JPS58126877A - Azetidinone compound or its salt and their preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formulaI(R<1> is H, amino, etc.; R<2> is H, lower aliphatic hydrocarbon group, etc.) and its pharmacologically permissible salt. EXAMPLE:3-[ 2-( 5-Amino-1,2,4-thiadiazol-3-yl )-2-( 1-carboxylato-1-methyl-ethoxyimino)acetamido]-2-oxoazetidine-1-sulfonic acid disodium salt (syn isomer). USE:Antibacterial agent. PROCESS:The compound of formulaIcan be prepared e.g. by reacting the compound of formula II or its reactive derivative at the amino group or its salt with the compound of formula III or its reactive derivative at the carboxyl group or its salt.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to 3-acylaminoazetidinone derivatives and pharmaceutically acceptable salts thereof.

For more details, see Does this invention have antibacterial activity? 3-acylaminoacetidinone derivatives and pharmaceutically acceptable salts thereof, their tea methods, pharmaceutical compositions containing them, and their use as pharmaceuticals in the treatment of infectious diseases in humans and animals. .

That is, one object of the present invention is to provide a 3-acylaminoacetidinone derivative that exhibits activity against many pathogenic bacteria and a pharmaceutically acceptable salt thereof.

Another object of this invention is to provide a method for making 8-acylaminoazetidinone and pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a medical composition comprising the above-mentioned 3-acylaminoacetidinone derivative and its salts which can be used as pharmaceuticals as self-effective ingredients.

Yet another object of this invention is to provide a method for treating 1,000 bacterial infections in humans and animals.

The target 3-acylaminoazetidinone derivative is a new compound and can be represented by the following general formula.

[In the formula, tt' means hydrogen, an amine group or a protected amino paper, and R2 means hydrogen or a lower aliphatic hydrocarbon group which may have a suitable substitution method].

According to this invention, the novel 8-acylaminoacetidinone derivative [1] can be produced by various methods exemplified by the following reaction formula.

or 70 reactive derivatives divided into amino papers or their salts in a reactive transparent box or salts 1 Method for producing the salts 2 [IV] '' or its salts [1] or its salts or tenon salts [11J] or its salt production method 4 [IC] or its salt [1d] or its salt production method 5 You are its salt [I''] or its salt [in the formula, 11 h and R2 each have the same meaning as ml The mass is a lower aliphatic hydrocarbon group with a protected amino group; The leaf is a lower aliphatic hydrocarbon group with an amino group; The hemp is a lower aliphatic hydrocarbon group with a protected hydroxyl group or cyclo(lower aliphatic hydrocarbon group) ) Alkenyl group; kL5 is a lower aliphatic hydrocarbon group having a hydroxyl group or hydrogen; Per is a lower aliphatic hydrocarbon group having a protected carboxyl group; lt〒 is a lower aliphatic hydrocarbon group having a carboxy group
4 respectively].

Among the raw material compounds used in this investigation, several of compound [+lI] and compound [1v] are new compounds, and can be produced by the method exemplified by the reaction formula F.

Production method A [Vl [Vl] 1 da tenon salt or its salt NH2- (J-gi [1lIa] or its salt production method B / / U-) t2 042 [1111]
] [ll1c] or a salt thereof, or a base thereof [in the formula, R1 and R2u each have the same meaning as before; KA is a protected amino group or amino group;
Lower alkenyl group, lower alkanoyloxy (lower)
Alkyl group, hexyl group, benzhydryloxycarbonyl (lower) alkyl group or nitrobenzyloxycarbonyl (lower farkyl group; R8 refers to any lower alkyl group).

In the target compound [l] and the starting compound [111E and [1v], the formula; -C-GO-? The partial structure represented by -R2 includes two geometric isomers represented by the formula: %Formula%[].

In this Specification 1/i:'&'', all compounds having the partial structure 1: metal and the compound having the geometric isomer structure represented by the formula [A] are referred to as ``synisomers'', and the formula ``] A compound having another geometric anomaly shown by is defined as an "anti-isomer".

Suitable pharmaceutically acceptable salts of the target compound [1] are conventional non-toxic salts, such as inorganic salts, such as alkali metal salts such as sodium salts and potassium salts, such as calcium salts and magosylam salts. metal salts such as alkaline earth metal salts, ammonium salts, etc.; organic salts such as trimethylamine salts, triethylamine salts, pyridine salts, prohydramine salts, hicoline salts, dicyclohexylamine salts, N, N' -dibenzylethylenediamine salt, N-methylcurcamine salt, jetanolamine salt, triethanolamine salt, tris(
Free amine salts such as hydroxymethylaminotumethane salt, phenylethylbennylamine salt, dibenzylethylenediamine salt, etc.; For example, formate, acetate, trifluoroacetate, Maya M salt, n-trite, methanesulfone Acid acid, benzenesulfonic acid! ,) organic carboxylates or organic sulfonates such as luenesulfonate; e.g. hydrochloride, hydrobromide,
Inorganic acid salts such as sulfates and phosphates; Examples include salts with chlorinogenic amino acids or acidic amino acids such as arginine, aspartic acid, glutamic acid, and lysine.

In the description in section E of this specification and the following description, one preferred example and explanation of the definition of ``n'' included within the scope of the present invention will be described in detail below.

"Lower" means 1 to 6 carbon atoms, unless otherwise specified.
means a group containing a metal.

[Lower aliphatic hydrocarbon paper which may have a suitable substituent], "Lower aliphatic hydrocarbon group having a protected amino group", "Lower aliphatic hydrocarbon group having an amino group"
, "Lower aliphatic hydrocarbon group having a protected hydroxyl group", "Lower aliphatic hydrocarbon group having a hydroxyl group", "Lower aliphatic hydrocarbon group having a protected carboquine group" and "Lower aliphatic hydrocarbon group having a carboxylic group" Suitable "-lower aliphatic hydrocarbon groups" in the aliphatic hydrocarbon group J include lower alkyl claws described below; lower alkenyl groups described below; Examples: evaethynyl, l-propynyl, 2-propynyl,
-Methyl-2-propynyl, 1- or 2= or 3-
Butynyl, 1- or 2- or 3- or 4-pentynyl, l-4 or 2- or 3- or 4- or 5-
Lower alkynyl groups such as hequinnyl; Examples, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohaf0thyl; Examples, lower alkynyl groups such as cycloprobenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl Examples include alkenyl nails, etc. - [Preferred substitution paper for lower aliphatic hydrocarbon group J which may have a suitable substitution paper and , amine, protected amino in the meaning below, hydroxy, protected hydroxy as below, aryl as below, aryl with halogen where "halogen" and "aryl" have meaning as below, carboxy, protected in the meaning below san
Examples include carboxy, "lower aliphatic hydrocarbon group"
The appropriate number of substituents is 1 to 3.

]-lower aliphatic hydrocarbon group having a sacrificial substituent, cyano(lower alkyl, lower alkylthio(lower)alkyl, amine(lower alkyl,
Protected amino (lower) alkyl, hydroxy (lower) alkyl, protected hydroxy (lower) alkyl,
Al (lower) alkyl, Heroal (lower) alkyl,
carboxy (lower) alkyl, protected carboxy (
(lower) alkyl, carboxy (lower) alkenyl, protected carboxy (lower) alkenyl, and the like.

"protected amine group" and "protected r
Preferred examples of lower aliphatic hydrocarbon groups having an amino group include acylamino groups,
and al(lower)alkyl such as pencil, trityl, al(lower)alkylidene such as benzylidene, lower alkoxycarbonyl such as l-ethoxycarbonyl-2-10pylidene, dimethylaminomethylene, etc. ] Examples include amino groups substituted by conventional bed protection methods other than acyl nails, such as lower alkyritene substituted by alkylamino.

Suitable "acyl groups" and suitable "acyl" moieties of "acylamino method" and "acyloxy group" include carbamoyl groups, aliphatic acyl groups, and acyl groups containing aromatic or heterocycles. In this case, E
Preferred examples of the acyl include formyl, acetyl, propionyl, butyryl, imbutyryl,
Lower alkanoyl groups such as valeryl, isovaleryl, oxalyl, succinyl, piparoyl, preferably those having 1 to 4 carbon atoms, more preferably < is 1 carbon atom
-2; For example, methoxycarbonyl, ethoxycarbonyl, propoquinecarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, methoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, tertiary pentyloxycarbonyl, hexyl Lower alkoxycarbonyl groups having 2 to 7 carbon atoms, preferably those having 3 to 6 carbon atoms, such as oxycarbonyl; Alkanesulfonyl groups; For example, arenesulfonyl groups such as benzenesulfonyl and tosyl; Al(lower) alkanoyl groups such as phenylacetyl and phenylpropionyl; Examples include cyclo(lower) alkyl groups such as cyclohexylacetyl and cyclopentylacetyl; (lower) alkanoyl group; Examples include a (lower noalkoxycarbonyl group) such as pentyloxycarbonyl and phenethyloxycarbonyl.

Preferred examples of the acylamino group include lower alkanoylamino groups such as formamide, acetamido, propionylamino, butyrylamino, imbutyrylamino, valerylamino, isovalylamino, oxalylamino, succinylamino, and pivaloylamino; for example, methoxycarbonylamino, ethoxy Examples include lower alkoxycarbonylamino groups such as carbonylamino, propoxycarbonylamino, 1-cyclopropylethoxycarbonylamino, isopropoquinecarbonylamino, tertiary butoxycarbonylamino, pentyloxycarbonylamino, and hexyloxycarbonylamino. - As for the preferred "protected hydroxy method" and the preferred "protected hydroxy" moiety of the "lower aliphatic hydrocarbon group having a protected hydroxy group," the acyl moiety has the same meaning as before. Included are acyloxy groups and 16-substituted hydroxy groups with conventional protecting groups other than acyl groups, such as the alkyl groups mentioned above.

Preferred examples of the protected hydroxy group include lower alkanoyloxy groups such as formyloxy, acetoxy, propionyloxy, butyryloxy, and valeryloxy.

Preferred examples of the "protected carboxy 1 moiety" of the "protected carboxyl group", 2 and "lower aliphatic hydrocarbon group having a protected carboxy Mif" include an esterified carboxyne group, n, < Examples of esters include methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, 41. Lower alkyl esters such as those in which the lower alkyl moiety preferably has 1 to 4 carbon atoms; e.g. eva vinyl ester,
Lower alkenyl esters such as allyl esters, lower alkyl esters such as ethynyl esters and glovinyl esters; mono(or di- or tri)- such as 2-ethyl iodide, 2,2.2-)lichloroethyl esters, etc. Halo(
Low 1. l alkyl ester; ml, tJf acetoxymethyl ester, propionyloxymethyl ester, 1-acetoxypropyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester,
Lower alkanoyloxy (lower noalkyl esters such as l-acetoxyethyl ester, 2-propionyloxyethyl ester, 1-impltyryloxyethyl ester; lower alkanesulfonyl such as t-hamesylmethyl ester, 2-mesylethyl ester, etc.) (lower) alkyl ester; al(lower) alkyl ester, examples of which include e.g. evapencil ester, 4-methoxybenzyl ester, 4-methoxybenzyl ester;
-Nitrobenzyl ester, pheothyl ester, trityl ester, benzhydryl ester, bis(methoxyphenylene methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tertiary butylbenzyl ester, etc.) Phenyl (lower noalkyl ester; substituted by azide, such as methoxycarbonyloxymethyl ester, ethoxysulfonyloxymethyl ester, ethoxysulfonyloxyethyl ester, etc.), which may be substituted with a suitable substituent of subgroup E; Lower alkoxycarbonyl maxi(lower) alkyl ester which may be substituted with oxo group: pyrocyclic ester, preferably benzotetrahydrofuryl ester which may be substituted with oxo group, more preferably phthalidyl ester; is aroyloxy ((a) class) alkyl ester such as benzoyloxymethyl ester, benzoyloxyethyl ester, toluoyloxyethyl ester; Mention may be made of esters such as esters, aryl esters, etc., which may have a suitable substitution paper of one fine line F, such as esters, cumenyl esters, etc.

Suitable examples of protected carboxyl groups include ehamethoxycarbonyl, etquincarbonyl, propoxysulfonyl, poxysulfonyl, tertiary butoxycarbonyl, tertiary pentyloxycarbonyl, hexyloxycarbonyl, and the like. 2-7 carbon atoms? lower alkoxycarbonyl groups, preferably those having 2 to 5 carbon atoms; Therefore, optionally substituted phenyl (lower noalkoxycarbonyl is included).

Examples of the preferred "aryl paper" and the preferred "aryl 9 moiety" of the "haloal (lower) alkyl group" include phenyl, naphthyl, xylyl, mesityl, cumenyl, and the like.

Suitable halokenes include fluorine, chlorine, bromine and iodine.

Suitable "lower alkyl groups", as well as "lower alkylthio, lEj, r haloal(lower) alkyl groups", "lower alkanoyloxy (lower noalkyl & J, r benzhydryloxycarbonyl (lower J alkyl dispersion)" and U nitro Suitable "lower alkyl" moieties of "benzyloxycarbonyl (lower) alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Mention may be made of straight-chain or branched alkyls having from 7zl to 6 carbon atoms, such as tertiary-butyl, pentyl, tertiary-pentyl, hexyl, and the like.

Preferred "lower alkenyl" moieties of "lower alkenyl IJ and U lower alkoxycarbonyl (lower] alkenyl group" include vinyl, ■-propenyl, allyl, 1-methylallyl, 1 or 2 or 3-butenyl, 1 '! Fi2 or straight chain alkeni/L- or branched alkenyl having 2 to 6 carbon atoms such as 3 or 4-pentenyl, I or 2 or 3 or 4 or 5-hexenyl etc. Keranuru.

"Lower alkoxycarbonyl f lower) alkenyl group J
As the "lower alkoxycarbonyl" moiety and the "lower alkanoyl moiety of [lower alkanoyloxy(lower)alkyl &]", the same compounds as those exemplified in the definition of "acyl J" can be mentioned.

Preferred examples of the target compound are illustrated below.

Preferred examples of R1 are hydrogen, amino, or lower alkanoylamino, and preferred examples of R2 include hydrogen, lower alkyl, lower alkenyl, lower alkynyl, and cyclo (lower).
Alknyl, cyano (lower) alkyl, lower alkylthio (lower dialkyl, amino (lower) alkyl, acylamino (lower dialkyl [more preferably lower alkoxycarbonylamino (lower) alkyl]), hydroxy (lower) alkyl, acyloxy (lower) alkyl [ More preferably, (is lower alkanoyloxy (lower dialkyl), al (lower) alkyl [more preferably L<U phenyl (lower) alkyl], haloal (lower) alkyl [most preferably halo phenyl (lower) alkyl]
, carboxy(lower) alkyl, esterified carboxy(lower) alkyl, preferably lower alkoxycarbonyl (lower dialkyl, e.g. mono- or -phenyl(lower) alkoxycarbonyl (lower))
Al(lower)alkoxycarbonyl(lower)alkyl such as alkyl, nitro-al(lower)alkyl such as nitrophenyl(lower alkoxycarbonyl(lower)alkyl)
Alkoxycarbonyl (lower dialkyl) and carboxy(4U&)alkylthio are esterified carboxy(lower)alkenyl [more preferably lower alkoxycarbonyl(lower)alkenyl].

The method for producing the object compound of this invention will be described in detail below.

Production method 1 The target compound [1] or a salt thereof is obtained by reacting the compound [u] or a reactive derivative thereof at an amine group or a salt thereof with a reactive derivative thereof or a salt thereof at a carboxy group or a compound l'3. It can be manufactured by

Suitable reactive derivatives of the amine group of compound [ll) include imino base type of nuff produced by reaction of compound [l) with carbonyl compounds such as aldehydes and ketones, and its tautomeric enamine type. Isomers:
Silyl derivatives produced by the reaction of the compound [11] with a silyl compound such as bis(trimethylsilyl)acetamide; derivatives produced by the reaction of the compound [11] with phosphorus trichloride or phosgene, and the like.

Suitable salts of compounds [Tan] and [1) include hexagonal salts such as acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate, etc., such as hydrochloride, hydrogen bromide, etc. Salts of acids such as inorganic acid salts such as acid salts, sulfates, phosphates; metal salts such as sodium salts, potassium salts, calcium salts, magnesium salts; ammonium salts;
Examples include organic amine salts such as triethylamine salt and dicyclohexylamine salt.

Suitable reactive derivatives for the carboxy group of compound [-] include acid halides, acid anhydrides, activated amides, activated esters, and the like.

Preferred examples include acid chlorides, acid azides; for example, dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid,
Substituted phosphoric acid such as dibenzyl phosphoric acid, halogenated phosphoric acid, dialkyl phosphorous acid, 1IIIt acid, tertiary quaternary phosphoric acid
'J, mixtures with sulfuric acid, alkyl carbonates, aliphatic carboxylic acids such as pivalic acid, pentanoic acid, impentanoic acid, 2-ethylbutyric acid or trichloroacetic acid or aromatic carboxylic acids such as benzoic acid. Acid anhydride; Symmetrical acid anhydride; 1 with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole
Paleoamide; e.g. cyan methyl ester, methoxymethyl ester, dimethyliminomethyl deca (CMB32N=-Cti-1 estenopevinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, tri- Chlorophenyl ester, penkchlorophenyl ester, mesyl phenyl ester, phenylazophenyl ester, phenylthioester, P-nitrophenyl thioester, p-cresyl thioester, calfoxydimethyl 1,000 ester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl activated esters such as thioesters or e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(lti)-pyridone,
Examples include esters with N-hydroxy compounds such as N-hydroxysuccinimide, N-hydroxyphthanolimide, and l-hydroxy-6-chloro-1ti-benzotriazole. These reactive derivatives can be appropriately selected from among the following depending on the type of compound [-] to be used.

The reaction is usually carried out in conventional solvents such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, NIN-dimethylformamide, pyridine, but there are no adverse effects on the reaction. Any other organic solvent can be used as long as it is a non-toxic organic solvent. These conventional solvents may be used in combination with water.

When a compound [cliff] is used in the form of a free acid or in the form of a salt with
1, the reaction is performed with N,N'-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclo. Ehexyl-N'-(4-di% thylaminocyclohexyl)carbodiimide: N,N'-diethylcarbodiimide: N,N'-diisopropylcarbodiimide;N-ethyl-N'-+8-dimethylaminepropyl]sulfoshiimide; N, N-carbonylbis-(2-methylimidazole); bentamethyleneketene-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; l-alkoxy-1-chlorostyrene; trialkyl phosphite; ethyl polyphosphate ; Isopropyl polyphosphate; Phosphorus oxychloride (phosphoryl chloride); Phosphorus trichloride: Thionyl chloride; Oxalyl chloride;
Triphenylphosphine: 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-
Sulfophenyl)inoxazolium hydroxide inner salt: 1-(p-chlorobenzenesulfonyloxy)-
6-chloro-IH-benzotriazole; 1-hydroxybenzotriazole; in the presence of a conventional condensing agent such as the so-called Vilsmeier reagent prepared by the reaction of dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride, etc. This is desirable.

This reaction also applies to alkali metal carbonates, alkali metal bicarbonates, tri(lower)alkylamines, pyridine, H(lower)alkylmorpholines, N-di(lower)
The reaction may be carried out in the presence of an inorganic or organic base such as an alkylbenzylamine. The reaction temperature is not particularly limited, and the reaction is usually carried out in the range of cooling to room temperature.

Production method 2 Compound [1] or a salt thereof can be produced by subjecting compound [1v] or a salt thereof to a sulfo group introduction reaction.

As suitable salts for compound [1v], the same salts as those exemplified for compound [1] can be used.

This introduction reaction can be carried out by reacting the compound ID or a salt thereof with sulfur trioxide or a reactive derivative thereof.

Suitable reactive derivatives of sulfur trioxide include pyridine-sulfur trioxide, lutidine-sulfur trioxide, sulfur trioxide-sulfur trioxide, trimethylamine-sulfur trioxide, dimethylformamide-sulfur trioxide, picoline-sulfur trioxide. Each complex etc. are mentioned.

In addition to this reciprocal payment, boron trihalides such as boron trichloride and boron trifluoride, titanium tetrahalides such as titanium tetrachloride and titanium tetrabromide, and tetrahalogens such as soot tetrachloride and tin tetrabromide, etc. Aluminum halides such as tin oxide, aluminum quaternide, aluminum bromide, zinc halides such as 1f chloride, lead, zinc fluoride, trihalogenated acetic acids such as trichloroacetic acid, trifluoroacetic acid, etc. It can be significantly promoted by the presence of L = Y'-acid.

On the other hand, any other common soot may be used in a solvent such as 7n, water, dimethylformamide, pyridine, etc., but which does not have an adverse effect on the reaction.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, room temperature, or heating.

Production method 3 The target compound [1b) or its salt can be produced by subjecting the compound [1a] or its salt to an elimination reaction using an amine protection method in a lump.

A suitable salt of compound [1a] is compound h+cI″3
The metal salts, ammonium salts and organic amine salts exemplified for can be used.

Elimination reaction is hydrolysis; reduction: Compound [1a] in which the protected amine moiety is acylamino [1a] Cheiminohalogenation, treatment with an iminoetherification agent, and then, if necessary, hydrolyzing the product It can be carried out by conventional methods such as method. Examples of the hydrolysis method include methods using acids, bases, hydrazine, and the like. These methods may be selected depending on the type of protecting group to be removed.

In method F, acid? The hydrolysis used may include substituted or unsubstituted aralkoxycarbonyl, such as tertiary butoxycarbonyl, tertiary pentyloxycarbonyl; lower alkanoyl, such as formyl, acetyl, etc.; cycloalkoxycarbonyl; substituted or unsubstituted aralkoxycarbonyl; aralgyl, e.g. It is one of the most common and preferred methods for the removal of protective papers such as trityl; substituted phenylthio; substituted aralkylidene; substituted alkylidene, substituted cycloalkylidene, etc.

Examples of suitable acids include organic acids such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, and hydrochloric acid. Examples of such substances include formic acid, trifluoroacetic acid, and hydrochloric acid. The type of acid can be selected depending on the type of protecting group to be removed. When the elimination reaction is carried out using fil, the reaction can be carried out in the presence of a solvent (or in the absence of a solvent). Suitable solvents include water, conventional solvents or mixtures thereof.

Elimination reactions using trifluoroacetic acid may also be carried out in the presence of anisole. Hydrolysis with hydrazine is commonly used to remove phthaloyl, succinyl-type noamino protecting groups.

Elimination using chloride is used to eliminate acyl groups such as trifluoroacetyl. Suitable hydrochloric acids include inorganic bases and organic bases.

Elimination by reduction is generally used for the elimination of protected methods such as haloalcoquine carbonyl such as trichloroethoxycarbonyl, h-substituted or unsubstituted aralcoquine carbonyl such as benzyloxycarbonyl, and 2-pyridylmethoxycarbonyl. Applies. Suitable reduction methods include, for example, reduction with an alkali metal borohydride, such as sodium borohydride; metals such as tin, zinc, iron, or these metals, such as chromous chloride, dichloromethane acetate, etc. Examples include combinations of metal salts such as monochrome with organic or inorganic acids such as acetic acid, propionic acid, hydrochloric acid, and catalytic reduction. Suitable catalysts include, for example, Raney nickel, platinum oxide, palladium black, and the like.

In the protective paper, the acyl groups can usually be removed by hydrolysis. In particular, halogen-substituted alkoxycarbonyl groups and 8-quinolyloxycarbonyl groups are usually copper,
It is eliminated by treatment with heavy metals such as zinc.

Furthermore, among the protecting groups, the acyl group can also be removed by iminohalogenation, e.g. It is also possible to detach by

The reaction temperature is not particularly limited and can be appropriately selected depending on the type of amino protecting group and the type of the above-mentioned elimination method. It is preferable to do so.

In accordance with the present invention, during the reaction or during the straightening step of this operation, another protected amino group and/or a protected carboxy group and/or a protected hydroxy group is removed from the corresponding free amino group. And/or a change to a free carboxy group and/or a free hydroxy group is also included within the scope.

Production method 4 The target compound [Id': or a salt thereof can be produced by subjecting the compound [Id' or a salt thereof to an elimination reaction of the hydroxy protecting group at =N-OR'c.

As suitable salts of compound [IO3, those exemplified for compound [1] can be used.

This elimination reaction is carried out by conventional methods such as hydrolysis, reduction, elimination using tubesic acid, enzyme-catalyzed hydrolysis, etc.

The method described in Production Method 5 may be referred to for the chemical method in Section L.

Enzyme-catalyzed hydrolysis can be carried out by contacting the hydroxy-protected paper with the aforementioned acyl compound CIC'3w, an esterase obtained from a microorganism.

Suitable microorganisms to be used in this invention include:
Examples include strains belonging to the genus Aureobasidi, such as esterases that hydrolyze protected acyl groups.

Esterases can be used to hydrolyze acyl groups in several different ways. Thus, for example, a sample of liquid culture broth itself can be used as a source of esterase.

The esterase is preferably used to synthesize the compound [1
Contact with cl.

The target compound thus produced in the cultured tissue can be isolated and purified by conventional methods.

Production method 5 The target compound [If] or a salt thereof can be produced by subjecting the compound [le] or a salt thereof to an elimination reaction of the carboxy protecting group at R'+9.

As a suitable salt of the compound [1e':l, the acid exemplified for the compound m can be used as a salt.

All conventional methods used for the elimination reaction of carboxy protecting groups can be applied to this elimination reaction, such as hydrolysis, reduction, elimination using bovine=1 mass acid, etc. When the carboxy protecting group is an ester, the protecting group can be removed by hydrolysis or an elimination method using sulfuric acid.

Hydrolysis is preferably carried out in the presence of a base or an acid.

Suitable bases include the inorganic bases and organic bases mentioned above.

Suitable acids include organic acids such as formic acid, acetic acid, 7'ropionic acid, trifluoroacetic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid.

This hydrolysis is usually carried out in an organic solvent, water or a mixed solvent thereof.

The reaction temperature is not particularly limited and may be appropriately selected depending on the type of carboxy protecting group and the type of elimination method.

The elimination method using sulfuric acid is preferably applied to the elimination of substituted or unsubstituted alkyl esters (lower alkyl esters), such as compounds such as boron trichloride, boron trifluoride, etc. Boron trihalides, such as titanium tetrahalides such as titanium tetrachloride and titanium tetrabromide, soot tetrahalides such as tin tetrachloride and soot tetrabromide, aluminum halides such as aluminum chloride and aluminum bromide, For example, trihalogenated acetic acids such as trichloroacetic acid and trifluoroacetic acid are reacted with a KM acid.Elimination reaction is preferable. It is usually carried out in a solvent such as a nitroalkane such as nitromethane or nitroethane, a halogenated alkylene such as methylene chloride or ethylene chloride, diethyl ether, carbon disulfide, etc., but the reaction may be adversely affected. Any solvent can be used as long as it does not cause any will be carried out.

Removal by reduction, preferably of protective groups such as halo (lower alkyl esters such as 2-ethyl iodide, 2,2,2-trichloroethyl), al (lower alkyl esters such as benzyl), etc. Applies to distance.

Examples of reduction methods that can be applied to desorption include, for example, zinc,
Reduction using a combination of a salt of a metal, such as zinc amalgam, or a chromium compound, such as e.g. chromous chloride, chromic acetate, and an organic or inorganic acid, e.g. acetic acid, propionic acid, hydrochloric acid, and e.g. palladium- Examples include conventional catalytic reduction in FK in the presence of conventional metal catalysts such as black, porcelain, and the like.

In this elimination reaction of the carboxy protecting group, compound [I
It is also included within the scope if the protected amino group of C] is converted into a free amino group during the course of the reaction and/or during the acid treatment of the reaction depending on the reaction conditions and the type of protecting group.

The method for producing the raw material compound of this invention will be described in detail below.

Compound 11V:] , [Vl] b- and [VIll]
Examples of suitable salts include hydrochloride, hydrobromide,
Examples include inorganic acid salts such as sulfates, and organic acid salts such as acetic acid and p-)luic acid.

Compounds [Vl), Cl1la), [1Ilb], [1
Suitable salts of [llC] and […] include the compound [
Is it the same as the examples given for 1]? can be mentioned.

Manufacturing corporation +) [V) - [VI] Compound [■] or a salt thereof can be produced by subjecting compound [V] or a salt thereof to hydrolysis.

This hydrolysis can be carried out according to the method of Production Method 5 above.

In this reaction, the case where the amine protecting group of kLA is eliminated during the reaction and R4 is changed to an amino group is also included within the scope.

ii) (Vl) + (■]-cap a] compound (la)
Or a salt thereof can be produced by reacting compound CVI) or a salt thereof with compound [■] or a salt thereof.

The reaction is usually carried out in conventional solvents such as water, alcohols such as methanol, ethanol, etc., or mixtures thereof, although any solvent can be used as long as it does not adversely affect the reaction.

It is desirable to carry out the reaction in the presence of a group.

The reaction temperature is not particularly limited, and the reaction is usually carried out in a temperature range from cooling to heating.

Production method B (Wb) -(file) Compound C) or a salt thereof can be produced by reacting compound C1lb'3 or a salt thereof with a nitrosating agent.

Suitable nitroning agents include compounds represented by the formula: R-ONO (wherein R means an alkyl group), such as nitrous acid and isoamyl nitrite.

The reaction is usually carried out in a conventional solvent such as tetrahydrofuran, but any solvent can be used as long as it does not adversely affect the reaction.

The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature or under heating.

Production method CCVIID +CI) -(IV) Compound [1
v) or a salt thereof is a compound [l'
) or a reactive derivative thereof at the carboxyne group or a salt thereof.

This reaction can be carried out according to the method of Production Method 1 above.

In this invention, a protected amino group and/or a protected carboxy group and/or a cryoprotected hydroxy group may be present during the reaction and/or in Production Methods 1 to 5, depending on the reaction conditions and the type of protecting group. Also included within the scope are cases where, during the post-treatment of the reaction of A-C, they are converted into the respective corresponding free amino groups and/or free carboxyl groups and/or hydroxy groups.

When the target compound (1) has a free carboxy group, a sulfo group and/or a free amino group, the target compound can be converted into the above-mentioned pharmaceutically acceptable salts thereof by a conventional method.

The object compound [1] of the present invention exhibits high bactericidal activity and inhibits the growth of many pathogenic bacteria, including pathogenic Durum-positive bacteria and Durum-negative bacteria.

The 3-acylaminoazetidinone compounds according to the present invention can be used for therapeutic administration by administering the compounds orally,
It is used in the form of a pharmaceutical preparation containing in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for parenteral or external administration. The dosage form may be a solid dosage form such as a tablet, dragee, ointment or tablet, or a liquid dosage form such as a solution, suspension or emulsion. Agents, wetting agents or emulsifying agents, buffers and other commonly used additives may also be included.

Although the dosage of the compound will vary depending on the age and condition of the patient, the compound according to the invention has an average single dose of about 50 Da, 100 Da. 250 and 500 da were proven to be effective in treating many pathogenic bacterial infections. Generally, dosages of 1/individual to about 1000/individual or more may be administered per day.

Next, in order to demonstrate the usefulness of the target compound [1], antibacterial activity test data of representative compounds of this invention are shown below.

Test method Each test strain was cultured on tryptocase soy brone medium-night, and one platinum loop (viable bacteria count 10@/+7) was placed on heart infusion agar (H) containing antibiotics at each concentration level.
After streaking on 1-agar) and incubating for 20 hours at 87°C, the minimum inhibitory concentration (MIC) was expressed in μQ/xl.

Test compound (11B-[2-(5-amino-1,2,4-thiadiazole-3-i/1/)-2-(ethoxyimino)acetamidocousodium 2-oxoazetidine-1-sulfonate (syn isomer ).

(2) 8-(2-(5-amino-1,2,4-thiadiazole-3-i)v) to 2-(1-carboxilade-
1-Methylethoxyimino)acetamidocou 2-oxoazetidine-1-sulfonic acid disodium (syn isomer).

Test Results The present invention will be explained below according to production examples and examples.

Production Example 1 2-(5-formamido-1,2,4-thiadiazol-3-yl)thioglyoxylic acid S-methytv(80,
A 2N aqueous solution of sodium hydroxide (195 ml) of No. 09) was stirred at 50°C for 30 minutes. The solution was adjusted to pH 7.0 with 10% hydrochloric acid at 20°C. P-nitrobenzyloxycarbonylmethoxyamine (82.8 g
) and ethanol (25 (ly/)) were added, and the reaction mixture was adjusted to pH 8.0 with 10% hydrochloric acid and stirred at room temperature for 2 hours.

The mixture was adjusted to pH 7 with a 10% aqueous solution of sodium hydroxide.
, 0, and the insoluble matter was separated by p]. The filtrate was concentrated and washed with ethyl acetate. Add ethyl acetate to this solution,
The mixture was adjusted to pH 1.0 with 10% hydrochloric acid. After separating and taking the ethyl acetate layer and drying with magnesium sulfate,
The solvent was evaporated to give 2-(5-γmino1.2.4-thiadiazol)v-8-yl)-2-(p-nitrobenzyloxycarbonylmethoxyimino)acetic acid (syn isomer).
(7,59) was obtained.

Melting point 89-95°C (decomposition).

IR (Nujoor →: 8400-8100.178
0.1610゜1520cm' NMR (DMSO-d6.δ): 8.18-7.80 (
4B, m'), 7.70 (2H, d, J=7Hz)
, 5.44(2H,S), 4.98(2H,S) Production Example 2 The following compound was produced according to the method of Production Example 1.

(112-(5-amino-1,2,4-thiadiazol-3-yl)-2-(4-fluorobenzyloxyimino)acetic acid (syn isomer).

NMR (DMSO-d6.δ): 8.10 (2I(
, b, 8'1.7.68-6.98 (4H, m),
5.20(21(,5)(2)2-(5-amino-1,
2,4-thiadiazol-ro-3-yl)-2-(8-tert-butoxycarbonyl-trans-allyloxyimino)acetic acid (syn isomer).

NMR (DMSO-d6.δ): 1.98 (9H,
ri, 4.85 (2H.

m), 5.85 (IH, d, J = 16Hz), 6
．． 80 (IH.

dt, J=16Hz, 4Hz), 8.07(2H
, b, 8) (3) 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-acetoxyethoxyimino)acetic acid (syn isomer).

NMR (DMSO-d 6.δ): 2.05 (8H
, S), 4.4 (4H.

m), 8.8 (2H, m) (4) 2-(5-amino-1,2,4-thiadiazol-8-i/L/) -2-(hexyloxyimino)
Acetic acid (syn isomer), melting point 158-161°C.

NMR (DMSO-d6.δ): 0.67-2.
00 (IIH, m).

4.20-4.88(2H,m) (512-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-penzhydryl oxinecarponyl-1-methylethoxyimino) Acetic acid (syn isomer)
. Melting point: 170-178°C.

IR (Nujol'): 8800.1?20.16
2θcW1-'NMR (DMSO-d6.δ) 1.5
8 (6H, S), 6.80 (IH.

S), 7.8 (12H, m), 8.2 (2H, m)
Production Example 8 Phosphorus pentachloride (8, IM) was converted into 2-(5-amino-1,2,
4-Thiadiazo-tV-8-I/I/)-2-(4-fluorobenzyloxyimino)acetic acid (syn isomer) was added to a suspension of dry dichloromethane (40*t) under stirring at 20°C. , the mixture was stirred at the same temperature for 30 minutes. Dry diisopropyl ether (501/) was added to this mixture, and the mixture was stirred for 1 hour while cooling with water to form a precipitate. This precipitate was separated, washed with diisopropifurether, and dried to produce 2-(5-amino-1,2,4-thiadiazol-8-yl)-2-(4-fluorobenzyloxyimino)acetyl chloride. Hydrochloride (syn isomer).

(8,159) was obtained.

IR (Nugeot/I/): 1780.1680.15
00α-1 Production Example 4 A solution of isoamyl nitrite (9.88 g/) in tetrahydrofuran (45 g, ?) was mixed with 2-(5-amino-1°2.
A suspension of 4-thiadiazole-8-i/I/)-2-(ethoxyimino)acetic acid (syn isomer) (10.0 g) in tetrahydrofuran (100 fft) at 50° C. was added with stirring. The mixture was heated to reflux for 6 hours. The aqueous solution was washed with ethyl acetate (50 d).The aqueous solution was then adjusted to pH 2.0 with 10% hydrochloric acid and dissolved in ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate, the solvent was distilled off, and 2-(1,2,4--
? -7'thiasotv-a-yl)-2-(ethoxyimino)acetic acid (syn isomer) (6.9 g) was obtained. Melting point 9
9-108℃.

IR (Nujol): 1720. 1600cI
R'NMR (DMSO-d6.δ): 10.28
(LH,S), 4.28 (2H.

Q, J=7Hz), 1.28(8H,t, J=7
Hz) Production Example 5 The following compound was produced according to the method of Production Example 4.

2-(1,2,4-thiadiazol-3-yl)-2-
(p-nitrobenzyloxylponylmethoxyimino)acetic acid (synisomer), mp 58-63°C.

IR (Nujol'): 1750-1700.15
20cN'NMR (DMSO-d6.δ): 10.8(
IH, s), 8.18 (2H.

d, J=7Hz), 7.65 (2H, d, J=7Hz)
, 5.88 (2H,S), 5.07 (2H,s) Production Example 6 3-Amino-2-oxoazetidine (420■) was dissolved in water (
1 (1+?) and acetone (10 yttl), and in this solution, 2-(5-amino-1゜2.4-
A solution of thiadiazol-3-yl)-2-ethoxyiminoacetyl chloride (syn isomer) (1□71q) in tetrahydrofuran (8.5 m/) and an aqueous sodium carbonate solution were heated to pH 8.5 with stirring under water cooling. Added alternately. The mixture was stirred for an additional 30 minutes at 0-5°C. Ethyl acetate was added to the reaction mixture, and the separated aqueous solution was adjusted to pH 7.0 with 10% hydrochloric acid and evaporated to dryness under reduced pressure. The residue was pulverized in cold water and the resulting powder was divided into '8-C2-(5-amino-1,2,4
-Thiadiazo-/l/-8-yl)-2-(ethoxyimino)acetamido-2-oxoazetidine (syn isomer), (5601f) was obtained. Melting point 255-260℃
(Disassembly).

IR (Nujol): 8400, 8850, 826
0,1760°1650z' NMR (DMSO6, δ): 1.21 (8H, t, J
=8Hz).

8.04 (IH, Q, J=2Hz), 8.47 (IH,
-t.

J=5Hz), 4.14(2H,t, J=8Hz)
, 4.95(IH,m), 7.94(1)(,b,
s), 8.06 (2H.

b, s), 9.08 (IH, d, J=8Hz) Production Example 7 The following compound was produced according to the method of Production Example 6.

8-C2-(5-amino-1,2,4-thiadiazol-8-yl)-2-(methoxyimino)acetamido-2-oxoazetidine (syn isomer), melting point 250°C
That's it (disassembly).

IR (Nujol): 8260.1?45. 166
0α-INMR (nMsO-d6.δ): 8.05 (
IH, q, J=2Hz).

8.47 (IH, t, J=5Hz), 8.90 (8H
,s).

4.98 (IH, m), 7.98 (LH, b, s)
, 8.08 (2H, b, s), 9.10 (IH, d,
J=8Hz) Example 1 3-amino-2-oxoazetidine-1-sulrh7 acid (480w1) was mixed with water (9gl) and acetone (9Wll).
) was dissolved in a mixture with Add 2-(5-amino-1,2,4-thiadiazole-3-y/l/) to this solution.
-2-(Ethoxyimino)acetyl chloride hydrochloride (syn isomer) (1,729) in 7 setsone (4 m/) and an aqueous solution of sodium carbonate were adjusted to pH 8 while stirring under water cooling.
5 were added alternately. This mixture was further stirred at 0-5°C for 5 hours. After recovering the acetone, the aqueous layer was adjusted to pH 8.8.
and subjected to column chromatography using Diaion HP-20 (trade name, manufactured by Mitsubishi Kasei Corporation). Both fractions eluted with water were lyophilized, and the residue was dissolved in water (25
8-C2-(5-amino-
1゜2.4-Thiadiazol-3-yl)-2-(ethoxyimino)acetamidocy2-oxoazetidine-
Sodium 1-nulfonate (syn isomer) (882ml
) was obtained. Melting point 230-240°C (decomposition).

IR (nusho zL/): 1780.1625,1
255. IQ80i 1NMR (DMSO-d,,δ)
: 1.24 (8H, t, J=7.0Hz).

8.87 (IH, m), 8.70 (IH, t, J=5.
0Hz).

4.15 (2B, Q, J-5,0Hz), 4.96 (I
H, m).

7.96 (IH, b, s), 8.12 (2H, b, s)
, 9.25 (IH, d, J = 7.0 Hz) Example 2 2-(6-amino-1,2,4-thiadiazole-3-
Phosphorous pentachloride (2,159) was added to a solution of 2-(hexyloxyimino)acetic acid (syn isomer) (2,689) in methylene chloride (25 cm) at -20°C, and the solution was added at the same temperature. Stir for 1.5 hours [7. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in dry tetrahydrofuran (15 kg) (solution 7iA).

3-amino-2-oxo7zetidine-1-sulfone fj
l (810'l) water (20ml) and acetone (15ml)
/), and to this solution, solution A and an aqueous sodium carbonate solution were added to pH 8, while stirring under water cooling.
5 were added alternately. The mixture was further stirred at 0-5°C for 1 hour and extracted with ethyl acetate (10 proof). The separated aqueous solution was adjusted to pH 8.0 with 10% hydrochloric acid and subjected to activated carbon (50 g/) chromatography. After washing with water, 5
Elute with 0% aqueous acetone and lyophilize to give 8-C
2-(5-amino-1,2,4-thiadiazole-8-
yl)-2-(hexyloxyimino)acetamido-2-oxoazetidine-1-sulfonate (
syn isomer) (510 Da) was obtained.

IR (Nujol): 8800.1?60.124
0.10454'NMR (D20, δ): 0
．． 87 (8H, m), 1.10-1.90 (8H, m
), 8.70-4.47 (4H, m), 5.88 (
IH, m) Example 3 3-amino-2-oxoazetidine-1-sulfonic acid (
1,5 g) and triethylamine (1,49.

ynl) in dimethylformamide (180 ml), 2-(5-amino-1,2,4-thiadiazole-
a-yl)-2-(1-penzhydryloxycarboni)v-1-methylethquinimino)acetic acid (syn isomer)
(1,95g), 1-hydroxybenzotriazole (
o, 77 g) and dicyclohexylcarbodiimide (
1.18 g) was added at 3°C, and the mixture was heated to 1.1 g at the same temperature.
Stirred for 2 hours.

After removing the precipitate, dimethylformamide was distilled off, and water (20 #11) and sodium hydrogen carbonate were added to the residue at pH 7.2 with stirring under water cooling. Insoluble materials were removed and subjected to 1ri#lt activated carbon column chromatography. The 30% aqueous acetone elution fraction was aml and lyophilized. The residue was completely dried to give 3-(2-(5-amino-
1,2,4-thiadiazol-8-yl)-2-(1-
Benzhydryloxycarbonyl-cetamidocy 2-oxoazetidine-1-sulfonic acid triethylamine salt (syn isomer) (1.4 89)
I got it. Melting point 150-156°C (decomposition).

IR (Nujol): 8100-8500. 17
50. 1670.

1620, 1580 α-1 NMR (DMSO-d6, δ): 9.15 (IH
．． d. J-=8Hz).

8, 18 (2H.b.S), 7.0-7.28 (IOH
, m).

6, 77 (IH.S), 5, 15-4.78 (IH, m
), 8.17-8.87 (2H. m), 2.85 (
6H. q, J = 7Hz).

1, 5 (6H, s), 1.07 (9H.t, J=7Hz
) Example 4 The following compounds were produced according to the methods of Examples 1 to 3.

(1) Sodium 8-[2-(5-amino-1.2.4-thiadiazol-8-yl)-2-(methoxyimino)acetamido-2-oxoazetidine-1-sulfonate (syn isomer), melting point 240℃ or higher (decomposition).

IR (nujo ylz): 8420.8270.1
770.1660.

1620, 1250. 1085n-”MMR (DM
SO-d6, δ): 8.19 (IH, q. J
= 2.5Hz).

8, 62 (IH. t, J=5.5Hz), 8.8
8 (8H.s).

4, 84 (IH. m), 8.02 (2H, b.
s), 9.28 (IH.

'． J=8Hz) (2) 8-(2-(5-amino-1,2.4-thiadiazol-8-ylv)-2-(propoxyimino)acetamidocou 2-oxoazetidine-1-sulfonic acid triethylamine salt ( syn isomer), melting point 87~
98℃.

IR (Nujol): 8100-8500.1760
．． 1670°1620, ! 580CIIK-1 NMR (DMSO-da, δ): 9.17 (IH,
d, J=8Hz).

8.06 (2H, b, s), 5.07-4. ．． 70(
1'H, m).

4.07(2I(,m), 8.8-8.1(2H,m
), 8.07 (6H, q, J=7Hz), 1.8
8-1.25 (2H, m).

1.17 (9H, t, J=7Hz), 0.88 (8
H,m)(318-42-(5-amino-1,2,4-
thiadiazole) v-3-itev) -2-(allyloxyimino)acetamidocou-2-oxoazetidine-
]-Sodium sulfonate (syn isomer), melting point 240
℃ or higher (decomposition).

IR (Nujol): 8800.1?65. 1
665. 1620°1240, 1050a” NMR (DMSOds, δ): 8.28 (LH,
q, J=2.5Hz).

8.67 (IH, t, J=5.5Hz), 4.88
-6.06 (6H, m), 8.07 (2H, b, s)
, 9.25 (IH.

', J=8Hz) (4) f9-(2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-provinylogycyimino)acetamidocou 2-oxoazetidine-1 - Sodium sulfonate (syn isomer), melting point 145-15
0°C (decomposition).

IR (Nujo-tv): 8100-8500. 1
760. 1670°1620, 1580CIIt-' NMR (DMSOda, δ): 9.8 (IH, d,
J=8Hz).

8.12 (2H, b, s), 5.17-4.58 (8
H, m').

8.82-8.1 (8H, m) (5) 8-(-2-(5-amino-1,2,4-thiadiazol-3-yl)-'2-(2-cyclopentene-
1-yloxyimino)acetamidocou 2-oxoazetidine-1-sulfonic acid triethylamine salt (syn isomer), M point 1ta to 121°C.
Fight IR (Nujol): 81
00-8400.1760,1670°1620,15
80clII-1 HMR (DMSO-da, δ): 9.18 (IH,
d, J=8Hz).

6.78 (2H, b, s), 6.28-6.0 (IH,
m), 6.0-5.78 (IH, m), 5.45-5.
18 (IH, m), 5.07-4.72 (IH, m),
8.78-8.1 (2H, m), 8.07 (6H, Q,
J=7Hz), 2.7-1.67 (4H, m).

1.17(9)1. t, J=7Hz) (618-C2-(5-formamido-1,2,4-thiasiacyzlz-8-yl)-2-(cyanomethoxyimino)acetamidocou-2-ogisoazeticin-1-
Sulfonic acid triethylamine salt (syn isomer), melting point 1
05-110°C (decomposition).

IR(KBr): 1760.1680.1270.
1040°1015-1 NMR (DMSO-d g , δ): 1.16 (9
H, t, J=8Hz).

8.12 (6H, q, J=8Hz), 8.5-8.
8 (2H, m).

4.8-5.2 (IH, m), 5.2 (2H, 8),
8.84 (LH, S), 9.2-9.7 (18,
m), 9.6 (IH, d.

J=8Hz) (7) a-[2-(5-amino-1,2,4-thiadiazol-3-y/l/)-2-(cyanomethoxyimino)acetamide)-2-(oxoazetidine-1- Nurphonic acid triethylamine salt (syn isomer), melting point 81~
85°C (decomposition).

IR(KBr): 1760.1675.16B0
．． 1260°1240, 1040.1010clII-
'NMR (DMSO-da, δ): 1.16 (9
H, t, J=8Hz).

8.04 (6H, Q, J=8Hz), 8.4-8.
7 (2H.

m), 4.7-5.1 (IH, m), 8.18 (2
H, b, S).

9.40 (2H, d, J=8H2) (8) 8-(2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methylthiomethoxyimino)acetamide]-2- Sodium ogisoazetidine-1-sulfonate (syn isomer), melting point 200-210°C
(Disassembly).

IR (Nujol): 1760.1670. 1
620. 1240°1200, 101050c11-1N (DMSO-d+,,δ): 2.16(8
H, S), 8.4-8.7 (2H, m), 4.7-
5.1 (IH, m), 5.24 (2H.

8), 8.08 (2H, b, s), 9.28 (I
H, d, J=8Hz) (9j8-C2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamidocy2-oxoazetidine -1-sulfonic acid triethylamine salt (syn isomer), melting point 200°C or higher (decomposed).

IR (Nujol): 1750. 1270.1
．． 085CIR'NMR (DMSO-d6, δ)
: 1.1.8 (9H, t, J=8Hz).

1.40 (9H, 8), 2.96-8.88 (8H,
m), 8.70 (IH, t, J=5Hz), 4.
12 (2H, m), 5.04 (IH, m), 8.1
6 (2H, b, s), 9.20 (IH, d.

J = 8Hz) (108-(2-(5-amino-1,2,4-thiadiazole-3-i/L/)-2-(2-aminoethoxyimino)acetamidocy2-oxoazetidine-1-sulfonic acid Sodium (syn isomer), melting point 230-24
0°C (decomposition).

IR (Nushor): 8400.8800.81
60. 1760゜1200, 1040cIN' 0υ8-C2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-acetoxyethoxyimino)acetamidocy 2-ogisoazetidine-1-sulfonic acid triethylamine salt ( syn isomer), melting point 68~
73℃ IR (Nujol): 1760. 1670. 1
220-1280°10104O' NMR (DMSO-d 6.δ): 1.16 (9H
, t, J=8Hz).

2.05 (8H, S), 8.08 (6H, Q, J=
8Hz), 8.67 (2H, m), 4.27 (4H,
m), 4.92 (LH, m).

8.08 (2H, m), 9.28 (IH, d, J=
8Hz) α-8-C2-(5-amino-1,2,4-thiadiazole-8-I/I/)-2-(2-hydroxyethquinimino)acetamidocy 2-oxoazetidine-1-sulfonic acid triethylamine Salt (syn isomer)
, melting point 128-182°C (decomposition).

IR (Nujol'): 8400.1750.16
60.1220-1280, 1080n-' 038-C2-(5-amino-1,2,4-thiadiazol-8-yl)-2-(benzyloxyimino)acetamidocy 2-oxoazetidine-1-sulfonic acid triethylamine salt (syn isomer), melting point 134-187
℃.

IR (Nushor) + 1760.1670. 162
0.12B0゜1040, 10101-1 NMRlolol-1N, δ): 1.16 (9H, t
, J=8Hz).

8.04 (6H, Q, J=8Hz), 8.4-8.7 (
2H.

m), 4.7-5.1 (IH, m), 5.24 (2H,
S).

7.26 (5H, S), 8.02 (2H, b, s), 9
．． 04 (IH.

d, J=8Hz) Q418-C2-(5-amino-1,2,4-thiadiazol-8-yl)-2-(4-fluorobenzyloximino)acetamidocy 2-ogisoazetidine-1
-Sodium sulfonate (syn isomer), melting point 205~
208°C (decomposition).

IR (Nujol): 8800, 1760, 166
0,1620°1510α-1 FJMR (DMSOd6, δ): 9.80(I
H, d, J=8Hz).

8.10 (2H, b, s), 7.0-7.67 (4H
, m).

5.18 (2H, S), 4.82-5.88 (IH
, m), 8.08-8.82 (2H, m) 058-C2-(5-amino-1,2,4-thiadiazol-8-yl)-2-(tert-butoxycarbonylmethoxyimino)acetamide Sodium 2-oxoazetidine-1-sulfonate (syn isomer), melting point 28
0 to 240°C or higher (decomposition).

IR (Nujol): 8270.1750.124
5.1o45as-”NMR (D20.δ): 1
．． 50 (9H, S), 8.75-4.16 (2H.

m), 4.82 (2H, s), 5.17 (IH, m
)(1G8-C2-(5-amino-1,2,4-thiadiazol-8-i)v) -2-(carboxinemethoxyimino)acetamidocy2-oxoazetidine-1-
Sulfonic acid (syn isomer), melting point 200℃ or higher (decomposition)
.

IR (Nujol): 8280.1750.178
0.1665゜1210, 101085c' Q7) 8-C2-45--7mi/-1,2,4-1,7diazo-)v-3-yl)-2-(1-carboxylad-1-methyl Ethoxyimino) acetamidocy 2-oxoazetidine-1-nurphonate disodium (syn isomer), mp 188-198°C (decomposed).

IR (Nugeot/I/): 8500-8100.1
760.1660° 1590, 1580 cm' α approx. 3-(2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(8-tert-butoxycarbonyl-trans-aryl leoxiimino) Acetamide-2-oxoazetidine-1-sulfonic acid triethylamine salt (syn isomer), melting point 115-122°C (decomposition)
.

IR (Nujol): 1760.1710.167
0.1620°1040-1 NMR (DMSO-ds, δ) + 1.18 (9
H, t, J=8Hz).

1.48 (9H, S), 8.12 (6H, Q, J=
8Hz), 8.6-8.8 (2H, m), 4.90 (
2H, b, s), 5.96 (LH.

d, J=16Hz), 6.96(IH, d, t,
J=16Hz.

4Hz), 8.16 (2H, b, S), 9.4
0 (IH, d, J=8Hz) 098-C2-(1,2,4-thiadiazole-/l/-8
-yl)-2-(ethoxyimino)acetamido2
-Oxoazetidine-1-sulfonic acid triethylamine salt (syn isomer), melting point 68-70°C.

IR (Nujo) v): 84B0.8260.80
50.1?60゜1670, 1250th 08 (1011
'NMR (DMSOd6.δ): 1.88 (9H, t
, J=7Hz).

II5 (8H, t, J=7Hz), 8.08 (6H
,Q.

J-7Hz), 8.28 (IH, Q, J=15Hz
), 8.68 (IH, t, J=5.5Hz),
4.25 (2H, Q, J=7Hz).

5.00 (IH, m), 9.86 (1, H, d, J
=8Hz), 1021(IH,S) 8-C2-(1,2,4-thiadiazol-3-yl)-2-(4-nitrobenzyloxycarboni-methoxyimino)acetamido-2-oxoazetidine-1
-Sulfonic acid triethylamine salt (syn isomer).

NMR (DMSO-d6.δ): 1.18 (9H,
t, J=8Hz).

8.12 (6H, ABq, J-8Hz), 11-4
．． 0 (2H.

m), 5.08 (2H, s), 5.05 (II (, m
), 5.40 (2H, s), 7.71 (2H, d,
J-=9Hz), 8.25(2H,d, J=9
Hz), 9.55 (IH, d, J=8Hz).

10.88 (IH,s) Cυ8-C2-(1,2,4-thiadiazol-3-yl)-2-(carboxinemethoxyimino)acetamido-2-oxoazetidine-1-10, ff Nurphonic acid (synisomer body), melting point 98~##-℃.

IR (Nushor): 1750, 1670, 1540
Taku-1(2)8-C2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)
Acetamide]-2-oxoazetidine-1-sulfonic acid trifluoroacetate (syn isomer), melting point 160-1
68°C (decomposition).

IR (Nujol): 8400-8100. 17
60. 1660°1680, 1580cM' Example 5 8-1: 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(ethoxyimino)acetamiF')-2-ogisoazetidine (synisomer body) (0,7
2G+), pyridine-sulfur trioxide complex (1,01M)
and boron trifluoride ether addition compound (0.76 g
) in dimethylformamide (4yxl) was stirred at room temperature for 4 hours. Add this to ethanol (10g?)
was added, and the resulting precipitate was collected. This solid was dissolved in saturated aqueous sodium bicarbonate solution (6 m/) and cooled at water bath temperature. The number of reprecipitated substances is 8-(2-(
5-amino-1,2,4-thiadiazole-3-i)v
) -2-(ethoxyimino)acetamido2-
Sodium oxoazetidine-1-sulfonate (syn isomer) (0.60 g) was obtained.

It was confirmed that the NMR data of the compound obtained above matched the data of the compound obtained in Example 1.

Example 6 According to the method of Example 5, the following compound was obtained.

(118-C2-(5-amino-1,2,4-thiadiazol-3-itv)-2-(methoxyimino)acetamido-2-oxoazetidine-1-sulfonic acid sodium (synisomer), melting point 240°C Tomokami (disassembly)
.

IR (Nujol'): 8420.8270. 1
770. 1660°1620, 1250.108 yesterday -
1 (2+8-[:2-(5-amino-1,2,4-thiadiazol-8-yl)-2-(propoxyimino)acetamidocy 2-ogisoazetidine-1-sulfonic acid triethylamine salt (syn isomer), Melting point 87-98°C.

IR (Nujol): 8100-8500.1760
, 1670° 1620, 1580c1R-' (318-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hexyloxyimino)acetamidocy2-ogisoa right tidine-1-sulfone Sodium chloride (syn isomer).

IR (5 (shawl>: 8800, 1760, 12
40.1045011-'(4)8-(2-(5-amino-1,2,4-thianazol-3-Iv) -2
-(allyloxyimino)acetamidocy 2-oxoazetidine-1-sulfonate sodium (syn isomer)
, melting point 240°C or higher (decomposition).

IR (Nujol): 8800.1765.1665
．． 1620゜1240, 1050α-1 (5) 8-C2-(5-amino-1,2,4-thiadiazole)v-8-i)+z)-2-(2-provinylogycyimino)acetamidocy 2-Ogisoazetidine-
Sodium 1-sulfonate (syn isomer), melting point 145
~150°C (decomposition).

(6) 8-(2-45-amino-1,2,4-thiadiazole-3-itev)-2-(2-cyclopentene-1
-yloxyimino)acetamidocy 2-oxoazetidine-1-sulfonic acid triethylamine salt (syn isomer), melting point 113-121°C.

IR (Nujo zL/): 8100-8400.1
760.1670° 1620, 1580 cN-' (7) 8-(2-(5-formamide-1,2,4-thiadiazole-3-i/L/) -2-(cyanomethoxyimi.))acetamide sea 2 -oxoazetidine-1-sulfonic acid triethylamine salt (syn isomer),
Melting point 105-110°C (decomposed). and IR(K
Br): 1760.1680.1270.1040
．． 1015m'(8)8-C2-(5-amino-1,2
,4-Thiadiazo-/L/-8-yl)-2-(cyanomethoxyimino)acetamidocy 2-oxoazetidine-1-sulfonic acid triethylamine salt (syn isomer)
, melting point 81-85°C (decomposition).

IR(KBr): 1760.1675.1680
．． 1260.1240°1040,1010α-1 (9!8-[:2-(5-amino-1,2,4-thiadiazol-8-yl)-2-(methylthiomethquinimino)acetamidocy2-ogisoazetidine- Sodium 1-sulfonate (syn isomer), melting point 200-210
°C (decomposition).

IR (Nujol): 1760.1670. 1
620.1240°1200,1050z-' Ql) 8-(2-(5-amino-1,2,4-thiadiazol-tL/-8-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino ) Acetamide sea 2-
Oxoazetidine-1-sulfonic acid triethylamine salt (syn isomer), melting point 200°C or higher (decomposed).

IR (Nuji:I-/l/): 1750.1270.
1085z-'(11)8-(2-(5-amino-1,
2,4-thiadiazole/L/-8-i/L/)-2-(
2-Aminoethoxyimino)acetamidosodium 2-ogisoazetidine-1-sulfonate (syn isomer), mp 280-240°C (decomposed).

IR (Nujol): 8400.8800.81
60.1760゜1200, 1040n-1 02) 8-C2-(5-amino-1,2,4-thiadiazole-3-iw)-2-(2-acetogyethoxyimino)-acetamido-2-oxoazetidine -1-
Sulfonic acid triethylamine salt (syn isomer), melting point 6
8-78℃.

IR (Nujol): 1760.1670.122
0-1280゜1040cII-' 038-(2-(5-amino-1,2,4-thiadiazol-3-y)v)-2-(2-hydroxyethoxyimino)acetamidocy2-ogisoazetidine-1-sulfone Acid triethylamine salt (syn isomer), melting point 12
8-132°C (decomposition).

IR (nujo-/l/): 8400,1750.1
660.1220-1280, 101080c' α滲8-42-(5-amino-i,2.4-thiacyaso/L/-8-yl)-2-(pencyloxyimino)
Acetamide di-2-oxoazetidine-1-sulfonic acid triethylamine salt (syn isomer) 5 Melting point 134-1
87℃0 IR (Nushor): 1760.1670.162
0.1280°1040, l0IOCIII-1 Q58-(2-(5-amino-1,2,4-thiadiazole-8-itev)-2-(4-fluoropencyloxyimino)acetamidodi-2-oxoazetidine- 1
-Sodium sulfonate (syn isomer), melting point 205~
208°C (decomposition).

IR (Nujol): 8800, 1760, 166
0.1620゜1510011-1 (+18-[2-(5-amino-1,2,4-thiadiazol-8-iv) -2-(tert-butoxycarbonylmethoxyimino)acetamidodi-2-oxoazetidine- 1-sodium sulfonate (syn isomer),
Melting point 280-240℃ or higher 1 1R (Nujol): 8270.1750.124
5.1045cIlα718-(2-(5-amino-1
,2,4-thiadiazol-3-yl)-2-(carboxinemethoxyimino)acetamidodi-2-oxoazetidine-1-sulfonic acid (non-isomer), melting point 200°C
That's it (disassembly).

IR (Nujol): 8280.1750.17
B0.1665゜1210, 108 nails 11 Q8) 8-(2-(5-amino-1,2,4-thiadiazol-8-yl)-2-(1-benzhydryloxycarbonyl-1-methylethquin) imino)acetamidodi-2-oxoazetidine-1-sulfonic acid triethylamine salt (syn isomer), mp 150-156°C (decomposed).

IR (Nujol): 8500-8100.175
0,1670° 1620, 1580n-1
Methylethoxyimino)acetamidodi-2-oxoazetidine-1-sulfonic acid disodium (syn isomer)
, melting point 188-198°C (decomposed).

IR (Nujol): 8500-8100. 17
60. 1660°1590, 15803-' t2fJ8-(2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(8-tert-butoxycarbonyl-trans-7lyloxyimino)acetamidodi-2 -Oxoazetidine-1-sulfonic acid triethylamine salt (syn isomer), melting point 115-122°C (decomposed).

IR (Nujol): 1760.1710.16
70.1620°1040α-1 C21J8-(2-(1,2,4-thiadiazole-3
-yl)-2-(D-ximino)acetamidodi-
2-Oxoazetidine-1-sulfonic acid triethylamine salt (V-isomer'), melting point 68-70°C.

IR (Nujol): 8480.8260.80
50. 1?60°1670, 1250.1080a+
+-')8-(2-(1,2,4-thiadiazole-
3-yl)-2-(4-nitrobenzyloxycarbonylmethoxyimino)acetamidodi-2-oxoazetidine-1-sulfonic acid triethylamine salt (syn isomer).

NMR (DMSO-d6.δ): 1.18 (9H,
t, J=8Hz).

8.12 (6H, ABQ, J=8Hz), a, i
-4,0 (2B.

m), 5. os(2H,8), 5.05(IH,m
), 5.40 (2H, s), 7.71 (2H, d,
J=9Hz), 8.25(2H,d, J=9Hz
), 9.55 (IH, d, J=8Hz).

10.88(1)1. @) (238-(2-(1,2,4-thiadiazole-Iv-8
-yl)-2-(carboxymethoxyimino)acetamidodi-2-oxoazetidine-1-sulfonic acid (syn isomer), mp 98-105°C.

IR (Nujol); 1750. 1670.
15401:lll-'(c)8-(2-(5-amino-1,2,4-thiadiazol-8-yl)-2-(hydroxyimino)acetamidodi-2-oxoazetidine-1-sulfonic acid trifluoro Acetate (syn isomer)
, melting point 160-168°C (decomposition).

IR (Nujol): 8400-8100. 17
60.1660°1680, 1580cII-' Example 7 8-C2-(5-amino-1,2,4-thiadiazole-t
L/-8-i/L/)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamidodi-2-oxoazetidine-1-sulfonic acid triethylamine salt (
syn isomer) (0,669), anisole (2,6 books?
) and trifluoroacetic acid (2,6jIl) in methylene chloride (9xl) was stirred at 15-20°C for 2.5 hours]. Dry isopropyl ether (40%) was added to this under water cooling, and a precipitate was collected. This solid was dissolved in water (It)tt) and the solution was adjusted to pH 0 with 10% hydrochloric acid.
5, and then p
Adjusted to H8.0.

This solution was subjected to activated carbon chromatography.

Elute with 80% aqueous acetone and lyophilize to obtain 3-C2
-(5-Amino-1,2,4-thiadiazol-3-y1v)-2-(2-aminoethquinimino)acetamidodi-2-oxoazetidine-1-sulfonate sodium (syn isomer) (0, 189) was obtained. Melting point 230~
240°C (decomposition).

IR (Nujol'): 8400.8800.81
60.1?60°1200, 1040aII-” NMR (DMSO-da, δ): 8.00-8.4
8 (4H, m).

8.71 (IH, t, J=5Hz), 4.16-4
．． 60 (2H.

m), 4.88-5.20 (IH, m), 8.10
(2H, b, a).

9.17 (IH, d, J=8Hz) Example 8 I) Glucose 1%, peptone 0.8%, beef extract 0.
An aqueous medium (pH 7,0) containing 8% (100 ml) was added to four Erlenmeyer flasks of volume Ik 500 tel with one platinum loop of a slant culture (available from Osaka, Japan). . 7 acres of microorganisms, 25
The cells were cultured at ℃ for 2 days.

Furthermore, the same aqueous medium (C2ol) as above was poured into a jar fermentor with a capacity of 301 and sterilized at 120° C. for 20 minutes. The entire amount of the culture prosthesis obtained above was added to this medium. The pathogenic organisms were cultured at 25°C for 2 days.

The culture broth thus obtained in VC1~ was used in the following examples 1. Ta.

++) 8-[2-(5-Amino-1,2,4-thiadiazol-8-yl)-2-(2-acetoxyethoxyimino)acetamidocy 2-ogisoazetidine-1-nurphonic acid triethylamine salt (syn isomer )(0,49
) was dissolved in water (20 ytl).

Next, a culture broth containing a catalytic amount of the crude deacylase obtained in Example 8-1) was added thereto, and the mixture was incubated at 30° C. for 6 hours at pH 4.5 to 4.7. The reaction mixture was filtered and the filtrate was subjected to activated carbon chromatography. 3
The fractions eluted with 0% aqueous acetone were lyophilized at 7 and 8.
-C2-(5-amino-1゜2.4-thiadiazole-
3-I/I/)-2-(2-hydroxyethoxyimino)acetamide 2-ogisoazetidine-1-sulfonic acid triethylamine salt (syn isomer) (0.2 g) was obtained. Melting point 128-182°C (decomposition).

IR (5 (Joe #): 8400.1750.
1660.1220-1280, 10801-1 NMR10801-1N, δ): 1.18(91(
, t, J=8Hz).

2.98 (6H, Q, J=8Hz), 8.0-4.0 (
2H, m).

8.60 (2H, t, J=5Hz), 4.18 (2H,
t, J=5Hz), 4.92 (IH, m), 8.06 (
2H, m), 9.08 (IH, d, J = 8 Hz) Example 9 Trifluoroacetic acid (80 L) was added to 8-C2-(5-amino-1,2,4-thiadiazole-8-y /L/)-
2-(2-cyclopenten-1-yloxyimino)acetamido di-2-oxoazetidine-1-sulfonic acid triethylamine salt (syn isomer) (added to a suspension of 1,5i in dichloromethane (50 ml) at 3°C, The mixture was stirred for 4 hours under water cooling.The reaction mixture was concentrated, and the residue was washed with n-hexane and ether, dried, and the 8-
[2-(5-amino-1,2,4-thiadiazole-8
-iv) -2-(Hydroxyimino)acetamidocy 2-ogisoazetidine-1-sulfonic acid trifluoroacetate (syn isomer) (0,959) was obtained. Melting point 160-168°C (decomposition).

IR (Nushor): 8100-8400. 176
0. 1660°1680, 1580cm-1 NMR (DMSOdr, δ): 9.10 (IH,
d, J=8Hz).

7.22 (2H, b, s), 5.10-4.70 (I
H, m).

8.77-8.17 (2H, m) Example 10 8-C2-(5-amino-1,2,4-thiadiazol-3-yl)-2-11-benzhydryloxycarbonyl-1-methyl ethoxyimino) acetamidocou 2
-Trifluoroacetic acid (9.65 m?) is added to a mixture of oxoazetidine-1-sulfonic acid triethylamine salt (syn-X form) (2,889) and anisole (20 l).
was added and the mixture was stirred at 5°C for 1.5 hours. The reaction mixture was poured into Improvil ether under stirring and the precipitate formed was separated [also. Vacuum dry the precipitate and add water (20g?)
The mixture was suspended in hydrogen carbonate and adjusted to pH 8.0 with IJum.

It was subjected to column chromatography. The fraction eluted with water was lyophilized and 8-C2-(5-amino-1,2,4
-thiadiazol-3-yl)-2-(1-carboxylade-1-methylethoxyimino)acetamidocou 2-oxofuzetidine-1-nurphonate disodium (
Syn isomer) (o, 68 g) was obtained. Melting point 188-19
8°C (decomposition).

IR (Nujo-zu): 8100-8500.1
760. 1660°1590, 1580(II-' NMR(DMSO-d6.δ): 11.0(II(
, d, J=88Z).

8.10 (2H, b, s), 5.2-4.88 (I
H, m), 8.88-3°10 (2H, m), 1.4
2(6H,m) Example 11 Palladium-black (1,09) was added to 8-(2-(1°2.
4-thiadiazol-8-yl)-2-(4-nitrobenzyloxycarbonylmethoxyimide)
) Acetamidocou 2-oxoazetidine-1-sulfonic acid triethylamine salt (syn isomer) (1,49) was added to a solution of 10% aqueous acetic acid (80xl) under an atmosphere of nitrogen gas. Hydrocracking was continued for 2 hours under atmospheric pressure. Palladium black was taken from house to house, and the p solution was adjusted to pH 8.0 with a saturated aqueous solution of sodium bicarbonate and subjected to activated carbon column chromatography at 1-. The elution fraction with 80% aqueous acetone was concentrated and lyophilized to give 8-(2-(1,2,
4-thousandiazol-3-yl)-2-(carboxymethoxyimino)acetamidocou-2-oxoazetidine-1-sulfonic acid (syn-14-mer) (52.

wl) was obtained. Melting point: 98-105°C.

IR (nujo/L'): 1750. 1670
．． 15404-1NMR (DMSOda, δ):
10.2B(IH,s), 9.41(IH.

d, J=8Hz), 8.07 (2H, b, s),
4.77 (2H.

S), 8.85-118 (2H, m) Example 12 The following compound was produced according to the method of Examples 10 and 11.

8-[2-(5-amino-1,2,4-thiadiazol-8-yl)-2-(carboxinemethoxyimino)acetamidodi-2-ogisoazetidine-1-sulfonic acid (
syn isomer), melting point 200°C or higher (decomposition).

IR: 8280. 1750.178
0.1665°1210, 1085 pieces-1 NMR (DMSO-d6.δ): 8.20 (IH,
m), 8.67 (IH.

t, J=8Hz), 4.40-5.20(8H, m
), 8.15 (2H, m), 8.78 (IH, d,
J=7.5Hz) Cut-throat burial man Aomizu Takashi

Claims (1)

[Claims] ■ General formula: [In the formula, R1 is hydrogen, an amino group or a protected amine group, and R2 is hydrogen, or a lower amine group hydrocarbon which may have an appropriate substituent.] and pharmaceutically acceptable salts thereof. 2) The compound according to claim 1, wherein R2 is a carboxy(lower) alkyl group or a protected carboxy(lower) alkyl group. 3) Synisomer of the compound according to claim 2, wherein R1 is an amine paper and R2 is a carboxy(lower) alkyl group. 4-8-[2-(5-amino-1,2,4-) thiadiazol-3-yl)-2-(1-carboxylade-1
-Methylethoxyimino)acetamide]-2-oxoazetidine-1-sulfonic acid disodium (syn isomer). 5) (Formula 11: [1) A compound represented by the following formula or a reactive derivative thereof in an amino group or a salt thereof is expressed by the formula: [where kL+ is hydrogen, amine paper or a protected amino group, Hydrogen, or a lower aliphatic hydrocarbon group which may have an appropriate substituent, respectively] is reacted with a reactive derivative thereof or a salt thereof in the case or carboxyl group to form the compound represented by the general formula: (2) In the formula 26, R1s and R2 each have the same meanings as before] to obtain a compound or a salt thereof; (3) Formula: [1] [In the formula, the compound [I] is a protected amino acid. It means a lower aliphatic hydrocarbon group having a group of [(] [In the formula, means a lower aliphatic hydrocarbon group having a diamino group, and R1 has the same meaning as before]) or a salt thereof; [IC] [In the formula, Ito represents a lower aliphatic hydrocarbon group having a protected hydroxyl group or a compound represented by cyclo(lower falkenyl, R1 has the same meaning as above), or a salt thereof, with the formula: =N-(J For the elimination reaction of the hydroxy protecting group in the -kL% group, the formula: be〕
or obtain a compound represented by the formula (5): [In the formula, kL mo means a lower aliphatic hydrocarbon group having a protected carboxyne group, and R1 has the same meaning as before.] The compound represented by or a salt thereof is subjected to the cleavage reaction of the carboxy-protecting group at dawn, VCli, and the formula: A method for producing a compound represented by the general formula [I] or a salt thereof, which comprises adding a compound represented by the formula [I] or a salt thereof. 6) General formula: (% formula % [In the formula, % is a protected amino group or amino method, 1☆ is haloal (lower) alkyl i, lower alkoxy sulfonyl (lower) alkeni/L, scrap, lower alkanoyl A compound or its salt represented by an oxy(lower) alkyl group, hexyl method, benzhydryloxycarbonyl (lower) alkyl method, or nitrobenzyloxycarbonyl (lower farkyl method, respectively). 7) Formula ゛[V] [In the formula, ratio 8 means lower alkyl group t, -% kLa
means a broken amino group or an amino group, respectively], or a salt thereof, is produced after hydrolyzing V Kokeshi, and the formula: [In the formula, < has the same meaning as before. ] A compound or a salt thereof represented by the formula: % formula % [wherein is a haloal(lower) alkyl group, a lower alkoxycarbonyl(lower) alkenyl group, a lower alkanoyloxy(lower) argyl group, a hexyl group, a penzyl group] % Formula % [Formula A method for producing a compound represented by η or a salt thereof. 8) General formula: % Formula % [In the formula, 2 means hydrogen or a lower aliphatic hydrocarbon which may have one or more suitable substituents] or a salt thereof. 9) Formula: % Formula % [In the formula, R2 means hydrogen, a lower aliphatic hydrocarbon group which may have one or more suitable substituents] or a salt thereof is nitronized. 10) General formula: [In the formula, R1 is A compound represented by hydrogen, an amino group or a protected amino group, wherein R2 represents hydrogen or a lower aliphatic hydrocarbon group which may have an appropriate substituent, or a salt thereof. 11) A compound represented by the formula: ] or a reactive derivative thereof in an amino group, or a salt thereof, with the formula: 20-R2 [l) [wherein R1 is hydrogen, an amino group or a protected amino group] , li2 means hydrogen or a lower aliphatic hydrocarbon group which may have an appropriate substitution method] or a reactive derivative thereof or a salt thereof on a carboxy group. A general formula characterized by: [1v] [In the formula, 1 (1 and kL2 n so r it rqD - the same meaning]) A method for producing a compound or a salt thereof. 12. Compounds according to claim 1 are all pharmaceutically acceptable. An antibacterial composition comprising a substantially non-toxic carrier or cedar shavings.