R4 is hydrogen, carbamoyloxy, thiadiazolylthio or triazolylthio.
1 7. A compound of claim 16, wherein R2 is (C2-C6)alkyl and R4 is hydrogen.
18. A compound of claim 1 7 wherein R1 is amino orformamido and R2 is propyl or hexyl.
19. A compound of claim 18, which is 7-[2-propoxy-imino-2-(2-aminothiazol-4-yl)acetamido]-3- methyl-3-cephem-4-carboxylic acid (syn isomer).
20. A compound of claim 18, which is 7-[2-hexyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3methyl-3-cephem-4-carboxylic acid (syn isomer).
21. A compound of claim 16, wherein R4 is carbamoyloxy.
22. A compound of claim 21, wherein R1 is amino orformamido and R2 is ethyl, propyl, isopropyl, isobutyl, allyl or 2-propynyl.
23. A compound of claim 22, which is 7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3- carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).
24. A compound of claim 22, which is 7-[2-propoxy-imino-2-(2-aminothiazol-4-yl)acetamido]-3- ca rba moyloxy-methyl-3-cephem-4-carboxylic acid and its hydrochloride (syn isomer).
25. A compound of claim 22, which is 7-[2- isopropoxy-imino-2-(2-aminothiazol-4yl)acetamido]-3-carbamoyloxy-methyi-3-cephem-4-carboxylic acid (syn isomer).
26. A compound of claim 22, which is 7-[2-isobutoxyimino-2-(2-aminothiazol-4-yl)acetamido]- 3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).
27. A compound of claim 22, which is 7-[2-allyloxy-imino-2-(2-aminothiazol-4-yl)acetamido]-3 carbamoyloxy-methyl-3-cephem-4-carboxylic acid (syn isomer).
28. A compound of claim 22, which is 7-[2-(2-propynylQxyimino)-2-(2-aminothiazol-4- yl)acetamidoj-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn Isomer).
29. A compound of claim 16, wherein R4 is thiadiazolylthio.
30. A compound of claim 29, wherein R1 is amino or formamido, R2 is ethyl, propyl, isopropyl, pentyl, allyl or 2-propynyl and R4 is 1 ,3,4-thiadiazol-2-ylthio.
31. A compound of claim 30, which is 7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3- (1,3,4-thiadiazol-2-yi)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
32. A compound of claim 30, which is 7-[2-propoxyimino-2-(2-aminothiazol-4-yI)acetamidoj-3- (1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
33. A compound of claim 30, which is 7-[2-isopropoxyimino-2-(2-aminothiazol-4-yl)acetamidoj- 3-(1 ,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4carboxylic acid (syn isomer).
34. A compound of claim 30, which is 7-[2-pentyloxyimino-2-(2-aminothiazol-4-yl)acetamido]- 3-( 1 ,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
35. A compound of claim 30, which is 7-[2-allyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3- (1 ,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
36. A compound of claim 30, which is 7[2-(2-propynyloxyimino)-2-(2-aminothiazol-4-yl)- acetamido]-3-( 1 ,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
37. A compound of claim 16, wherein R2 is (C2-C6)alkyl or lower alkynyl and R4 is triazolylthio.
38. A compound of claim 37, wherein R1 is amino orformamido, R2 is ethyl, propyl, isopropyl, isobutyl, hexyl or 2-propynyl and R4 is 1 K, 1 ,2,3-triazol-5-ylthio.
39. A compound of claim 38, which is 7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3- (1 K-i ,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
40. A compound of claim 38, which is 7-[2-propoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3- (1 H-1,2,3-triazol-5-yl)thiomethyi-3-cephem-4-carboxylic acid (syn isomer).
41. A compound of claim 38,which is 7-[2-isopropoxyimino-2-(2-aminothiazol-4-yl)acetamido] 3-(1 H-1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
42. A compound of claim 38, which is 7-[2-isobutoxyimino-2-(2-aminothiazol-4-yt)acetamido] 3-(1 H-1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
43. A compound of claim 38, which is 7-[2-hexyloxyimino-2-(2-aminothiazol-4-yl)-acetamido]3-(1H-1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
44. A compound of claim 38, which is 7-[2-(2-propynyloxyimino)-2-(2-aminothiazol-4-yl) acetamido]-3-( 1 H-i ,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
45. A compound of claim 5, wherein Ri is amino or lower alkanoylamino.

R3 is carboxy, R2 is (C2-C6)alkyl or lower alkynyl and R4 is tetrazolylthio having a methyl.
46. A compound of claim 45, wherein R1 is amino orformamido, R2 is propyl, isopropyl, butyl, pentyl, hexyl, or 2-propynyl and R4 is 1-methyl-1 H-tetrazol-5-ylthio.
47. A compound of claim 46, which is 7-[2-propoxyimino-2-(2-aminothiazol-4-yI)acetamido]-3- (1-methyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
48. A compound of claim 46, which is 7-[2-isopropoxyimino-2-(2-aminothiazol-4-yl)-acetamido- 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
49. A compound of claim 46, which is 7-E2-butoxyimino-2-(2-aminothiazol-4-Yl)acetamido]-3- (1-methyl- 1 H-tetrazol-5-yi-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
50. A compound of claim 46, which is 7-[2-pentyloxyimino-2-(2-aminothiazol-4-yl)acetamidoj- 3-( 1 -m ethyl- 1 K-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxvlic acid (svn isomer).
51. A compound of claim 46, which is 7-[2-hexyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3 (1-methyl-i H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
52. A compound of claim 46, which is 7-[2-(2-propynyloxyimino-2-(2-aminothiazol-4-yl) acetamido]3-(l -methyl-l H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
53. A compound of claim 5, wherein R2 is lower alkyl, lower alkenyl or lower alkynyl and R4 is aroyloxy which may have nitro or amino, cycio(lower)alkanecarbonyloxy, carbamoyloxy, having an aryl which may be substituted with halogen, ar(lower)alkanoyloxy, aryloxy(lower)alkanoyloxy having lower alkoxy, thenoyloxy, tetrazolylthio having a (C3-C6) alkyl or benzothiazolylthio.
54. A compound of claim 53, wherein Ri is amino or halo(lower)alkanoylamino, R2 is lower alkyl and R4 is aroyloxy which may have nitro or amino.
55. A compound of claim 54, wherein R1 is amino or 2,2,2-trifluoroacetamido, R3 is carboxy or benzhydryloxycarbonyl, R2 is methyl and R4 is benzoyloxy, 4nitrobenzoyloxy or 4 aminobenzoyloxy.
56. A compound of claim 55, which is 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3- benzoyloxymethyl-3-cephem-4-carboxyiic acid (syn isomer).
57. A compound of claim 55, which is 7[2-methoxyimino-2-(2-aminoth:azol-4.yl)acetamidoj-3- (4-nitrobenzoyl)oxymethyl-3-cephem-4-carboxylic acid (syn isomer).
58. A compound of claim 55, which is 7-[2-methoxyimino..2- (2-aminothiazol-4-yl)acetamido]-3- (4-aminobenzoyl)oxymethyl-3-cephem-4-carboxylic acid (syn isomer).
59. A compound of claim 53, wherein R1 is amino, R2 is lower alkyl and R4 is cyclo(lower)alkanecarbonyloxy.
60. A compound of claim 59, wherein R3 is carboxy or benzhydryloxycarbonyl, R2 is methyl and R4 is cyclohexanecarbonyloxy.
61. A compound of claim 60, which is 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamidoj-3- cyclohexanecarbonyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).
62. A compound of claim 53, wherein R1 is amino, R2 is lower alkyl and R4 is carbamoyloxy having an aryl which may be substituted with halogen.
63. A compound of claim 62, wherein R3 is carboxy or benzhydryloxycarbonyl, R2 is methyl and R4 is N-phenylcarbamoyloxy or chloro-phenyl)carbamoyloxy.
64. A compound of claim 63, which is 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3- (N-phenylcarbamoyloxymethyl)-3-cephem-4-carboxylic acid (syn isomer).
65. A compound of claim 63, which is 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3- [N-(3-chlorophenyl)carbamoyloxymethyl]-3-cephem-4-carboxylic acid (syn isomer).
66. A compound of claim 53, wherein R1 is amino, R3 is carboxy, R2 is lower alkyl and R4 is ar(lower)alkanoyloxy.
67. A compound of claim 66, which is 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3- phenylacetoxymethyl-3-cephem-4-ca rboxylic acid (syn isomer).
68. A compound of claim 53, wherein R1 is amino, R2 is lower alkyl and R4 is aryloxy(lower)alkanoyloxy having lower alkoxy.
69. A compound of claim 68, wherein R3 is carboxy or benzhydryloxycarbonyl, R2 is methyl and R4 is 4-methoxyphenoxyacetoxy.
70. A compound of claim 69, which is 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3- (4-methoxyphenoxy)acetoxymethyl-3-cephem-4-ca rboxylic acid (syn isomer).
71. A compound of claim 53, wherein R1 is amino, R2 is lower alkyl and R4 is thenoyloxy.
72. A compound of claim 71, wherein R3 is carboxy or benzhydryloxycarbonyl, R2 is methyl and R4 is 2-thenoyloxy.
73. A compound of claim 72, which is 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3- (2-thenoyl)oxymethyl-3-cephem-4-carboxylic acid (syn isomer).
74. A compound of claim 53, wherein R1 is amino or lower alkanoylamino, R3 is carboxy and R4 is tetrazolylthio having a (C3-C6)alkyl.
75. A compound of claim 74, wherein R1 is amino orformamido, R2 is methyl, isopropyl, hexyl, allyl or 2-propynyl and R4 is 1propyl1 H-tetrazol-5-ylthio or 1 hexyl-1 H-tetrazol-5-ylthio.
76. A compound of claim 75, which is 7- [2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3- (1 propyl 1 H-tetrazol-5-yl-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
77. A compound of claim 75, which is 7-[2-allyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3- (1 -propyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
78. A compound of claim 75, which is 7-[2-(2-propynyloxyimino)-2-(2-aminothiazol-4-yl) acetamido]-3-( 1 -propyl- 1 H-tetrazol-5-yl-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
79. A compound of claim 75, which is 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3- (1 -hexyl- 1 H-tetrazol-5-yl-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
80. A compound of claim 75, which is 7-[2-isopropoxyimino-2-(2-aminothiazol-4-yl)acetamido]- 3-(1-hexyl-1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
81. A compound of claim 75, which is 7-[2-hexyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3 (1 -hexyl- 1 H-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
82. A compound of claim 75, which is 7-[2-allyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3- (1 -hexyl-1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).
83. A compound of claim 53, wherein R1 is lower alkanoylamino, R3 is carboxy, R2 is lower alkyl and R4 is benzothiazolylthio.
84. A process for preparing 3,7-disubst'tuted-3- cephem-4-carboxylic acid compounds of the formula:

wherein R1 is amino or a protected amino; R3 is carboxy or a protected carboxy; R2 is isobutyl and R4 is acetoxy; or R2 is cyclo(lower)alkyl or lower alkynyl and R4 is lower alkanoyloxy; or R2 is lower alkyl and R4 is (C5-C6)alkanoyloxy; or R2 is (C2-C6) alkyl, lower alkenyl, cyclo(lower)alkyl or lower alkynyl and R4 is hydrogen, carbamoyloxy, thiadiazolylthio which may have a lower alkyl or triazolylthio; or R2 is (C2-C6) alkyl, cyclo(lower)alkyl or lower alkynyl and R4 is tetrazolylthio having a methyl; or R2 is lower alkyl, lower alkenyl, cyclo(lower)alkyl or lower alkynyl and R4 is aroyloxy which may have nitro or amino, cyclo(lower)alkanecarbonyloxy, carbamoloxy having an aryl which may be substituted with halogen, ar(lower)alkanoyloxy, aryloxy(lower)alkanoyloxy having lower alkoxy, thenoyloxy, tetrazolylthio having a (C3C6)alkyl or benzothiazolylthio; or pharmaceutically acceptable salts thereof; which comprises reacting a compound of the formula:

wherein R3 and R4 are each as defined above, or its reactive derivative at the amino group or a salt thereof, with a compound of the formula:

wherein R1 and R2 are each as defined above, or its reactive derivative at the carboxy group or a salt thereof.
85. A process for preparing a compound of the formula:

wherein R3 is carboxy or a protected carboxy; R2 is isobutyl and R4 is acetoxy; or R2 is cyclo(lower)alkyl or lower alkynyl and R4 is lower alkanoyloxy; or R2 is lower alkyl and R4 is (C5-C6) alkanoyloxy; or R2 is (C2-C6)alkyl, lower alkenyl, cyclo(lower)alkyl or lower alkynyl and R4 is hydrogen, carbamoyloxy, thiadiazolylthio which may have a lower alkyl or triazolylthio; or R2 is (C2-C6)alkyl, cyclo(lower)alkyl or lower alkynyl and R4 is tetrazolylthio having a methyl; or R2 is lower alkyl, lower alkenyl, cyclo(lower)alkyl or lower alkynyl and R4 is aroyloxy which may have nitro or amino, cyclo(lower)alkanecarbonyloxy, carbamoyloxy having an aryl which may be substituted with halogen, ar(lower)alkanoyloxy, aryloxy(lower)alkanoyloxy having lower alkoxy, thenoyloxy, tetrazolylthio having a (C3-C6)alkyl or benzothiazolylthio; or pharmaceutically acceptable salts thereof; which comprises subjecting a compound of the formula:

wherein Rta is a protected amino and R2, R3 and R4 are each as defined above, or a salt thereof, to elimination reaction of the amino protective group.
86. A process for preparing a compound of the formula:

wherein R' is amino or a protected amino; R2 is isobutyl and R4 is acetoxy; or R2 is cyclo(lower)alkyl or lower alkynyl and R4 is lower alkanoyloxy; or R2 is lower alkyl and R4 is (C5-C6)alkanoyloxy; or R2 is (C2-C6)alkyl, lower alkenyl, cyclo(lower)alkyl or lower alkynyl and R4 is hydrogen, carbamoyloxy, thiadiazolylthio which may have a lower alkyl or triazolylthio; or R2 is (C2-C6)alkyl, cyclo(lower)alkyl or lower alkynyl and R4 is tetrazolylthio having a methyl; or R2 is lower alkyl, lower alkenyl, cyclo(lower)alkyl or lower alkynyl and R4 is aroyloxy which may have nitro or amino, cyclo(lower)alkanecarbonyloxy, carbamoyloxy having an aryl which may be substituted with halogen, ar(lower)alkanoyloxy, aryloxy(lower)alkanoyloxy having lower alkoxy, thenoyloxy, tetrazolylthio having a (C3-C6)alkyl or benzothiazolylthio, or pharmaceutically accepable salts thereof; which comprises subjecting a compound of the formula:

wherein R3a is a protected carboxy and Rt, R2 and R4 are each as defined above, to elimination reaction of the carboxy protective group.
87. A process for preparing a compound of the formula:

wherein R1 is amino or a protected amino; R3 is carboxy or a protected carboxy; R2a is lower alkyl, lower alkenyl, cyclo(lower)alkyl or lower alkynyl; and R4b is aroyloxy having an amino group(s); or pharmaceutically acceptable silts thereof which comprises subjecting a compound of the formula:

wherein R1, R3 and R2a are each as defined above and R4á is aroyloxy having nitro group(s) or a salt thereof to reduction.
88. A compound of the formula:

wherein R3 is carboxy or a protected carboxy and R7 is (C3-C6)alkyl, and salts thereof.
89. A compound of claim 88, wherein R3 is carboxy and R7 is propyl or hexyl.
90. A compound of the formula:

wherein R3 is carboxy or a protected carboxy and R4C is carbamoyl having an aryl which may be substituted with halogen, aryloxy(lower)alkanoyl having lower alkoxy, thenoyl, cyclo(lower)alkanecarbonyl or aroyl having nitro, and salts thereof.
91. A pharmaceutical antibacterial composition comprising the compound of claim 1 in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.
92. A method for producing a pharmaceutical anti-bacterial composition which comprises mixing a compound of claim 1, as an active ingredient with an inert carrier.