GB2031411A

GB2031411A - 3,7-Disubstituted-3-cephem-4- carboxylic Acid Compounds and Processes for the Preparation Thereof

Info

Publication number: GB2031411A
Application number: GB7929773A
Authority: GB
Original assignee: Fujisawa Pharmaceutical Co Ltd
Current assignee: Fujisawa Pharmaceutical Co Ltd
Priority date: 1978-08-31
Filing date: 1979-08-28
Publication date: 1980-04-23
Also published as: GB2031411B

Abstract

The invention comprises 3,7- disubstituted-3-cephem-4-carboxylic acid compounds of the formula: <IMAGE> wherein R<1> is amino or a protected amino, R<2> is an aliphatic hydrocarbon group which may have suitable substituent(s), R<3> is carboxy or a protected carboxy, and R<4> is N- containing 5-membered heteromonocyclic group having lower alkenyl group(s), with proviso that R<2> is not methyl when R<4> is tetrazolyl having a lower alkenyl group, and pharmaceutically acceptable salts thereof, processes for the preparation thereof and pharmaceutical compositions. These salts have antibacterial activities and are useful in treating infectious diseases in humans and animals.

Description

SPECIFICATION 3,7-Disubstituted-3-cephem-4-carboxyl ic 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 diseases in human being and animals.

Accordingly, it is one object of the present invention to provide 3,7-disubstituted-3-cephem-4carboxylic acid compounds and pharmaceutically acceptable salt 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 for the treatment of infectious diseases caused by pathogenic bacteria in human being 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 R' is amino or a protected amino, R2 is an aliphatic hydrocarbon group which may have suitable substituent(s), R3 is carboxy or a protected carboxy, and R4 is N-containing 5-membered heteromonocyclic group having lower alkenyl group(s), with proviso that RZ is not methyl when R4 is tetrazolyl having a loweralkenyl group.

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

wherein R', R2, R3 and R4 are each as defined above, RIB is a protected amino, R2a is a protected carboxy(lower)alkyl, R2b is a carboxy(lower)alkyl and X is a group which can be substituted by a group of the formula: R4-S- wherein R4 is as defined above.

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.

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

The other starting compound (II) can be prepared by the processes as illustrated below.

(II) or a salt; thereof wherein (it) or a saiL hereo R3 and R4 are each as defined above.

Regarding the object compounds of the formulae (I), (Ib) and (Id), and the starting compounds of the formulae (Ia), (Ic), (Ill), (ills), (IIIa,), (Illb), (VII), (VIII), (X)-(Xll) and (XVI), 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 R' is as defined above) in the formula of said object and starting compounds take the formula:

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

can be also alternatively represented by its tautomeric formula:

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

(wherein R' and Rib are each as defined above).

These types of tautomerism between 2-aminothiazole compounds and 2-iminothiazoline compounds as stated above have been well known in the literature, and it is obvious to a 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 and examples, 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), (lib) and (Id), and the starting compounds (lea) (it), (Ill), (lily), (Illa,), (Illb), (lV)-(Vll), (X)-(XlI) and (XVI), 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 synisomer and the anti-isomer can be also 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 (erg., 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, benzenesulfonate, 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.

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 acylimino 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 "acylamino", "acylimino" 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, etc.), preferably one having 1 to 4 carbon atom(s), more preferably one having 1 to 2 carbon atom(s); lower alkoxycarbonyl having 2 to 7 carbon atoms (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1 -cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, etc.); lower alkanesulfonyl (e.g., mesyl, ethanesulfonyl, propanesulfonyl, isopropane sulfonyl, 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.); and the like.

The acyl moiety as stated above may have 1 to 3 suitable substitutent(s) such as halogen (e.g., chlorine, bromine, iodine or fluorine), hydroxy, cyano, nitro, lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy etc.), lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, etc.), lower alkenyl (e.g., vinyl, allyl etc.), aryl (e.g., phenyl, tolyl, etc.), or the like.

Preferable example of acylamino may be lower alkanoylamino or halo(lower)alkaloylamino [more preferably trihalo(lower)alkanoylamino] and preferable example of acyloxy may be lower aikanoyloxy.

Aliphatic hydrocarbon group is intended to mean straight, branched or cyclic aliphatic hydrocarbon having 1 to 6 carbon atom(s) and may include lower alkyl, cyclo(lower)alkyl, lower alkenyl, lower alkynyl and the like. And said aliphatic hydrocarbon group may have 1 to 2 suitable substituent(s) such as carboxy, protected carboxy, arylthio, lower alkylthio, aryl, acyloxy, lower alkoxy, aryloxy, a heterocyclic group or the like.

Suitable lower alkyl and lower alkyl moiety in the terms "lower alkylthio", "carboxy(lower)alkyl" and "protected carboxy(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 cyclo(lower)alkyl is one having 3 to 6 carbon atoms and may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

Suitable lower aikenyl 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 lower alkynyl is one having 2 to 6 carbon toms and may include ethynyl, 2-propynyl, 2 butynyl, 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 protected carboxy and protected carboxy moiety in the term "protected carboxy(lower) alkyl" may include esterified carboxy in which said ester moiety maybe the ones such as lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentylester, t-pentyl ester, hexyl ester, 1 -cyclopropylethyl ester, etc.), wherein lower alkyl moiety may be preferably one having 1 to 4 carbon atom(s), lower alkenyl ester (e.g., vinyl ester, allyl ester etc.); lower alkynyl ester (e.g., ethynyl ester, propynyl ester, etc.); mono(or di or tri)-halo(lower) alkyl ester e.g., 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower alkanoyloxy(lower)alkyl ester (e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2acetoxyethyl ester, 2-propionyloxyethyl ester, etc.); lower alkanesulfonyl(lower)alkyl ester (e.g., mesylmethyl ester, 2-mesylethyl ester etc.); ar(lower)alkyl ester, for example, phenyl(lower)alkyl ester which may have one or more suitable substituent(s) (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, diphenylmethyl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy 3,5-ditertian/butylbenzyl ester, etc.); aryl ester which may have one or more suitable substituent(s) (e.g., phenyl ester, tolyl ester, tertiarybutylphenyl ester, xylyl ester, mesityl 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.

Suitable aryl and aryl moiety in the terms "arylthio" and "aryloxy" may include phenyl, tolyl, xylyl, mesityl, cumenyl, naphthyl and the like, wherein said aryl group may have 1 to 3 suitable substituent(s) such as halogen, (e.g., chlorine, bromine, iodine or fluorine), hydroxy, and the like.

Suitable lower alkoxy may include one which may be branched, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy and the like.

Suitable heterocyclic group means saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like.

And, especially preferable heterocyclic group may be heterocyclic groups such as unsaturated 3 to 8-membered (preferably 5 to 6 membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1 H-1 2,3,-triazolyl, 2H-1 2,3-triazolyl, etc.), tetrazolyl (e.g., 1 H-tetrazolyl or 2H-tetrazolyl), etc.; saturated 3 to 8-membered (preferably 5 to 6 membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl etc.; unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyi, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.; unsaturated 3- to 8-membered (preferably 5 to 6 membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl, (e.g., 1,2,4oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.; saturated 3 to 8-membered (preferably 5 to 6 membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.; unsaturated 3 to 8-membered (preferably 5 to 6 membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, thiadiazolyl (e.g., 1 ,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, etc.), etc.; saturated 3 to 8 membered (preferably 5 to 6 membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.; unsaturated 3 to 8 membered (preferably 5 to 6 membered) heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc. and the like; wherein said heterocyclic group may have 1 to 2 suitable substituent(s) such as lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, etc.); lower alkenyl (e.g., vinyl, allyl, 1-propenyl, 2-butenyl, etc.); aryl (e.g., phenyl, tolyl, etc.); halogen (e.g., chlorine, bromine, iodine or fluorine); amino; di(lower)alkylamino(lower)alkyl (e.g. dimethylaminomethyl, dimethylaminoethyl, diethylaminopropyl, diethylaminobutyl, etc.); or the like.

Suitable N-containing 5 membered heteromonocyclic group means saturated or unsaturated 5 membered heteromonocylic group containing at least one nitrogen atom(s) such as unsaturated 5 membered heteromonocylic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrqlinyl, imidazolyl, pyrazolyl, triazolyl (e.g., 4H-1 ,2,4-triazolyl, 1 H-1 ,2,3-triazolyl, 2H-1 ,2,3-triazolyl, etc.), tetrazolyl (e.g., 1 H-tetrazolyl or 2H-tetrazolyl) etc.; or saturated 5 membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, etc. And said N-containing 5 membered heteromonocyclic group has 1 or 2 lower alkenyl group(s) as exemplified above as substituent(s).

Suitable group which can be substituted by a group of the formula: R4-S- may include an acid residue such as azido, halogen, acyloxy or the like, wherein halogen and acyloxy are as exemplified above.

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

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 R' may be amino or acylamino [more preferably lower alkanoylamino or halo(lower)alkanoylamino (most preferably tri halo(lower)alkanoylamino)]; preferable example of R2 may be lower alkyl, lower alkenyl, lower alkynyl, lower alkylthio(lower)alkyl, ar(lower)alkyl [more preferably phenyl(lower)alkyl] which may have one or two halogen(s), acyloxy(lower)alkyl [more preferably lower alkanoyloxy(lower)alkyl], carboxy(lower alkyl, protected carboxy(lower)alkyl [more preferably lower alkoxycarbonyi(Iower)alkyl], isoxazolyl(lower)alkyl or cyclo(lower) alkyl; preferable example of R3 may be carboxy; and preferable example of R4 may be tetrazolyl having a lower alkenyl group or triazolyl having a lower alkenyl group, with proviso that R2 is not methyl when R4 is tetrazolyl having a lower alkenyl group, 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 of 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.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkylcarbonic acid, aliphatic carboxylic-acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2 ethylbutyric acid ortrichloroacetic acid, etc.) or aromatic carboxylic acid (e.g. benzoic acid, etc.); a symmetrical acid anhydride; an activated amine with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole ortetrazle; or an activated ester (e.g., cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH3)2=CH-jester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4 dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl 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-l H-benzotriazole, etc.), and the like.

These reactive derivatives can optionally be selected from them according to the kind of the compound (Ill) 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,N dimethylformamide, 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' dicyclohexylcarbodiimide; 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-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1 alkoxy-1 -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)alkylmorphorine, 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 the 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 (lea) wherein the protective group is acyl group with iminohaiogenating 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 eliminated.

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.), substituted phenylthio, substituted aralkylidene, substituted alkylidene, substituted cycloalkylidene, or the like.Suitable acid may include an organic or an inorganic acid, for example, formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like, and preferable acid is an acid which can be easily removed from the reaction mixture by a conventional manner such as distillation under reduced pressure, 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 be preferably 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. Preferable base may be alkali metal acetate.

Among the protective groups, the acyl group can be generally 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, ha loal koxycarbonyl (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 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 be suitably 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 (Ic) or a salt thereof to elimination reaction of the carboxy protective group.

Suitable salt of the compound (Ic) can be referred to the ones exemplified for the compound (it).

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 phenyl(lower)alkyl, substituted phenyl(lower)alkyl, lower alkyl, substituted lower alkyl, or the like. Suitable acid may include inorganic or organic acid, for example, formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic 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, the cases that the protected carboxy group for R3 is transformed into the free carboxy group; that the protected amino group is transformed into the free amino group during the reaction or post-treating in the present reaction.

Process 4 The object compound (I) or a salt thereof can be prepared by reacting the compound (XVI) or a salt thereof with the compound (XVII) or its reactive derivative at the mercapto group.

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

Suitable reactive derivative at the mercapto group of the compound (XVII) may include a metal salt such as a alkali metal salt (e.g., sodium salt, potassium salt, etc.) or the like.

The present reaction may be carried out in a solvent such as water, phosphate buffer, acetone, chloroform, nitrobenzene, methylene chloride, ethylene chloride, dimethylformamide, methanol, ethanol, ether; tetrahydrofuran, dimethylsulfoxide, or any other organic solvent which does not adversely affect the reaction, preferably in ones having strong polarities. Among the solvents, hydrophilic solvents may be used in a mixture with water. The reaction is preferably carried out in around neutral medium. When the compound (XVI) or the compound (XVII) is used in a free form, the reaction is preferably conducted in the presence of a base, for example, inorganic base such as alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, organic base such as trialkylamine, and the like.The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or under slightly heating.

The present reaction includes, within its scope, the case that protected amino for R' is transformed to free amino according to the kind of protective group and/or reaction conditions.

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

1. The compound (XV) or a salt thereof can be prepared by reacting the compound (XIII) or a salt thereof with the compound (XIV) or its reactive derivative at the mercapto group.

Suitable salt of the compound (XIII) can be referred to the ones exemplified for the compound (lea) The suitable reactive derivative at the mercapto group of the compound (XIV) may include a metal salt such as alkali metal salts (e.g., sodium salt, potassium salt, etc.) or the like.

The present rnactionrriaybecar?ied out in a solvent such as water, acetone, chloroform, nitrobenzene, methylene chloride, ethylene chloride, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethylsulfoxide, or any other solvent which does not adversely affect the reaction, preferably in ones having strong polarities. Among the solvents, hydrophilic solvents may be used in a mixture with water. The reaction is preferably carried out in weakly basic or around neutral condition.

When the compound (XIII) and/or the thiol compound (XIV) is used in a free form, the reaction is preferably conducted in the presence of a base, for example, inorganic base such as alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, organic base such as trialkylamine, pyridine, and the like. The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming. The reaction product can be isolated from the reaction mixture by conventional methods.

2. The compound (II) or a salt thereof can be prepared by subjecting the compound (XV) or a salt thereof to elimination reaction of 5-amino-5-carboxyvaleryl group.

The present elimination reaction can be carried out by (i) reacting the compound(XV) or a salt thereof with a silylating agent, (ii) reacting the resulting compound with iminohalogenating agent, and then (iii) reacting the resulting compound with iminoetherifying agent Suitable salt of the compound (XV) can be referred to the ones exemplified for the compound (lea) Suitable silylating agent may include mono- or bis-trialkylsilylacetamide [e.g., trimethylsiliylacetamide, bis(trimethylsilyl)acetamide, etc.], trimethylchlorosilane, dimethyldichlorosilane, hexamethyldisilazane, and the like. The reaction of the compound (XV) with a silylating agent may be carried out in the presence of a base under warming or heating.

Suitable iminohalogenating agent may include phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride, phosgene and the like. The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under cooling.

Suitable iminoetherifying agent reacted with thus obtained reaction product may include an alcohol, metal alkoxide and the like. Suitable alcohol may include alkanol (e.g., methanol, ethanol, propanol, isopropanol, butanol, t-butanol, etc.) which may be substituted with alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy butoxy, etc.). Suitable metal alkoxide may include alkali metal alkoxide (e.g., sodium alkoxide, potassium alkoxide, etc.), alkaline earth metal alkoxide (e.g., calcium alkoxide, barium alkoxide, etc.) and the like. The reaction temperature is not critical, and the reaction is usually carried out under cooling or at ambient temperature.

Thus obtained product is, if necessary, subjected to hydrolysis. The hydrolysis can be readily carried out by pouring the reaction mixture obtained above into water, but there may be previously added a hydrophilic solvent (e.g., methanol, ethanol, etc.), a base (e.g., alkali metal bicarbonate, trialkylamine, etc.) or an acid (e.g., diluted hydrochloric acid, acetic acid, etc.) to the water.

In the aforementioned reactions and/or the post-treating of the reactions of the present invention, the aforementioned tautomeric isomers may be occasionally 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 by 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-cyclopentyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-( 1 -allyl- 1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) (2) 7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-( 1 -allyl- 1 H-tetrazol-5-yl)thiomethyl3-cephem-4-carboxylic acid (syn-isomer) (3) 7-[2-allyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-( 1-al lyl- 1 H-tetrazol-5-yl)thiomethyl3-cephem-4-carboxylic acid (syn-isomer) (4) 7-[2-(2-propynyl)oxyimino-2-(2-aminothiazol-4-yI)acetamido]-3-( 1 -allyl- 1 Ilyl-l H-tetrazol-5- yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) (5) 7-[2-methylthiomethoxyimino-2-(2-aminothiazol-4-yl)acetamidoj-3-( 1 -allyl- 1 H-tetrazol-5 yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

In Vitro Anti-bacterial Activity Test Method In vitro anti-bacterial activity was determined by the two-fold agar-plate dilution 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 cdmpounds and the minimal inhibitory concentration (MIC) was expressed in terms of yg/ml after incubation at 370C for 20 hours.

Test Results

MIC (ug/mO Test Compounds Test Bacteria (1) (2) (3) (4) {5J Bacillus subtilis ATCC 6633 0.39 0.78 0.78 1.56 1.56 Pseudomonas aeruginosa NCTC-10490 3.13 12.50 6.25 12.50 12.50 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, parenteral 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, conditions of the patient, a kind of disease, a kind of the compound (I) to be applied, etc., an average single dose of about 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 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 6000 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 of the Starting Compounds Preparation 1 (1) -allyl-1 H-tetrazole-5-thiol (21.3 g) was added at 76 to 780C to a solution of sodium bicarbonate (10.6 g) in water (220 ml). Sodium 7-(5-amino-5- carboxyvaleramido)cephalosporanate (54.9 g) was added thereto over 1 5 minutes and the mixture was stirred for 80 minutes at 76 to 780C.

The reaction mixture was adjusted to pH 3.0 with 6N hydrochloric acid under ice-cooling and filtered.

The filtrate was subjected to column chromatography on non-ionic adsorption resin "Diaion HP-20" (Trademark: prepared by Mitsubishi Chemical Industries Ltd.) and eluted with 30% aqueous solution of isopropyl alcohol. The eluate was adjusted to pH 6.5 with 28% aqueous solution of ammonia, concentrated and lyophilized to give ammonium 7-(5-amino-5- carboxyvaleramido)-3-(1-allyl-1 Htetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (21.7 g).

I.R. (Nujol): 3175, 1760, 1590 cm~1 N.R.R. (d8-DMSO, S): 1.23-2.42 (6H, m), 3.12-3.97 (3H, m), 4.37 (2H, broad s), 4.80-5.15 (3H, m), 5.15-5.51 (2H, m), 5.51-6.25 (2H, m), 8.77 (1 H, d, J=8 Hz).

(2) N,N-dimethylaniline (18.2 ml) was added to a mixture of ammonium 7-(5-amino-5 carboxyvaleramido)-3-(1 -allyl-1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (10.0 g), trimethylsilyl chloride (20.9 ml) and methylene chloride (75 ml), and the mixture was stirred under reflux for 2.5 hours. Phosphorus pentachloride (5.83 g) was added thereto at -30 to -350C and the mixture was stirred for 2 hours at the same temperature. 2-ethoxyethanol (38 ml) was added dropwise thereto at the same temperature and the mixture was stirred for 1 hour at the same temperature.

Water (80 ml) was added thereto at -5 to -1 00C over 10 minutes and the resulting mixture was stirred for 5 minutes at the same temperature. The aqueous layer was separated and adjusted to pH 4.2 with 28% aqueous solution of ammonia. Precipitates were collected by filtration, washed with 70% aqueous acetone (40 ml) and methanol (40 ml), and dried to give 7-amino-3-(1-allyl-1 H-tetrazol-5 yl)thiomethyl-3-cephem-4-carboxylic acid (4.1 g).

I.R. (Nujol): 3150, 1800, 1610, 1530 cm-' N.M.R. (d6-DMSO, S): 3.65 (2H, ABq, J=1 8 Hz), 4.33 (2H, ABq, J=1 3 Hz), 6.38--4.70 (7H, m).

Preparation 2 (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) with 2-propynyl bromide (43 g) in the presence of potassium carbonate (72.3 g) and N,N-dimethylformamide (280 ml).

I.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).

I.R. (Film): 3300, 2130, 1745, 1720, 1675 cm1.

(3) Ethyl 2-(2-propynyloxyimino)-2-(2-aminothiazol-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~'.

(4) 2-(2-propynyloxyimino)-2-(2-aminothiazol-4-yl)acetic acid (syn-isomer) (1.924 g) was obtained by hydrolyzing ethyl 2-(2-propynyloxyimino)-2-(2-aminothiazol-4-yl)acetate (syn-isomer) (2.8 g) in the presence of 1 N aqueous solution of sodium hydroxide (22.17 ml), methanol (23 ml) and tetrahydrofuran (20 ml).

I.R. (Nujol): 2190, 1740 cm~'.

Preparation 3 Formic acid (107 g) was added to acetic 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-(2 propynyloxyimino)-2-(2-aminothiazol-4-yI)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 the filtration, washed with diisopropyl ether and then dried to give 2-(2-propynyloxyimino)-2-(2-formamidothiazol-4-yI)acetic acid (syn-isomer) (118.4 g).

I.R. (Nujol): 3250, 2130, 1685, 1600,1 560 cm-l N.M.R. (d6-DMSO, b): 3.53 (1 H, m), 4.87 (2H, d, J=2 Hz), 7.63 (1 H, s), 8.61 H, s), 12.7 (1 H, broad s).

Preparation 4 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 ailyloxyamine 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 adiusted 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-allyloxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn-isomer) (25.3 g).

I.R. (Nujol): 3110,1730,1660,1540 cam~' N.M.R. (d6-DMSO, ): 4.70 (2H, m), 5.13-5.60 (2H, m), 5.73-6.27 (1 H, m), 7.57 (1 H, s), 8.35 (1H,s).

Preparation 5 (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-ethoxyimino-3-oxo-4-chlorobutyrate (syn-isomer) (53.8 9), 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 for40 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 1 31 OC.

I.R. (Nujol): 3450,3275,3125, 1715, 1620 cm-'.

(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 2ethoxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn-isomer) (2.9 g).

I.R. (Nujol): 3625, 3225 (shoulder, 3100, 1650, 1615 cm-l N.M.R. (d6-DMSO, S): 1.20 (3H, t, J=7 Hz), 4.09 (2H, q, J=7 Hz), 6.82 (1 H, s), 7.24 (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 3 to give 2ethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn-isomer) (99.1 g).

I.R. (Nujol): 3200,3140,3050, 1700 cm-l N.M.R. (d,-DMSO, 6): 1.18 (3H,t,J=6 Hz), 4.22 (2H,q,J=6 Hz), 7.56 (1H,s),8.56 (1H,s), 12.62 (1H, broad s).

Preparation 6 (1) Ethyl 2-hydroxyimino-2-(2-aminothiazol-4-yl)acetate (syn-isomer (126.4 g), formic acid (81.3 g) and acetic anhydride (180 g) were treated in a similar manner to that of Preparation 3 to give ethyl 2-hydroxyimino-2-(2-formamidothiazol-4-yl)acetate (syn-isomer) (109.6 g).

I.R. (Nujol): 3320, 3140, 3050, 1710, 1555 cm-l N.M.R. (d6-DMSO, b): 1.30 (3H, t, J=7 Hz), 4.33 (2H, q, J=7 Hz), 7.54 (1 H, s), 8.54 (1 H, s), 11.98 (1H, s), 12.58 (1 H, 5).

(2) A mixture of chloromethylthiomethane (7.97 g), powdered potassium iodide (15.1 g) and acetone (79 ml) was stirred at ambient temperature for an hour, the resulting mixture was filtered and washed with a small amount of acetone. The washings and the filtrate were combined and added to a stirred suspension of ethyl 2-hydroxyimino-2-(2-formamidothiazol-4-yl)acetate (syn-isomer) (17.5 g) and powdered potassium carbonate (15.5 g) in acetone (300 ml). The mixture was stirred at ambient temperature for 3 hours, filtered and washed with acetone. The washings and the filtrate were combined and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium chloride twice, dried over magnesium sulfate and concentrated in vacuo.The oily residue was subjected to column chromatography on silica gel and eluted with chloroform to give ethyl 2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)acetate (syn-isomer) (2.4g),mp 130 to 1310C.

I.R. (Nujol): 3160,3125,3050,1740,1695 cm-1 N.M.R. (d-DMSO, S): 1.32 (3H, t, J=7 Hz), 2.22 (3H, s), 4.38 (2H, q, J=7 Hz), 5.33 (2H, s) 7.67 (1H,s), 8.56 (1H,s).

(3) A mixture of ethyl 2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yI)acetate (synisomer) (2.4 g), N aqueous sodium hydroxide (23.8 ml) and methanol (19.8 ml) was stirred at 300C for 2.5 hours. The resultant solution was adjusted to pH 7 with 10% hydrochloric acid and methanol was distilled off in vacuo The aqueous solution was adjusted to pH 1 with 10% hydrochloric acid under ice cooling, and extracted with ethyl acetate three times. The extracts were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give 2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn-isomer) (1.13 g), mp 1 570C (dec.).

I.R. (Nujol): 3210, 3160, 3075, 1700, 1555 cam-1 N.M.R. (d ,-DMSO,8): 2.24 (3H, s),5.31 (2H, s), 7.61(1H, s),8.57 (1 H, s), 12.73 (1 H, s).

Preparation 7 The following compounds were obtained according to similar manners to those of Preparations 2 to 6.

(1) 2-isopropoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn-isomer), mp 168 to 1 690C (dec.).

I.R. (Nujol): 3200, 3130, 1710, 1600, 1560 cm~'.

(2) 2-butoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn-isomer).

I.R. (Nujol): 3350, 3160, 3050, 1700, 1680, 1570 cm~'.

(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, ô): 0.6-2.1(11 H, m), 4.15 (2H, t, J=6 Hz), 7.53 (1 H, s), 8.56 (1 H, s), 12.69 (1H,s).

(4) 2-(2-formyloxyethoxy)imino-2-(2-formamidothiazol-4-yl)acetic acid (syn-isomer).

I.R. (Nujol):3200, 1710, 1690 cm-1.

(5) 2-benzyloxyimino-2-(2-aminothiazol-4- yl)acetic acid (syn-isomer).

I.R. (Nujol): 3330,3200,3100, 1660, 1590 cm-1.

(6) 2-ethoxycarbonylmethoxyimino-2-(2-forma midothiazol-4-yl)acetic acid (syn-isomer), mp 1 120C (dec.).

I.R. (Nujol): 3150, 1740, 1670, 1550 cm-1.

(7) 2-t-butoxycarbonyl methoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn-isomer), mp 1 170C (dec.).

I.R. (Nujol): 3180, 3140, 1750, 1690, 1630 cm~'.

(8) 2-(3-isoxazolyl)methoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn-isomer), mp 1 100C (dec.).

I.R. (Nujol): 3270, 3130, 1680, 1540 cm~'.

Preparation 8 (1) Ethyl 2-hydroxyimino-3-oxobutyrate (syn-isomer, 40.0 g), 4-fluorobenzyl chloride (43.6 g), N,N-dimethylformamide (60.0 ml), potassium carbonate (52.0 g) and ethyl acetate (60.0 ml) were treated in a conventional manner to give ethyl 2-(4-fluorobenzyloxyimino)-3-oxobutyrate (syn-isomer, 64.4 g).

I.R. (Film): 3000, 2940, 1730, 1690, 1600 cm-' N.M.R. (DMSO-de, b): 1.21 (3H, t, 5-7.0 Hz), 2.34 (3H, s),4.26 (2H, q, J=7.0 Hz), 5.32 (2H, s), 6.97-7.73 (4H, m).

(2) Ethyl 2-(4-fluorobenzyloxyimino)-3-oxobutyrate (syn-isomer, 64.0 g) and sulfuryl chloride (35.6 g) and acetic acid (70.0 ml) were treated in a similar manner to that of Preparation 5-( 1) to give ethyl 2-(4-fluorobenzyloxyimino)-3-oxo-4-chlorobutyrate (syn-isomer, 29.55 g).

I.R. (Film): 1720, 1600 cm-l N.M.R. (DMSO-de, d): 1.20 (3H, t, J=7.0 Hz), 4.28 (2H, q, J=7.0 Hz), 4.87 (2H, s), 5.36 (2H, s), 7.00-7.75 (4H, m).

(3) Ethyl 2-(4-fluorobenzyloxyimino)-3-oxo-4-chlorobutyrate (syn-isomer, 29.0 g), thiourea (8.8 g), sodium acetate (7.9 g), water (72.5 ml), tetrahydrofuran (60 ml) and ethanol (72.5 ml) were treated in a similar manner to that of Preparation 5-(2) to give ethyl 2-(4-fluorobenzyloxyirnino)-2-(2 aminothiazol-4-yl)acetate (syn-isomer, 28.0 g).

I.R. (Nujol): 3450, 3150,3100, 1710, 1620 cm-1 N.M.R. (DMSO-d6, S): 1.23 (3H, t, J=7.0 Hz), 4.30 (2H, q, J=7 Hz), 5.15 (2H, s), 6.90 (1 H, s), 6.95-7.60 (4H, m).

(4) Ethyl 2-(4-fluorobenzyloxyimino)-2-(2-aminothiazol-4-yI)acetate (syn-isomer, 25.5 9), 1- methylimidazole (1.3 g), 1 N sodium hydroxide solution (118.3 ml), methanol (250 ml) and tetrahydrofuran (200 ml) were treated in a similar manner to that of Preparation 5-(3) to give 2-(4fluorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetic acid (syn-isomer, 22.11 9).

I.R. (Nujol): 3650, 3450, 3300, 3150, 1630 cam-1 N.M.R. (DMSO-d6, S): 5.16 (2H, 5), 6.88 (1 H, s), 7.04--7.66 (4H, m).

(5) 2-(4-fluorobenzyloxyimino)-2-(2-aminothiazol-4-yI)acetic acid (syn-isomer, 23.4 g), bis(trimethylsilyl)acetamide (32.2 g) 2,2,2-trifluoroacetic anhydride (49.9 9) and dry ethyl acetate (234 ml) were treated in a similar manner to that of Preparation 3 to give 2-(4-fluorobenzyloxyimino)2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]acetic acid (syn-isomer, 1 8.9 9), mp 180 to 1 820C.

I.R. (Nujol): 3200, 3150, 1730 cm-1 N.M.R. (DMSO-d6, S): 5.25 (2H, s), 7.02-7.60 (4H, m), 7.72 (1 H, s).

Preparation 9 (1) The following compounds were obtained by reacting ethyl 2-hydroxyimino-3-oxobutyrate (syn-isomer) with cyclopentyl bromide or 3,4-dichlorobenzyl chloride respectively, in a conventional manner.

(i) Ethyl 2-cyclopentyloxyimino-3-oxobutyrate (syn-isomer), oil.

I.R. (Film): 1740, 1670, 1495, 1430 cm-1 N.M.R. (CCI4, #): 1.32 (3H, t, J=7 Hz), 1.4-2.2 (8H, m), 2.33 (3H, s),4.27 (2H, q, J=7 Hz), 4.87 (1H,m).

(ii) Ethyl 2-(3,4-dichlorobenzyloxyimino)-3-oxobutyrate (syn-isomer), oil.

I.R. (Film): 1730, 1690, 1600, 1470, 1400, 1370, 1310, 1240, 1130,1080,1010cm-1 N.M.R. (CCl4, S): 1.30 (3H, t, J=6 Hz), 2.30 (3H, s), 4.30 (2H, q, J=6 Hz), 4.47 (2H, s),7.00 7.53 (3H, m).

(2) The following compounds were obtained according to a similar manner to that of Preparation 5(1).

(i) Ethyl 2-cyclopentyloxyimino-3-oxo-4-chlorobutyrate (syn-isomer), oil.

I.R. (Film): 1750,1735,1465, 1435 cm-1 N.M.R. (CC14, S): 1.33 (3H, t, J=7 Hz), 1.3-2.4 (8H, m), 4.28 (2H, q, J=7 Hz), 4.46 (2H, s),.4.86 (1H,m).

(ii) Ethyl 2-(3,4-dichlorobenzyloxyimino)-3-oxo-4-chlorobutyrate (syn-isomer), oil.

I.R. (Film): 1740,1710,1590,1470, 1400,1370,1320,1260, 1200,1130, 1O1Ocm1 N.M.R. (CCI4, #): 1.37 (3H, t, J=6 Hz), 4.23 (2H, q, J=6 Hz), 4.43 (2H, s), 5.27 (2H, s),7.10 7.60 (3H, m).

(3) The following compounds were obtained according to a similar manner to that of Preparation 5-(2).

(i) Ethyl 2-cyclopentyloxyimino-2-(2-aminothiazol-4-yl)acetate (syn-isomer), mp 134 to 1 36 0C.

I.R. (Nujol): 3490, 3450, 3250, 3120, 1735, 1540, 1460 cm-1 N.M.R. (DMSO-d6, #): 1.25 (3H, t, J=7 Hz), 1.62 (8H, broad s),4.27 (2H, q,J=7 Hz), 4.70 (1 H, m), 6.85 (1 H, s), 7.20 (2H, s).

(ii) Ethyl 2-(3,4-dichlorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetate (syn-isomer).

I.R. (Nujol):3460, 3460,1720,1600,1540,1460,1390,1260,1180,1020,1010,880,810 1010, 880, 810 cm-1 N.M.R. (DMSO-de, S): 1.25 (3H, t, J=7 Hz), 4.30 (2H, q, J=7 Hz), 5.17 (2H, s), 6.93 (1 H, s), 7.27-7.73 (3H, m).

(4) The following compounds were obtained according to a similar manner to that of Preparation 5-(3).

(i) 2-cyclopentyloxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn-isomer), mp 1 860C (dec.) I.R. (Nujol): 3330, 3120, 1635,1450 cm-1 N.M.R. (DMSO-de, S): 1.1-2.2 (8H, m), 4.68 (1 H, m), 6.81 H, 5), 7.18 (2H, broad s).

(ii) 2-(3,4-dichlorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetic acid (syn-isomer).

I.R. (Nujol): 3430, 3430,1660,1590,1400,1010 cm~' N.M.R. (DMSO-d6, S): 5.23 (2H, s), 6.93 (1 H, s), 7.30--7.77 (3H, m).

(5) the following compounds were obtained according to a similar manner to that of Preparation (i) 2-cyclopentyloxyimino-2-[2,2,2-trifluoroacetamido)thiazol-4-ylgacetic acid (syn-isomer).

I.R. (Nujol: 3200, 3130, 1720, 1590, 1580 cm-1 N.M.R. (DMSO-dH, S): 1.34-2.22 (8H, m), 4.81(1 H, m), 7.71(1 H, s).

(ii) 2-(3,4-dichlorobenzyloxyimino)-2-[2-(2,2,2- trifluoroacetamido)thiazol-4-yl]acetic acid (synisomer).

I.R. (Nujol): 1720, 1580, 1300, 1260, 1200, 1160, 1150 cm-1 N.M.R. (DMSO-d6, S): 5.40 (2H, s), 7.47--7.93 (4H, m).

Example 1 2-allyloxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn-isomer) (0.80 g) and dry ethyl acetate (10 ml) were added at 0 two 50C with stirring to a suspension of Vilsmeier reagent prepared from dry dimethylformamide (0.25 g) and phosphorus oxychloride (0.528 g) in dry ethyl acetate (0.75 ml) by conventional method, and the resulting mixture was stirred for 30 minutes at the same temperature to give a yellow solution. The solution was added at-I 00C with stirring to a solution of 7-amino-3-(1 -allyl-l H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.11 g) and trimethylsilylacetamide (2.96 g) in dry ethyl acetate (15 ml), and the mixture was stirred for 1.5 hours at the same temperature.After addition of water (15 ml) to the reaction mixture, the ethyl acetate layer was separated and extracted with an aqueous solution of sodium bicarbonate (30 ml). The aqueous extract was acidified to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate (150 ml).

The extract was washed with water, dried and evaporated. The residue was pulverized with diisopropyl ether to give colorless powder of 7-[2-allyloxyimino-2-(2-formamidothiazol-4-yI)acetamido]-3-( 1-a Ilyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) (1.48 g).

I.R. (Nujol): 3180, 1775, 1665cm1 N.M.R. (d6-DMSO, 6): 9.68 (1 H, d, J=8 Hz), 8.51 H, 5), 7.40 (1 H, s), 5.60--6.33 (3H, m), 4.85-5.57 (7H, m), 4.27-4.77 (4H, m), 3.70 (2H, ABq, J=1 8 Hz).

Example 2 The Vilsmeier reagent was prepared from dry dimethylformamide (2.6 g), phosphorus oxychloride (5.4 g) and dry ethyl acetate (10.4 ml) by the conventional method. Dry ethyl acetate (100 m!) was added thereto and then 2-cyclopentyloxyimino-2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]acetic acid (syn-isomer) (10.4 g) was added thereto at OOC. The mixture was stirred for 30 minutes at the same temperature. The resulting mixture was added under =1 00C to a stirred solution of 7-amino-3-( 1 -allyl- 1 H-tetrazol-5-yi)thiomethyl-3-cephem-4-carboxylic acid (9.6 g) and trimethylsilylacetamide (24.8 g) in dry ethyl acetate (192 ml), and the mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was added water.The ethyl acetate layer was separated and extracted with aqueous solution of sodium bicarbonate (pH 7.5). The aqueous layer was washed twice with ethyl acetate and adjusted to pH 2.0 with 10% hydrochloric acid after addition of ethyl acetate and tetrahydrofuran. The organic layer was separated, washed with water, dried over magnesium sulfate, treated with an activated charcoal and concentrated to dryness. The residue was pulverized with diethyl ether and the powder was collected by filtration and washed with diethyl ether to give 7-[2-cyclopentyloxyimino-2 (2-(2,2,2-trifluoroacetamido)thiazol-4-yl Iacetamido]-3-( 1-al lyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem- 4-carboxylic acid (syn-isomer) (1 8.1 8 g).

N.M.R. (DMSO-de, ô): 1.28-2.26 (8H m), 3.73 (2H, m), 4.39 (2H, ABq, J=14 Hz), 4.77 1 H, m), 4.88-5.47 (5H, m), 5.70-6.52 (2H, m), 7.50 (1 H, d, 9.67 (1 H, d, J=8.0 Hz).

Example 3 The Vilsmeier reagent was prepared from dry dimethyl formamide (0.4 g), phosphorus oxychloride (0.9 g) and dry ethyl acetate (1.6 ml) by the conventional method. Dry ethyl acetate (18 ml) was added thereto and then 2-ethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn-isomer) (1.3 g) was added thereto at OOC. The mixture was stirred for 30 minutes at the same temperature. The resulting mixture was added under --100C to a stirred solution of 7-amino-3-(1 -allyl-1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (1.8 g) and trimethylsilylacetamide (4.6 g) in dry ethyl acetate (36 ml), and the mixture was stirred for 1 hour at the same temperature. To the reaction mixture was added water (30 ml). The ethyl acetate layer was separated and extracted with a saturated aqueous solution of sodium bicarbonate (pH 7.5).The aqueous layer was washed three times with ethyl acetate and adjusted to pH 2.0 with conc. hydrochloric acid after addition of ethyl acetate (100 ml). The ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with an activated charcoal and concentrated to dryness to give 7-[2-ethoxyimino-2-(2-formamidothiazol-4-yI)acetamido]-3-( 1 -allyl-1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) (2.56 g).

I.R. (Nujol): 3200, 1765, 1665 cm-l N.M.R. (d6-DMSO, S): 1.26 (3H, t, J=7.0 Hz), 3.68 (2H, m), 4.18 (2H, q, J=7.0 Hz), 4.36 (2H, ABq, J=14.0 Hz), 4.75-5.57 (5H, m), 5.68-6.40 (2H, m), 7.37 (1H, s),8.48 (1 H, s), 9.60 (1 H, d, J=8.0 Hz).

Example 4 The Vilsmeier reagent was prepared from dry dimethylformamide (0.5 g), phosphorus oxychloride (1.3 g) and dry ethyl acetate (2.0 ml) by the conventional method. Dry tetrahydrofuran (20 ml) was added thereto and then 2-(2-propynyl)oxyimino-2-(2-formamidothiazol-4-yI)acetic acid (syn-isomer) (1.6 g) was added thereto at OOC. The mixture was stirred for 30 minutes at the same temperature. The resulting mixture was added at 00C to a stirred solution of 7-amino3-(1-allyl-1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.0 g) and trimethylsilylacetamide (5.1 g) in dry ethyl acetate (40 ml), and the mixture was stirred for 1 hour at --10 to -20"C. To the reaction mixture was added water (30 ml).The organic layer was separated and extracted with a saturated aqueous solution of sodium bicarbonate (30 ml). The aqueous layer was adjusted to pH 2.2 with conc. hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give colorless powder of 7-[2-(2-propynyl)oxyimino-2-(2-formamidothiazol-4 yl)acetamido]-3-(1-allyl-1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.40 g).

I.R. (Nujol): 3310, 2170, 1780, 1680 cam~' N.M.R. (d6-DMSO, â): 3.49 (1 H, m), 3.72 (2H, m), 4.38 (2H, ABq, J=14 Hz), 4.57-5.52 (7H, m), 5.69-6.40 (2H, m), 7.46 (1 H, s), 8.55 (1 H, s), 9.75 (1 H, d, J=8 Hz).

Example 5 The Vilsmeier reagent was prepared from dry dimethylformamide (0.209 g), phosphorus oxychloride (0.434 g) and dry ethyl acetate (0.75 ml) by the conventional method. Dry tetrahydrofuran (6.5 ml) was added thereto and then 2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yI)acetic acid (syn-isomer) (0.65 g) was added thereto at OOC. The mixture was stirred for 30 minutes at the same temperature. The resulting mixture was dropwise added at -5 to OOC to a stirred solution of 7 amino-3-(1-alIyI-iH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.25 g) in a mixture of water (10 ml) and acetone (10 ml) keeping the pH at 7.5 by triethylamine, and the mixture was stirred for 30 minutes at the same temperature at pH 7.5.To the reaction mixture was added ethyl acetate (60 ml) and the mixture was adjusted to pH 2.5 with 10% hydrochloric acid. Insoluble material was filtered off and the filtrate was extracted twice with ethyl acetate. The combined extracts were washed twice with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off and the residue was pulverized with diethyl ether to give yellowish powder of 7-[2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1 -allyl-1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) (1.03 g).

I.R. (Nujol): 3250, 3200, 1780, 1670, 1540 cm~' N.M.R. (d6-DMSO, ): 2.23 (3H, s), 3.72 (2H, s), 4.38 (2H, ABq, J=1 4 Hz), 4.8-5.6 (7H, m), 5.7-6.4 (2H, m), 7.48 (1H, s), 8.55 (1H, s), 9.75 (1H, d, J=8 Hz), 12.69 (1H, broad s).

Example 6 The Vilsmeier reagent was prepared from dry dimethylformamide (0.74 g), phosphorus oxychloride (1.56 g) and dry ethyl acetate (2.0 ml) by the conventional method. Dry tetrahydrofuran (15 ml) was added thereto and then 2-(3-isoxazolyl)methoxyimino-2-(2-formamidothiazol-4-yI)acetic acid (syn-isomer) (1.50 g) was added thereto at OOC. The mixture was stirred for 30 minutes at the same temperature. The resulting mixture was added dropwise at -5 to OOC to a stirred solution of 7 amino-3-(l-allyl-l H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.34 g) in a mixture of water 11.5 ml) and acetone (11.5 ml) keeping the pH at 7.5 by triethylamine, and the mixture was stirred for 30 minutes at the same temperature at pH 7.5.To the reaction mixture was added ethyl acetate (60 ml) and the mixture was adjusted to pH 2.5 with 10% hydrochloric acid. Insoluble material was filtered off and the filtrate was extracted twice with ethyl acetate. The combined extracts were washed twice with a saturated sodium chloride aqueous solution and dried over magnesium sulfate.

The solvent was distilled off and the residue was pulverized with diethyl ether to give yellowish powder of 7-[2-(3-isoxazolyl)methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-( 1 -allyl-1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) (2.15 g).

I.R. (Nujol): 3250, 1 780, 1670, 1 550 cam~' N.M,R. (d6-DMSO, d): 3.72 (2H, s), 4.40 (2H, ABq, J=14 Hz), 4.8-5.6 (7H, m), 5.6-6.5 (2H, m), 6.67 (1 H, d, J=2 Hz), 7.50 (1 H, 5), 8.56 (1 H, s), 8.92 (1 H, d, J=2 Hz), 9.80 (1 H, d, J=8 Hz), 12.72 (1 H, broad s).

Example 7 Phosphorus oxychloride (1.0 g) was added at a time to a suspension of 2-benzyloxyimino-2-(2aminothiazol-4-yl)acetic acid (syn isomer) (1.4 g) in dry tetrahydrofuran (14 ml) at 20C and the mixture was stirred for 15 minutes at 2 to 4 C. Trimethylsilylacetamide (1.0 g) was added dropwise thereto and the resulting mixture was stirred for 20 minutes at 2 to 60C. Phosphorus oxychloride (1.0 g) was added thereto and the mixture was stirred for 20 minutes. Dry dimethylformamide (0.5 g) was added thereto at a time at 4 to 60C and the mixture was stirred for 1 hour to give a clear solution.On the other hand, trimethylsilylacetamide (5.3 g) was added to a stirred suspension of 7-amino-3-(l-allyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.8 g) in dry ethyl acetate (27 ml) and the solution was stirred for 30 minutes at 4O0C. 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-benzyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1 -allyl-1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) (0.85 g).

I.R. (Nujol): 3350, 3230, 1780, 1675, 1635 cam~' N.M.R. (d6-DMSO, â): 3.67 (2H, m), 4.40 (2H, ABq, J=1 5.0 Hz), 4.85-5.56 (6H, m), 5.62-6.45 (2H, m), 6.77 (1H,s), 7.01-7.65 (7H, m), 9.71 (1H,d,J=8 Hz).

Example 8 The Vilsmeier reagent was prepared from dry dimethylformamide (0.44 9), phosphorus oxychloride (0.9 g) and dry ethyl acetate (1.0 ml) by the conventional method. Dry ethylacetate (20 ml) was added thereto and then 2-methoxyimino-2-(2-formamidothiazol-4-yl)-acetic acid (syn isomer) (1.1 9) was added thereto at --5 to -1 00C. The mixture was stirred for 10 minutes at the same temperature. The resulting mixture was dropwise added at O to 50C and pH 6.5 to 7.5 with stirring to a solution of 7-amino-3-(4-allyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (2.12 g) and sodium bicarbonate (2 9) in a mixture of water (20 ml) and acetone (20 ml), and the mixture was stirred for 20 minutes at the same temperature. The aqueous layer was separated and acetone was evaporated.The aqueous layer was adjusted under ice-cooling and stirring to pH 3.0 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2 methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-allyl-4H- 1,2,4-triazol-3-yl)thiomethyl-3- cephem-4-carboxylic acid (syn-isomer (0.94 g).

I.R. (Nujol): 3200, 1780, 1680, 1550 cam-1 N.M.R. (de-DMSO, â): 3.72 (2H, broad s), 3.93 (3H, s), 4.20 (2H, broad s), 4.65 (2H, m),4.72 5.43 (3H, m), 5.55-6.45 (2H, m), 7.43 (1 H, s), 8.55 (1 H, s), 8.75 (1 H, s), 9.68 (1 H, d, J=8 Hz), 12.82 (1H, m).

Example 9 The following compounds were obtained according to similar manners to those of Examples 1 to 8.

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

I.R. (Nujol): 3220, 1780, 1670 cm-1 N.M.R. (d6-DMSO, ä): 1.20 (3H, s), 1.32, (3H, s), 3.70 (2H, broad 5), 4.07-4.87 (3H, m),4.93-- 5.50 (4H, m), 5.67-6.23 (2H, m), 7.40 (1 H, s), 8.50 (1 H, s), 9.58 (1 H, d, J=8 Hz).

(2) 7-[2-butoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1 -allyl- H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (sym isomer).

I.R. (Nujol): 3200, 1780, 1695, 1675, 1655 cm-1 N.M.R. (d6-DMSO,#): 0.88 (3H, m), 1.10-2.01 (4H, m), 371 {2H, m), 4.14 (2H,t, J=7.0 Hz), 4.38 (2H, ABq, J=1 4.0 Hz), 4.83-5.51 (5H, m), 5.63-6.40 (2H, m), 7.42 (1 H, s), 8.56 (1 H, s), 9.65 (1 H, d, J=9.0 Hz).

(3) 7-[2-hexyloxyimino-2-(2-formamidothiazol-4-yl)-acetamidoi-3-( 1 -allyl-1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

IR. (Nujol): 3175,1780,1757,1684,1640 cm-1 N.M.R. (d6-DMSO, â): 0.84 (3H, m), 1.06-2.03 (8H, m), 3.73 (2H, m), 4.14 (2H, t, J=6.0 Hz), 4.40 (2H, ABq, J=1 4.0 Hz), 4.85-5.52 (5H, m), 5.75-6.45 (2H, m), 6.97 (1 H, broad s), 7.41(1 H, s), 8.54 (1 H, s), 9.63 (1 H, d, J=8.0 Hz).

(4) 7-[2-(2-formyloxyethoxy)imino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1 -allyl-1 H-tetrazol 5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3265, 1780, 1720, 1680 cm-1 N.M.R. (d6-DMSO,#): 3.74 (2H, m), 4.13-4.70 (6H, m), 4.85-5.53 (5H, m), 5.70-6.42 (2H, m), 7.48 (1 H, s), 8.26 (1 H, s), 8.56 (1 H, s), 9.69 (1 H, d, J=9.0 Hz).

(5) 7-[2-ethoxycarbonylmethoxyimino-2-(2-formamido thiazol-4-yl)acetamido]-3-(1-allyl- 1H- tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3500, 3280, 1780, 1735, 1690 cm-1 N.M.R. (d6-DMSO, â): 1.24 (3H, t, J=7 Hz), 3.74 (2H, s), 4.20 (2H, q, J=7 Hz), 4.42 (2H, s),4.77 (2H, s), 4.5--5.6 (5H, m), 5.7-6.4 (3H, m), 7.50 (1 H, s), 8.57 (1 H, s), 9.68 (1 H, d, J=8 Hz), 12.69 (1H, broads).

(6) 7-[2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]3(1 -allyl- 1 Htetrazol-5-yl)thiomethyl-3-cephem-4-ca rboxylic acid (syn-isomer).

I.R. (Nujol: 3250, 1780, 1720, 1680 1540 cam- N.M.R. (d-DMSO, #): 1.44 (9H, s), 3.71 (2H, ABq, J=1 8 Hz), 4.37 (2H, ABq, J=1 4 Hz), 4.62 (2H, s), 4.8-5.4 (5H, m), 5.5-6.4 (2H, m), 7.46 (1 H, s), 8.52 (1 H, s), 9.58 (1 H, d, J=8 Hz), 12.60 (1 H, broad s).

(7) 7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3 1 -allyl- 1 H-tetrazol-5-yl)thiomethyl3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol: 3350, 1780, 1675, 1635 cm- (8) 7-[2-isopropoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3350, 3250, 1780, 1675, 1630 cm-1 (9) 7-[2-Butoxyimino-2-(2-aminothiazol-4-yl)aceta mido]3-(1-allyl-1 H-tetrazol-5-yl)thiomethyl3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3360, 1 780, 1672 cm-l (10) 7-[2-hexyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-( 1 -allyl- 1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

l.R. (Nujol): 3350, 3240, 1780, 1675, 1630 cm-1 (11) 7-t2-allyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-( 1 -aIlyl- 1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3350,3210, 1778, 1675 cm1.

(12) 7-[2-(2-propynyl)oxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3330, 2170, 1780,1683, 1630cm1.

(1 3) 7-[2-ethoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1 -allyl-1 Htetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3360, 3230, 1780, 1680, 1630 cm-.

(1 4) 7-[2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H- tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3330, 1780, 1730, 1680, 1630 cm~'.

(15) 7-[2-methylthiomethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3270, 1760, 1650, 1520 cm-.

(1 6) 7-[2-(3-isoxazolyl) methoxyimino-2-(2-aminothiazol-4-yl)aceta mido]-3-( 1 -allyl- 1 H-tetrazol5-yl)thiomethyl-3-cephem-4-ca rboxylic acid (syn isomer).

I.R.(Nujol): 3300, 1770, 1660, 1530 cm~'.

(17) 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1 H-tetrazol-5yl)thiomethyl-3-cephem-4-ca rboxylic acid (syn-isomer).

I.R. (Nujol): 3360, 1780, 1 680, 1 630 cm-.

(18) 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(4-allyl-4H-1 ,2,4-triazol-3- yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. (Nujol): 3350, 1775, 1670, 1530 cm~'.

(19) 7-[2-cyclopentyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), mp 140 to 1 450C (dec.).

I.R. (Nujol): 3300, 33001770, 1 660;'1 620 cm~'.

(20) 7-[2-(4-fluorobenzyloxyimino)-2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl} -acetamido]3- (1 -allyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3250, 3170, 1780, 1720, 1650 cm~'.

N.M.R. (DMSO-d8,8): 3.64 (2H, m), 4.34 (2H, ABq, J=1 4 Hz), 4.79-5.44 (7H, m), 5.65-6.27 (2H, m), 6.95-7.61 (4H, m), 7.51 H, 5), 9.83 (1 H, d, J=8 Hz).

(21) 7-[2-(4-fluorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1 H-tetrazol-5 yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), mp 157 to 161 C (dec.).

I.R. (Nujol): 3500, 1770, 1660, 1630, 1600 cm~'.

(22) 7-[2-(3,4-dichlornbenzyloxyimino)-2-j2-(2,2,2-trifluornaceta mido)thiazol-4-yl}acetamido]- 3-(1 -allyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 1770, 1650 cam-1 N.M.R. (DMSO-d6, ä): 3.72 (2H, m), 4.40 (2H, m), 5.00--5.43 (7H, m), 5.73-6.60 (2H, m), 7.30-7.77 (4H, m), 9.00 (1 H, d, J=8 Hz).

(23) 7-[2-(3,4-dichlornbenzyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), mp 155 to 1 750C (dec.).

I.R. (Nujol): 1770, 1660--1620, 1450 cm-1.

Example 10 Conc. hydrochloric acid (0.33 g) was added to a solution of 7-[2-allyloxyimino-2-(2formamidothiazol-4-yl)acetamido]-3-(1 -allyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), (1.30 g) in methanol (13 ml) and the mixture was stirred for 4.5 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 (25 ml). the aqueous solution was washed with ethyl acetate (25 ml) and adjusted to pH 2.0 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give colorless powder of 7-[2-allyloxyimino-2-(2 aminothiazol-4-yl)aceta mido]-3-( 1-a Ilyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn- isomer) (0.95 g).

I.R. (Nujol): 3350, 3210, 1778, 1675 cm-1 N.M.R. (d6-DMSO, #): 3.68 (2H, ABq, J=1 8 Hz), 4.40-4.71 (4H, m),4.80--5.45 (7H, m), 5.64-6.24 (3H, m), 6.74 (1 H, s), 7.35 (2H, broad s), 9.62 (1 H, d, J=8 Hz).

Example 11 7-[2-cyclopenloxyimino-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-(1-allyl-1Htetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) (18.0 g) and tetrahydrofuran (36 ml) were added to a stirred solution of sodium acetate trihydrate (35.6 g) in water (360 ml). The mixture was stirred for 1 8 hours at ambient temperature and then tetrahydrofuran was distilled off from the reaction mixture. The remaining solution was adjusted to pH 3.0 with 1 5% hydrochloric acid and precipitates were collected by filtration, washed with water and dried to give crude 7-[2 cyclopentyioxyimino-2-(2-a minothiazol-4-yl )acetam ido]-3-( 1 -a Ilyl- 1 H-tetrazol-5-yl)thiomethyl-3cephem-4-carboxylic acid (syn-isomer) (20 g).The crude substance was purified by column chromatography on aluminum oxide (60 ml) using a 35% aqueous solution of sodium acetate as an eluent to give pure object compound (8.31 g), mp 140 to 1 45OC (dec.).

I.R. (Nujol): 3300, 1770, 1 660, 1 620 cam~' N.M.R. (DMSO-dG, S): 1.16-2.26 (8H, m), 3.73 (2H, m), 4.41 (2H, ABq, J=1 4 Hz), 4.68 11 H, m), 4.89-5.52 (5H, m), 5.62-6.43 (2H, m), 6.73 (1 H, s), 9.51 H, H, d, J=8 Hz).

Example 12 Conc. hydrochloric acid (0.9 g) was added at ambient temperature to a solution of 7-[2ethoxyiminso-2-(2-formamidothiazol-4-yl)aceta mido]-3-(1 -al lyl- 1 H-tetrazol-5-yl)thiomethyl-3cephem-4-carboxylic acid (syn-isomer) (2.4 g) in a mixture of methanol (16.8 ml) and tetrahydrofuran (4.8 ml) and the mixture was stirred for hours at 300C. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate. The aqueous solution was washed with ethyl acetate and adjusted to pH 2.8 with conc. hydrochloric acid.

Precipitates were collected by filtration, washed with water and dried to give 7-[2-ethoxyimino-2-(2 aminothiazol-4-yl)acetamido]-3-(1 -allyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (synisomer) (1.72 g).

I.R. (Nujol): 3350, 1780, 1 675, 1 635 cam~' N.M.R. (d6-DMSO, S): 1.24 (3H, t, J=7.3 Hz), 3.71 (2H, m), 4.13 (2H, q, J=7.3 Hz), 4.37 (2H, ABq, J=1 3.5 Hz),4.805.53 (5H, m), 5.64-6.45 (2H, m), 6.77 (1 H, s), 7.25 (2H, broad s), 9.62 (1 H, d, J=8.0 Hz).

Example 13 To a solution of 7-[2-(2-propynyl)oxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) (2.0 g) in methanol (14 ml) was added conc. hydrochloric acid (0.3 g) and the mixture was stirred for 3.5 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. The aqueous solution was washed with ethyl acetate and adjusted to pH 2.8 with conc. hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-(2-propynyl)oxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1 Htetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) (1.43 g).

I.R. (Nujol): 3330, 2170, 1780,1680, 1630cm1 N.M.R. (d8-DMSO, S): 3.46 (1 H, m), 3.70 (2H, m), 4.37 (2H, ABq, J=13.5 Hz), 4.57-5.47 (7H, m), 5.60-6.49 (2H, m), 6.77 (1 H, s), 7,25 (2H, broad s), 9.64 (1 H, d, J=8.0 Hz).

Example 14 A mixture of 7-[2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) (0.95 g), conc. hydrochloric acid (0.324 g), methanol (9.5 ml) and tetrahydrofuran (2 ml) was stirred for 2 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. The aqueous solution was washed with ethyl acetate (25 ml) and adjusted to pH 1.5 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-methylthiomethoxyimino-2-(2-aminothiazol-4 yl)acetamido]-3-(l -allyl-l H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) (0.78 g).

I.R. (Nujol): 3270, 1 760, 1650, 1 520 cm-l N.M.R. (d6-DMSO, S): 2.21 (3H, s),3.72 (2H s),4.38 (2H, ABq, J=14 Hz), 4.8-5.6 (7H, m), 5.7-6.4 (2H, m), 6.80 (1 H, s), 7.26 (2H, broad s), 9.66 (1 H, d, J=8 Hz).

Example 15 A mixture of 7-[2-(3-isoxazolyl)methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-( 1 -allyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) (1.5 g), conc. hydrochloric acid (0.497 g), methanol (15 ml) and tetrahydrofuran (3 ml) was stirred for 2 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. The aqueous solution was washed with ethyl acetate 125 ml) and adjusted to pH 1.5 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-(3-isoxazolyl)methoxyimino-2-(2-aminothiazoi-4-yl)acetamido]-3-(1- allyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) (0.65 g).

I.R. (Nujol): 3300, 1770, 1660, 1530 cm-1 N.M.R. (d6-DMSO, S): 3.71 (2H, s), 4.40 (2H, d, J=14 Hz), 4.8-5.6 (7H, m), 5.6-6.5 (2H, m),6.62 (1 H, d, J=2 Hz), 6.83 (1 H, s), 7.29 (2H, broad s), 8.92 (1 H, d, J=2 Hz), 9.73 (1 H, d, J=8 Hz).

Example 16 A mixture of 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-allyl-4H- 1,2,4triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) (0.9 g), conc. hydrochloric acid (0.3 ml), methanol (7 ml) and tetrahydrofuran (7 ml) was stirred for 4.5 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. The aqueous solution was washed with ethyl acetate (25 ml) and adjusted to pH 2.0 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(4-allyl-4H-1,2,4- triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) (0.5 g).

I.R. (Nujol): 3350, 1775, 1670, 1530 cm- N.M.R. (d6-DMSO, S): 3.65 (2H, broad s), 3.83 (3H, s), 4.15 (2H, broad s), 4.58 (2H, m),4.77 5.5 (3H, m), 5.58-6.33 (2H, m), 6.73 (1 H, s), 8.60 (1 H, s), 9.58 (1 H, d, J=8 Hz).

Example 17 The following compounds were obtained according to similar manners to those of Examples 10 to 16.

(1) 7-[2-benzyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3350, 3230, 1780, 1675, 1635 cm-1.

(2) 7-[2-isopropoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1 1-allyl-1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxyiic acid (syn-isomer).

I.R. (Nujol): 3350, 3250, 1780, 1675, 1630 cm-1 N.M.R. (da-DMSO, S): 1.20 (3H, s),1.30 (3H, s), 3.70 (2H, broad s), 4.30 (3H, m), 4.97-5V40 (4H, m), 5.63-6.27 (2H, m), 6.70 (1 H, s), 9.55 (1 H, d, J=8 Hz).

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

I.R. (Nujol): 3360, 1 780, 1672 cm~1 N.M.R. (d6-DMSO, S): 0.91 (3H,t,J=6.0Hz), 1.18-1.96 (4H,m),3.73 (2H,m),3.87--4.73 (4H, m), 4.83-5.57 (5H, m), 5.63-6.40 (2H, m), 6.74 (1 H, s), 7.20 (2H, broad s), 9.55 H, H, d, J=8.0 Hz).

(4) 7-[2-heXyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1 H-tetrazol-5 yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3350, 3240, 1 780, 1675, 1630 cm-1 N.M.R. (d6-DMSO, S): 0.85 (3H, m), 1.00-2.00 (8H, m), 3.68 (2H, m), 4.05 (2H, m), 4.37 (2H, m),4.80--5.47 (5H, m), 5.60-6.47 (2H, m), 6.69 (1 H, s), 7.20 (2H, broad s), 9.50 (1 H, d, J=8.0 Hz).

(5) 7-[2-ethoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H- tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3360, 3230, 1780, 1680, 1630 cm-1 N.M.R. (d6-DMSO, S): 1.21 (3H, t, J=7 Hz), 3.68 (2H, s),4.14 (2H, q, J=7 Hz), 4.38 (2H, s), 4.66 (2H, s), 4.8--5.5 (5H, m), 5.6-6.4 (3H, m), 6.80 (1 H, s), 7.20 (2H, broad s), 9.48 (1 H, d, J=8 Hz).

(6) 7-[2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1 H- tetrazol-5-yl)th iomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3330, 1780, 1730, 1680, 1630 cm- N.M.R. (d6-DMSO, S): 1.43 (9H, s), 3.67 (2H, s), 4.37 (2H, ABq, J=1 4 Hz), 4.56 (2H, s), 4.8-5.5 (5H, m), 5.6-6.4 (2H, m), 6.78 (1 H, s), 7.20 (2H, broad s), 9.43 (1 H, d, J=8 Hz).

(7) 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido-3-(1-allyl-1 H-tetrazol-5yl)thiomethyl-3-cephem-4-ca rboxylic acid (syn-isomer).

I.R. (Nujol): 3360, 1 780, 1 680, 1630 cm-.

(8) 7-[2-(4-fluorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1 -aIIyl-1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), mp 1 to 161 C (dec.).

I.R. (Nujol): 3500, 1770, 1660, 1630, 1600 cam- N.M.R. (DMSO-d6, S): 3.69 (2H, m), 4.39 (2H, ABq, J=1 4 Hz), 4.75-5.48 (7H, m), 5.63-6.57 (2H, m), 6.76 (1 H, s), 6.86-7.76 (4H, m), 9.67 (1 H, d, J=8 Hz).

(9) 7-[2-(3,4-dichlorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol- 5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), mp 1 55 to 1 750C (dec.).

I.R. (Nujol): 1770, 1660-1620, 1450 cm-1 N.M.R. (DMSO-d6, S): 3.63 (2H, m), 4.33 (2H, m), 4.93-5.37 (7H, m), 5.67-6.40 (2H, m), 6.73 (1 H, s), 7.10--7.70 (3H, m), 9.73 (1 H, d, J=8 Hz).

Example 18 Trifluoroacetic acid (20 ml) was added under ice-cooling to a stirred suspension of 7-[2-tbutoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)aetamido]-3-(1-allyl-1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) (2.05 9) in anisole (2 ml), and the resultant mixture was stirred for 2 hours at ambient temperature. The reaction mixture was concentrated under reduced pressure and diethyl ether was added thereto. Precipitates were collected by filtration, washed with diethyl ether, dried and dissolved in an aqueous solution of sodium bicarbonate. An insoluble material was filtered off and the filtrate was adjusted to pH 3.2 with conc. hydrochloric acid.

Precipitates were collected by filtration, washed with water and dried to give 7-[2carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1 H-tetrazol-5-yl)thiomethyl-3cephem-4-carboxylic acid (syn-isomer) (0.8 g).

I.R. (Nujol): 3360, 1780, 1680, 1630 cam- N.M.R. (d8-DMSO, S): 3.68 (2H, ABq, J=1 9 Hz), 4.36 (2H, ABq, J=1 4 Hz), 4.60 (2H, 5)4.60- 6.2 (7H, m), 6.80 (1 H, s), 7.24 (2H, broad s), 9.51 H, d, J=9 Hz).

Example 19 To a solution of 7-[2-allyloxyimino-2-(2-aminothiazol-4-yl)acetamido]cephalosporanic acid (synisomer) (4.8 g) in pH 6.4 phosphate buffer solution (100 ml) was added 1 -allyl-1 H-tetrazole-5-thiol (2.1 g) and then the mixture was stirred for 2 hours at 55 to 600C. The reaction mixture was cooled and adjusted to pH 3.0 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-allyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5- yl)thiomethyl-3-cephem-4-ca rboxylic acid (syn-isomer) (2.0 g).

I.R. (Nujol): 3350, 3210, 1778, 1675 cam- N.M.R. (DMSO-d6, S): 3.68 (2H ABq, J=1 8 Hz), 4.40--4.71 (4H, m), 4.80--5.45 (7H, m),5.64 6.24 (3H, m), 6.74 (1 H, s), 7.35 (2H, broad s), 9.62 (1 H, d, J=8 Hz).

Example 20 The following compounds were obtained according to a similar manner to that of Example 19.

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

I.R. (Nujol): 3180, 1775, 1665 cm~'.

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

I.R. (Nujol): 3200, 1765, 1665 cm~'.

(3) 7-[2-(2-propynyl)oxyimino-2-(2-formamidothiazot-4-yl)acetamido]-3-(1 -allyl- 1 -H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3310, 2170, 1780, 1680 cm~'.

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

I.R. (Nujol): 3250, 3200, 1780, 1670, 1540 cm~'.

(5) 7-[2-(3-isoxazolyl)methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-1 Htetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujoi): 3250, 1780, 1670, 1550 cm~'.

(6) 7-[2-benzyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1 H-tetrazol-5yl)thiomethyl-3-cephem-4-ca rboxylic acid (syn-isomer).

l.R. (Nujol): 3350,3230, 1780, 1675, 1635 cm~'.

(7) 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-allyl-4H-1,2,4-triazol-3- yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3200, 1780, 1680, 1550 cm~'.

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

I.R. (Nujol): 3220, 1780, 1670 cm~'.

(9) 7-[2-butoxyimino-2-(2-forma midothiazof-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5 yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3200, 1780, 1695, 1675, 1655 cm~'.

(10) 7-[2-hexyloxyimino-2-(2-forma midothiazol-4-yl)acetamido]-3-( 1 -allyl- 1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3175, 1780, 1757, 1684, 1640 cm~'.

(11) 7-[2-ethoxycarbonyl methoxyimino-2-(2-forma midothiazol-4-yl)acetamido]-3-( 1 -allyl- 1 Htetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

l.R. (Nujol): 3500, 3280, 1780, 1735, 1690 cm~'.

(12) 7-[2-t-butoxyearbonyl methoxyimino-2-(2-formamidothiazol-4-yl)acetamidoj-3-( 1 -a llyl- 1 H- tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3250, 1780, 1720, 1680, 1540 cm~'.

(13) 7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1 H-tetrazol-5-yl)thiomethyl3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3350, 1780, 1675, 1635 cm~'.

(14) 7-[2-isopropoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-( 1 -allyl- 1 H-tetrazol-5yi)thiomethyl-3-cephem-4-ca rboxylic acid (syn-isomer).

I.R. (Nujol): 3350, 3250, 1780, 1675, 1630 cm~'.

(15) 7-[2-butoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1 H-tetrazol-5-yl)thiomethyi 3-cephem-4-ca rboxylic acid (syn-isomer).

I.R. (Nujol): 3360, 1 780, 1672 cm~'.

(16) 7-[2-hexyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-( 1 -allyl- 1 H-tetrazol-5 yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3350, 3240, 1780, 1675, 1630 cm~'.

(1 7) 7-[2-(2-propynyl)oxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-( 1 -allyl-1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3330, 2170, 1780, 1683, 1630 cm~'.

(18) 7 [2-ethoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1 H-tetrazol5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3360, 3230, 1780, 1680, 1630 cm~'.

(19) 7-[2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1 H- tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3330, 1780, 1730, 1680, 1630 cm~'.

(20) 7-[2-methylthiomethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3270, 1760, 1650, 1520 cm~'.

(21) 7-[2-(3-isoxazolyl)methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-aIlyl- 1 H-tetrazol 5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3300, 1770, 1660, 1530 cm~'.

(22) 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-( 1 -allyl- 1 H-tetrazol-5- yl )thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3360, 1780, 1680, 1630 cm~'.

(23) 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(4-al lyl-4H- 1 ,2,4-triazol-3- yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

I.R. (Nujol): 3350, 1775, 1670, 1530 cm~'.

(24) 7-[2-cyclopentyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), mp 140 to 1 450C (dec.).

I.R. (Nujol): 3300, 1770, 1 660, 1 620 cm~'.

(25) 7-[2-(4-fluorobenzyloxyimino)-2-(2-a minothiazol-4-yl)acetamido]-3-( 1 -allyl- 1 H-tetrazol-5yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), mp 157 to 161 C (dec.).

I.R. (Nujol): 3500, 1770, 1660, 1630, 1600 cm~'.

(26) 7-[2-(3,4-dichlorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H- tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), mp 155 to 1 750C (dec.).

I.R. (Nujol): 1770, 1660--1620, 1450 cm-'.

Reference The Vilsmeier reagent was prepared from dry dimethylformamide (0.526 g), phosphorus oxychloride (1.10 g) and dry ethyl acetate (1.5 ml) by the conventional method. Ethyl acetate (10 ml) was added thereto and then 2-methoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn-isomer) (1.50 g) was added thereto at OOC. The mixture was stirred for 30 minutes at the same temperature.

The resulting mixture was added under -1 00C to a stirred solution of 7-amino-3-(1 -allyl-1 H-tetrazol5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.32 g) and trimethylsilylacetamide (6.18 g) in dry ethyl acetate (30 ml), and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was extracted by adding ethyl acetate (20 ml) and water (30 ml). The ethyl acetate layer was separated and extracted with a saturated aqueous solution of sodium bicarbonate (20 ml). The aqueous layer was adjusted to pH 2.0 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-1H- tetrazol-5-yl)thiomethyl-3-cephem-4-ca rboxylic acid (syn-isomer) (2.60 g).

I.R. (Nujol): 3200, 1770, 1710, 1665 cm-l N.M.R. (d8-DMSO, 8): 3.72 (2H, broad s), 3.93 (3H, s), 4.40 (2H ABq, J=1 4 Hz), 4.87-5.50 (5H, m), 5.73-6.37 (2H, m), 7.45 (1 H, s), 8.55 (1 H, 5), 9.70 (1 H, d, J=8 Hz).

Claims

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

wherein R' is amino or a protected amino R2 is an aliphatic hydrocarbon group which may have suitable substituent(s), R3 is carboxy or a protected carboxy, and R4 is N-containing 5 membered heteromonocyclic group having lower alkenyl group(s), with proviso that R2 is not methyl when R4 is tetrazolyl having a lower alkenyl group, and pharmaceutically acceptable salts thereof.

2. Syn-isomer of a compound of Claims 1, wherein

3. A compound of Claim 2, wherein R2 is lower alkyl, lower alkenyl, lower alkynyl or cyclo(lower)alkyl, each of which may have suitable substituent(s), R3 is carboxy and R4 is tetrazolyl having a lower alkenyl group or triazolyl having a lower alkenyl group, with proviso that R2 is not methyl when R4 is tetrazolyl having a lower alkenyl group.

4. A compound of Claim 3, wherein R2 is (C2-C6) alkyl, lower alkenyl, lower alkynyl, cyclo(lower)alkyl or lower alkyl having 1 to 2 substituent(s) selected from the group consisting of carboxy, protected carboxy, lower alkylthio, acyloxy, isoxazolyl and aryl which may have 1 to 3 halogen(s), and R4 is tetrazolyl having a lower alkenyl group.

5. A compound of Claim 4, wherein R' is amino or lower alkanoylamino and R2 is (C2-C6) alkyl.

6. A compound of Claim 5, wherein R1 is amino or formamido, R2 is ethyl, isopropyl, butyl or hexyl and R4 is tetrazolyl having an allyl group.

7. A compound of Claim 6, which is 7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-( 1 - allyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

8. A compound of Claim 6, which is 7-[2-isopropoxyimino-2-(2-aminothiazol-4-yl)acetamidoi-3 (1 -allyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxyJic acid (syn-isomer).

9. A compound of Claim 6, which is 7-[2-butoxyimino-2-(2-aminothiazol-4-ylYacetamido]-3-(1- allyl-1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

10. A compound of Claim 6, which is 7-[2-hexyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3 (1 -allyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

11. A compound of Claim 4, wherein R' is amino or lower alkanoylamino and R2 is lower alkenyl.

12. A compound of Claim 11, wherein R' is amino or formamido, R2 is allyl and R4 is tetrazolyl having an allyl group.

1 3. A compound of Claim 12, which is 7-[2-allyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3- (1 -allyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

14. A compound of Claim 4, wherein R1 is amino or lower alkanoylamino and R2 is lower alkynyl.

15. A compound of Claim 14, wherein R1 is amino or formamido, R2 is 2-propynyl and R4 is tetrazolyl having an allyl group.

1 6. A compound of Claim 15, which is 7-[2-(2-propynyl)oxyimino-2-(2-aminothiazol-4yl)aceta mido]-3-(1 -allyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

17. A compound of Claim 4, wherein R1 is amino or halo(lower)alkanoylamino and R2 is cyclo(lower)alkyl.

18. A compound of Claim 17, wherein R1 is amino or trifluoroacetamido, R2 is cyclopentyl and R4 is tetrazolyl having an allyl group.

19. A compound of Claim 18, which is 7-[2-cyclopentyloxyimino-2-(2-amino-thiazol-4 yl)acetamido]-3-( 1 -a llyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

20. A compound of Claim 4, wherein R1 is amino, lower alkanoylamino or halo(lower)alkanoylamino and R2 is lower alkyl having a substitutent selected from the group consisting of carboxy, lower alkoxycarbonyl, lower alkylthio, lower aikanoyloxy, isoxazolyl and phenyl which may have 1 or 2 halogen(s).

21. A compound of Claim 20, wherein R' is amino, formamido or trifluoroacetamido, R2 is carboxymethyl, ethoxycarbonyl methyl, t-butoxycarbonyl methyl, methylthiomethyl, formyloxyethyl, isoxazolylmethyl, benzyl, 44luorobenzyl or 3,4-dichlorobenzyl and R4 is tetrazolyl having an allyl group.

22. A compound of Claim 21, which is 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4 yl)aceta mido]-3-( 1 -allyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

23. A compound of Claim 21, which is 7-[2-ethoxycarbonylmethoxyimino-2-(2-aminothiazol-4- yl)aceta m ido]-3-(1 -allyl- 1 H-tetrazol-5-yI)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

24. A compound of Claim 21, which is 7-[2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4 yl)acetamido]-3-( 1 -allyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

25. A compound of Claim 21, which is 7-[2-methylthiomethoxyimino-2-(2-aminothiazol-4 yl)aceta m ido]-3-(1 -allyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

26. A compound of Claim 21, which is 7-[2-(3-isoxazolyl)methoxyimino-2-(2-aminothiazol-4- yl )acetam ido]-3-(1 -allyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

27. A compound of Claim 21, which is 7-[2-benzyloxyimino-2-(2-aminothiazol-4-yl)acetamido]- 3-(1-allyl-1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

28. A compound of Claim 21, which is 7-[2-(4-fluorobenzyloxyimino)-2-(2-aminothiazol-4 yl)acetamido]3-(l -allyl-l H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

29. A compound of Claim 21, which is 7-[2-(3,4-dichlorobenzyloxyimino)-2-(2-aminothiazol-4- yl)acetamido]-3-( 1 -a llyl- 1 H-tetrazol-5-yl)thiomethyl-3-cephem-4-ca rboxylic acid (syn-isomer).

30. A compound of Claim 3, wherein R' is amino or lower alkanoylamino, R2 is lower alkyl and R4 is triazolyl having a lower alkenyl group.

31. A compound of Claim 30, wherein R1 is amino or formamido, R2 is methyl and R4 is 4H-1,2,4triazolyl having an allyl group.

32. A compound of Claim 31, which is 7-[2-methoxyimino-2-(2-aminothiazol-4-yi)acetamido]-3 (4-allyl-4H- 1,2,4-triazol-3-yi)thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

33. A process for preparing 3,7-disubstituted-3-cephem-4-carboxylic acid compounds of the formula.

wherein R' is amino or a protected amino, R2 is an aliphatic hydrocarbon group which may have suitable substituent(s), R3 is carboxy or a protected carboxy, and R4 is N-containing 5 membered heteromonocyclic group having lower alkenyl group(s), with proviso that R2 is not methyl when R4 is tetrazolyl having a lower alkenyl group, 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.

34. A process for preparing a compound of the formula:

wherein R2 is an aliphatic hydrocarbon group which may have suitable substituent(s), R3 is carboxy or a protected carboxy, and R4 is N-containing 5 membered heteromonocyclic group having lower alkenyi group(s), with proviso that R2 is not methyl when R4 is tetrazolyl having a lower alkenyl group, or pharmaceutically acceptable salts thereof, which comprises subjecting a compound of the formula:

wherein R2, R3 and R4 are each as defined above and RIB is a protected amino or a salt thereof1 to elimination reaction of the amino protective group.

35. A process for preparing a compound of the formula:

wherein R1 is amino or a protected amino, R2b is carboxy(lower)alkyl, R3 is carboxy or a protected carboxy, and R4 is N-containing 5 membered heteromonocyclic group having lower alkenyl group(s), or pharmaceutically acceptable salts thereof, which comprises subjecting a compound of the formula:

wherein R1, R3 and R4 are each as defined above and R2a is a protected carboxy(lower)alkyl or a salt thereof, to elimination reaction of the carboxy protective group.

36. A process for preparing a compound of the formula

wherein R1 is amino or a protected amino, R2 is an aliphatic hydrocarbon group which may have suitable substituent(s), R3 iS carboxy or a protected carboxy, and R4 is N-containing 5 membered heteromonocyclic group having lower alkenyl group(s), with proviso that R2 is not methyl when R4 is tetrazolyl having a lower alkenyl group, or pharmaceutically acceptable salts thereof, which comprises reacting a compound of the formula:

wherein R1, R2 and R3 are each as defined above and X is a group which can be substituted by a group of the formula: R4-S- wherein R4 is as defined above or a salt thereof, with a compound of the formula:: R4-SH wherein R4 is as defined above or its reactive derivative at the mercapto group.

37. A compound of the formula:

wherein R1 is amino or protected amino, and R2 is cyclopentyl or 3,4-dichlorobenzyl.

38. A process for preparing a compound of the formula:

wherein R3 iS carboxy or a protected carboxy and R4 is N-containing 5 membered heteromonocyclic group having lower alkenyl group(s), or a salt thereof, which comprises reacting a compound of the formula:

wherein R3 iS as defined above, or a salt thereof, with a compound of the formula: R4-SH wherein R4 is as defined above or its reactive derivative at the mercapto group, and then subjecting the resulting compound of the formula:

wherein R3 and R4 are each as defined above or a salt thereof, to elimination reaction of 5-amino-5- carboxyvaleryl group.

39. A pharmaceutical anti-bacterial composition comprising a compound of Claim 1 or pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.

40. A method for producing a pharmaceutical anti-bacterial composition which comprises mixing a compound of Claim 1 or pharmaceutically acceptable salt thereof as an active ingredient with an inert carrier.

41. A process for preparing a compound of the formula:

wherein R1a is a protected amino and R2 is cyclopentyl or 3,4-dichlorobenzyl or salts thereof, which comprises reacting a compound of the formula:

wherein R2 is as defined above or salts thereof, with amino-protecting agent.