JPH01308288A - Novel cephem compound and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is (protected) amino; R<2> is H, OH-protecting group or (substituted) lower alkyl; R<3> is lower alkyl; R<4> is H, lower alkyl or OH; n is 1-3; A is lower alkylene which may have substituent group and is optionally interrupted by hetero-atom; Y is CH or N] and salts thereof. EXAMPLE:7-[2-(5-Amino-1, 2, 4-thiadiazol-3-yl)-2-methoxyimino acetamido]-3-(3- hydroxy-8-methyl-8-azoniabicyclo [3.2.2] oct-8-yl)-methyl-3-cephem-4-carboxylate (synisomer). USE:An antimicrobial agent. PREPARATION:A compound expressed by formula II (Q is leaving group) or salt thereof is reacted with a compound expressed by formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel cephem compounds and pharmaceutically acceptable salts thereof. More particularly, the present invention relates to novel cephem compounds having antibacterial activity and pharmaceutically acceptable salts thereof, a method for producing the same, and raw material compounds useful for producing the novel cephem compounds.

Thus, one object of this invention is to provide novel cephem compounds and pharmaceutically acceptable salts thereof that are effective against many pathogenic bacteria.

Another object of this invention is to provide a method for producing novel cephem compounds and their salts.

Yet another object of this invention is to provide starting compounds useful for producing the novel cephem compounds.

The desired new cephem compound (I>) is novel and can be represented by the following general formula.

−’／− (I) (In the formula, R is an amine group or a protected amino group.

R2 is hydrogen, a hydroxy protecting group or a lower alkyl group which may have a suitable substituent; R3 is a lower alkyl group; R4 is hydrogen, a lower alkyl group or a hydroxy group; n is an integer from 1 to 3; A is appropriate a lower alkylene group, optionally interrupted by a heteroatom, which may have substituents; Y means CH or N).

According to this invention, the novel cephem compound (I) can be produced by the production method illustrated in the following reaction formula.

(1) Production method 1 or a salt thereof (2) Production method 2 or a reactive derivative thereof or a salt thereof (1) <3> Production method 3 or a salt thereof (I-a) or a salt thereof (tb) (4) Production method 4 1l- (5) Production method 5 [In the formula, R, R, R, R, n, A and Y each have the same meaning as before, Q is an appropriate leaving group, and R1 is protected amine group, R2 is a protected carboxy(lower) alkyl group, R2
means a carboxy (lower) alkyl group, and R2 means a hydroxy protecting group].

In this invention, the target compounds and starting compounds include syn isomers, anti-isomers, and mixtures thereof. The syn isomer has the following formula: (wherein Y, R1 and R2 each have the same meaning as before)
An anti-isomer means one geometric isomer having a group represented by the formula: (wherein Y, R and R2 each have the same meaning as before) means.

Suitable pharmaceutically acceptable salts of the target compound (I) are the customary non-toxic salts, including inorganic salts, such as alkali metal salts such as sodium salts, potassium salts, and calcium salts, magnesium salts, etc. Metal salts such as alkaline earth metal salts, ammonium salts, etc.; organic base salts,
Examples include trimethylamine salt, triethylamine salt, biline salt, prochlorine salt, picoline salt, synchlohexylamine salt, N,N'-cyhenylethylenecyamine salt, N-methylglucamine salt, and ethanol salt. Organic amine salts such as amine salts, triethanolamine salts, tris(hydroxymethylamino)methane salts, phenylethylhemesylamine salts, and ethylene diamine salts; examples include formates, acetates, trifluoroacetates, and maleic salts. Organic carboxylates or organic sulfonates such as acid salts, tartrates, methanesulfonates, Hensensulfonates, and toluenesulfonates; inorganic salts such as hydrochlorides, hydrobromides, sulfates, and phosphates; Acid salts; for example, salts with basic amino acids or acidic amino acids such as alkynine, aspartic acid, glutamic acid, rylene, and the like.

In this specification, preferred examples and explanations of various definitions encompassed within the scope of this invention are described in detail below.

"Lower, unless otherwise specified, is used to mean groups having from 1 to 6 carbon atoms.

Suitable mono-protected amine groups include the commonly used amine protecting groups used in penyl and cephalosporin compounds, such as the following acyl groups, mono-( or al(
(lower) alkyl group, e.g. 1-methoxycarbonyl-1
-Lower alkoxycarbonyl such as propen-2-yl (
Examples include amine groups substituted with (lower) alkyritene groups or enamine-type tautomers thereof, such as cy(lower) alkylamino methylene such as dimethylamino methylene.

Suitable 1-anlu groups include aliphatic acyl groups, aromatic acyl groups, heterocyclic acyl groups, and aliphatic acyl groups substituted with aromatic or heterocyclic groups.

Examples of aliphatic acyl groups include formyl, acetyl,
Lower alkanoyl groups such as propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl; lower alkanesulfonyl groups such as mesyl, ethanesulfonyl, propanesulfonyl; examples include methoxycarbonyl, ethoxycarbonyl, propoquinecarbonyl, butquinecarbonyl; , lower alkoxycarbonyl groups such as tertiary butoxycarpol, lower alkenoyl groups such as acryloyl, methacryloyl, crotonoyl, etc. (C3-
07) - Saturated or unsaturated acyclic or cyclic acyl groups such as a cycloalkanecarbonyl group, an amidino group, and the like.

Examples of the aromatic acyl group include aroyl groups such as hensoyl, toluoyl, and xyloyl, and arenesulfonyl groups such as henzenesulfonyl and tosyl.

Examples of the heterocyclic acyl group include furoyl, thenoyl,
Examples include heterocyclic carbonyl groups such as nicotinoyl, innicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, and tetrazolylcarbonyl.

Examples of the aliphatic acyl group substituted with an aromatic group include phenyl (4ff) such as phenylacetyl, phenylpropionyl, and phenylhexanoyl.

(lower) alkanoyl groups, such as phenyl (lower) alkoxycarbonyl groups such as benzyloxycarbonyl and phenethyloxycarbonyl;
For example, fenoquine (lower) alkanoyl groups such as fenoquine aretyl, fenoquine propyl, and the like can be mentioned.

Examples of the aliphatic acyl group substituted with a heterocyclic group include thienyl acetyl, imidazolylacetyl, solylacetyl,
Examples include tetrasolyl acetyl, thiazolyl acetyl, thiathiazolylacetyl, thienylpropionyl, thiasiazolylpropionyl, and the like.

These acyl groups may further include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, halogens such as chlorine, bromine, iodine, fluorine, methoxy, ethoxy, propoxy, etc. , isopropoquine, b)hexy, pentylthio, hexyloxy, lower alkylthio groups such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, nitro groups, etc. Preferred acyl groups which may be substituted with one or more groups and have such substituents (Jl, for example, mono-(or 7- or tri-) such as 1-fluoroacetyl, bromoacetyl, cycloacetyl, trifluoroacetyl, etc. Halo(lower)alkanoyl groups, such as mono-(or tri)halo(lower)alkoxycarbonyl groups, such as chloromethoxycarbonyl, dichloromethoxycarbonyl, dichloromethoxycarbonyl, etc., such as nitrohemesyloxycarbonyl, chlorohemesylox7 Examples include carbonyl, methoxyhensyloxycarbonyl, noenyl (lower) alzquine carbonyl groups.

Suitable lower alkyl groups include 1 to 6 carbon atoms such as methyl, niger, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary-butyl, pentyl, tertiary-pentyl, hexyl, etc. Examples include straight chain or branched chain alkyl groups, and preferred ones include those having 1 to 4 carbon atoms.

Hydroxy protecting groups are commonly used groups in the field of cephalosporins to protect hydroquinimino groups;
Suitable examples of such groups include the aforementioned acyl groups, preferably lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, imbutyryl, valeryl, invaleryl, pivaloyl, hexanoyl and the like.

Suitable lower alkylene groups include those having 1 to 6 carbon atoms, preferably carbon 1 to 4 atoms
Examples include those with individual numbers.

Examples of "one suitable substituent for R2 and A" include a carboxyne group, a protected carboxy group, a halogen, a hydroquine group, a carbamoyloxy group, a hydroquine imino group, a lower alkoxy group, the above-mentioned lower alkyl group, and a 1xo group. Can be mentioned.

Suitable lower alkoxy groups include straight or branched chains having 1 to 6 carbon atoms, such as methoxy, ethoquine, propoxy, impropoxy, butoxy, inodoquine, tertiary butoxy, pentyloquine, hexyloxy and the like. Examples include alkoxy groups.

Suitable heteroatoms include oxygen, atom or nitrogen.

"Suitable protected carboxy moieties of protected carboxyne groups and 1-H-held carboxy (lower) alkyl groups include Nisdel moieties such as methyl ester, eternisdel, butyl ester, isopropyl ester, butyl Lower alkyl esters such as ester, isobutyl ester, tertiary butyl ester, pentyl ester, tertiary pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.
, the lower alkyl moiety preferably has 1 to 4 carbon atoms.
Lower alkyl esters having 2-alkylene esters; for example, lower alkenyl esters such as vinyl esters and allyl costyls; lower alkynylephthyls such as ethynyl esters and propynyl esters; for example, 2-iodoethyl esters,
2.2. Mono-(or tri)halo(lower) alkyl esters such as 2-1-ly-Tel loethyl ester; for example, f'hytoquine methyl ester, propionyloxymethyl ester, 1-acetoxy Lower compounds such as propylnisder, hareli oxdimethyl ester, bivaloyl oxine methyl ester, hensoyluoxine methyl ester, 1-acetoquine ethyl ester, 2-propionyl oxine ethyl ester, 1-isoglyloxyethyl ester, etc. Alkanoyluokyne (lower) alkyl ester; lower alkanesulfonyl (lower) alkyl nisfur: al(lower) alkyl ester, such as mesyl ethyl ester, 2-mesylethyl ester, etc., such as hennol ester, 4- Methoxyhennor ester, 4-nitrohensyl ester, phenethyl ester, trityl ester, diphenylmethyl ester, bis(methoxyphenyl)methyl ester, 3.
4-ene methoxyhenzyl ester, 4-hydroquine-3
, 5-tertiary phthylhennor ester, phenyl (lower) alkyl ester which may be substituted with one or more suitable substituents; examples are methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, Lower alkoxycarbonyloxy (lower) alkyl ester optionally substituted with azide such as ethoxycarbonyloxyethyl ester; heterocyclic ester, preferably henzotetrahydrofuryl ester optionally substituted with an oxo group, more preferably phthalidyl Ester: Aroyloxy (lower) alkyl JL, such as hensoyloki dimethyl ester, benzoyloxyethyl ester, toluoyloxyethyl ester, etc.:
r, stel: For example, aryl esters that may have one or more suitable substituents such as phenylene, lyl ester, tolylnisal, tertiary butyl phenyl ester, xylyl ester, menthyl ester, cumenyl ester, etc. Examples include esterified carboxy groups.

Suitable leaving groups are groups which can be substituted by a group of the formula: (wherein R3, R4, n and A each have the same meanings as before), preferably such as fluorine, chlorine, bromine, iodine, etc. halogen, for example, an acyluoquine group such as acetoquine.

The group represented by the formula: is preferably the formula: (wherein R1, R2 and Y each have the same meaning as above)
It is indicated by.

Further, the group represented by the formula: is more preferably the following formula=(in the formula, R'
3, R4 and A each have the same meaning as above), more preferably they are represented by the following formula: (wherein R3, R4 and A each have the same meaning as above)
It is indicated by.

The method for producing the object compound [I] of the present invention will be explained in detail below.

Production method 1 Target compound [I] or a salt thereof can be produced by reacting compound [1[] or a salt thereof with compound [1[[] or a salt thereof.

For suitable salts of Compound [I[] and [I[[], reference may be made to those exemplified for Compound [I].

The reaction consists of water, phosphate buffer, acetone, chloroform, acetonitrile, nitrohenzene, methylene chloride, ethylene chloride, formamide, N.

N-dimethylformamide, methanol, ethanol,
Although the reaction can be carried out in a solvent such as diethyl ether, tetrahydrofuran, or dimethyl sulfoxide, the reaction can also be carried out in any other solvent as long as it does not adversely affect the reaction.Preferably in a strongly polar solvent. The reaction takes place. Hydrophilic solvents may be used as a mixture with water. When the compound [In] is a liquid, it can also be used as a solvent.

The reaction is preferably carried out in the presence of a base such as an inorganic base such as an alkali metal hydroxide, an alkali metal carbonate or an alkali metal hydrogen carbonate, or an organic base such as a trialkylamine.

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

This reaction is preferably carried out in the presence of an alkali metal halide such as sodium iodide or potassium iodide, for example an alkali metal thiocyanate such as sodium thionanate or potassium thiocyanate.

Production method 2 Target compound [I] or a salt thereof is obtained by combining compound [IV] or its reactive derivative at the amine group or its salt with compound [V] (2 or its reactive derivative at the carboxy group or It can be produced by reacting with its salt.

Suitable reactive derivatives of the amine group of compound [IV] include base-type imino or enamine-type tautomers thereof, which are produced by the reaction of compound [IV] with carbonyl compounds such as aldehydes, ketones, etc. Compound [IV] and bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide such as N-(trimethylsilyl)acetamide, silyl compound such as bis(trimethylsilyl)urea; ] and a trichloride groove or a derivative produced by the reaction with phosgene.

For suitable salts of compound [IV] and its reactive derivatives, reference may be made to the salts exemplified for compound [I].

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

Suitable examples of reactive derivatives include acid chlorides, acid and; substituted phosphoric acids such as dialkyl phosphoric acid, phenyl phosphoric acid, nphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, dialkyl phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid. , for example sulfonic acids such as methanesulfonic acid, such as acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid,
Mixed acid anhydrides with acids such as aliphatic carboxylic acids such as isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid or aromatic carboxylic acids such as benzoic acid; symmetrical acid anhydrides: henzosulfimide, imidazole, Activated amides with 4-substituted imidazoles, dimethylvirazoles, triazoles, 1-hydroxy-IH-hencytriazoles or tetrasols, or e.g. cyan methyl esters, methoxymethyl esters, dimethyliminomethyl [(CH
3) 2 noble=CH-] ester, vinyl ester, propalkyl ester, p-nitrophenyl ester, 2.4
-nitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenyl asophenyl ester, phenylthioester, p-nitrophenylthioester, p-talesylthioester, carboxyl methylthioester,
Activated esters such as pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolylthioester,
or for example N,N-dimethyl droxylamine, 1
-hydroxy-2=(IH)-pyridone, N-hydroquine succinimide, N-hydroxyphthalimide, 1-
Examples include esters with N-hydroxy compounds such as hydroxy-IH-hensitriasol. These reactive derivatives can be arbitrarily selected depending on the type of the compound [V] used.

For suitable salts of the compound [■] and its reactive derivatives, reference may be made to those exemplified for the compound [CI].

The reaction is usually carried out using water, alcohols such as methanol and ethanol, acetone, dioxane, acetonylsil,
It is carried out in common solvents such as chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, but also in any other organic solvent as long as it does not adversely affect the reaction. reactions can be carried out. These conventional solvents may be used in mixtures with water.

In this reaction, when compound [V] is used in the form of a free acid or a salt thereof, N.

N'-cyclohexylcarbodiimide;N-cyclohexyl-N'-morpholinoethylcarbodiimide; N
-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;N,N'-diethylcarbodiimideisopropylcarbosiimide;N-ethyl-N'-(3
-dimethylaminopropinocarbodiimide, N.
N'-carbonylbisole); Hentamethyleneketene-N-cyclohequinolimine: Nphenylketene-N-cyclohequinolimine; Ethoxyacetylene; 1-alcoquino-1-chloroethylene; Trialkyl phosphite, polyethyl phosphate, poly Isopropyl phosphate; phosphorus oxychloride (phosphoryl chloride): trichloride; thionyl chloride; oxalyl chloride: lower alkyl haloformates such as ethyl chloroformate and isopropyl chloroformate; triphenylphosphine; 2-ethyl-7-
Humanoquinbensisoxasolium salt; 2-ethyl-5
-(m-sulfophenyl)isoxazolium hydroxide inner salt; t-(p-10lopenvinsulfonyluoquine)-6-chloro-IH-hensotriazole. N,N
- The reaction is preferably carried out 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, trichloromethyl chloroformate, phosphorus oxychloride, etc.

The reaction can also be performed using alkali metal bicarbonates, tri(lower 32=)alkylamines, pyridine, N-lower alkylmorpholines, N. It may be carried out in the presence of an inorganic or organic base such as N-di(lower)alkylbenzylamine and the like.

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

Production method 3 Compound (I-b) or a salt thereof can be produced by subjecting compound (I-a) or a salt thereof to an elimination reaction of the amine protecting group of R1.

Preferred methods for this elimination reaction include hydrolysis, reduction,
Examples include a combination method in which iminohalogenation is followed by iminoetherification, followed by further hydrolysis if necessary.

(1) Hydrolysis Hydrolysis is preferably carried out in the presence of an acid.

Suitable acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, for example formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid, helensulfone M,
l)-Organic acids such as toluenesulfonic acid, acidic ion exchange resins, and the like. 1-Lifluoroacetic acid and p-
When an organic acid such as toluenesulfonic acid is used in this reaction, it is preferable to carry out the reaction in the presence of a cation scavenger such as anisole.

The acid suitable for this hydrolysis can be selected depending on the type of protecting group without elimination. ], is preferably applied to the amino protecting group of UNA R1.

Hydrolysis is usually carried out in conventional solvents that do not adversely affect the reaction, such as water, methanol, ethanol, propatool, tertiary butyl alcohol, tetrahydrofuran, N,N-methylformamide, or mixtures thereof such as water, methanol, ethanol, propatool, tertiary butyl alcohol, tetrahydrofuran, N,N-methylformamide, or Furthermore, when the above-mentioned acids are liquids, they can also be used as solvents.

The reaction temperature for this hydrolysis is not particularly limited, and the reaction is usually carried out in a range of from cooling to slightly elevated temperature.

(11) Reduction Reduction is carried out by conventional methods including chemical reduction and catalytic reduction.

Suitable reducing agents used for chemical reduction include, for example, soot,
Metals such as zinc and iron or metal compounds such as chloride chloride and chromium acetate, and phosphoric acid, acetic acid, propionic acid, etc.
It is a combination with an organic or inorganic acid such as trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, or hydrobromic acid.

Suitable catalysts used for catalytic reduction are platinum catalysts such as platinum plates, platinum sponges, platinum black, colloidal platinum, platinum oxide, platinum wires, e.g. palladium sponges, haladium black, palladium oxide, palladium-carbon, colloidal palladium. ,
Palladium catalysts such as palladium-barium sulfate and palladium-barium carbonate, nickel catalysts such as reduced nickel, nickel oxide and Raney nickel, cobalt catalysts such as reduced cobalt and Raney cobalt, iron catalysts such as reduced iron and Raney iron, etc. Examples include commonly used copper catalysts such as reduced copper, ferrous copper, and Ullmann steel.

The reduction method can be selected depending on the type of protecting group to be removed, and chemical reduction is preferably applied to the amino protecting group of R1 such as halo(lower)al-7xycarpo, -l group, etc. Reduction is preferably applied to protecting groups such as substituted or unsubstituted alkoxycarbonyl groups and the like.

The reduction is usually carried out in conventional solvents that do not adversely affect the reaction, such as water, methanol, ethanol, propatool, N,N-metherformamide, or mixtures thereof.

Furthermore, when the above-mentioned acids used for chemical reduction are liquids, they can also be used as solvents. Suitable solvents used in the catalytic reduction also include the above-mentioned solvents and other commonly used solvents such as diethyl ether, oxane, tetrahydrofuran, etc., or mixtures thereof.

The reaction temperature for this reduction is not particularly limited, but the reaction is usually carried out under cooling or heating.

(iii) Iminohalogenation (first step) and iminoetherification (second step) and hydrolysis (final step)
The first and second steps of the combination method - are preferably carried out in an anhydrous solvent. Suitable solvents for the first step, i.e., iminohalogenation, are aprotic solvents such as methylene chloride, chloroform, diethyl ether, tetrahydrofuran, oxane, etc., and suitable solvents for the second step, i.e., iminoetherification, are usually the first step. It is the same as the solvent of

These two steps are usually performed under cooling or at room temperature. , - These two steps and the final step, i.e. hydrolysis, are most preferably carried out in a single hatch system.

Suitable iminohalogenating agents include, for example, trichloride,
Examples include halogenating agents such as phosphorus halo compounds such as pentachloride, tribromide, pentabromide, and oxidiphosphorus chloride, thionyl chloride, phosgene, and the like.

Suitable iminoetherification agents include, for example, methanol,
Alcohols such as alkanols such as ethanol, propatool, impropateur, butanol, or corresponding alkanols with an alkoxy group such as e.g. 2-methoquinoethanol, 2-ethquinoethanol, and e.g. sodium methquine, potassium ethoxy Examples include alkoxides of metals such as alkali metals, alkaline earth metals, etc.

The reaction product obtained in this way can be
Can be hydrolyzed using conventional methods. Hydrolysis is preferably carried out at room temperature or under cooling, and the reaction mixture is diluted with water or water.
Hydrolysis proceeds by simply pouring into an alcohol such as methanol or ethanol, which is moistened with water or mixed with water, and an acid or base is added as necessary.

Suitable acids include the same acids listed above in the explanation of hydrolysis in section (1), and suitable bases include the same bases listed in the explanation of production method 1. can be mentioned.

The methods described above may be selected depending on the type of protecting group that does not leave off.

In this invention, cases where the protected carboxyne groups of R2 and A are converted into free carboxyne groups during the reaction are also included within the scope of the invention.

Production method 4 Compound (I-d) or a salt thereof can be produced by subjecting compound (I-c) or a salt thereof to an elimination reaction of the carboxy protecting group of R2.

This reaction is carried out by conventional methods such as hydrolysis, reduction, etc.

Hydrolysis and reduction methods and e.g. reaction temperatures,
The reaction conditions such as the solvent are substantially the same as the explanation for the elimination reaction of the amino protecting group of compound (I-a) in Production Method 3, so the explanation can be referred to.

In this invention, cases where the protected amino group of R1 and/or the unprotected carboxyne group of A are changed to free amino groups and/or free carboxyl groups are also included within the scope of this invention.

Production method 5 Compound (I-f) or its salt is compound (1,-e)
Alternatively, it can be produced by subjecting a salt thereof to an elimination reaction of the hydroquine protecting group of R2.

This reaction is carried out by conventional methods such as hydrolysis, reduction, etc.

Hydrolysis and reduction methods and e.g. reaction temperatures,
The reaction conditions such as the solvent are substantially the same as those described for the elimination reaction of the amine protecting group of compound (I-a) in Production Method 3, and therefore, reference may be made to the explanation.

In this invention, cases where the unprotected amino group of R1 and/or the protected carboxyl group of A are converted into free amino groups and/or free carboxyne groups during the reaction are also included within the scope of this invention. .

Certain of the starting compounds (I[) and (IV) are new and can be produced by the following production methods A, B and C.

Production method A Production method B Production method C group, R6 means a protected amine group).

R5's preferred "unprotected carboxy group"
The examples given above may be referred to, and preferred examples include an alkoxycarbonyl group which may have an appropriate substituent such as benzhydryloxycarbonyl.

Suitable "protecting groups" for the "protected amine group" of R6 include common amine protecting groups used in the penicillin and senoalosvorin compounds described above, and examples thereof include acyl groups, and preferred examples thereof include as,
Substituted or unsubstituted alkylidene groups such as benzylitine, hydroxybenzylidene, etc., such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tertiary-pentyloxycarbonyl,
Examples include lower alkoxycarbonyl groups such as hexyloxycarbonyl, and aroyl groups such as benzoyl, toluoyl, naphthoyl and the like.

Manufacturing methods A, B and C of raw material compounds (1) and (IV) will be explained in detail below.

Production method A-■ Compound (■) or a salt thereof can be produced by reacting compound (Vl) or a salt thereof with compound (V) or a reactive derivative thereof at a carboxy group or a salt thereof.

This reaction can be carried out in the same manner as in Production Method 2,
Therefore, for the reagents to be used and reaction conditions such as solubility and reaction temperature, please refer to the explanation of Production Method 2.

1. Method A-■ Compound (I[) or a salt thereof can be produced by subjecting compound (■) or a salt thereof to an elimination reaction of the carboxy protecting group of R.

This reaction can be carried out according to conventional methods such as hydrolysis.

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

Suitable bases include, for example, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and carmine, hydroxides or carbonates or hydrogen carbonates of these metals, such as trimethylamine, triethylamine, etc. Alkylamine, picoline, 1.5-
Diazabicyclo[4,3,0]non-5-ene, 1.4
Inorganic and organic bases such as -diazabicyclo[222]octane, 1,8-cyazabicyclo[5,4,'O]undec-7-ene, and the like.

Suitable acids include organic acids such as formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, and the like.

Desorption using a Lewis acid such as a trihaloacetic acid such as trichloroacetic acid or trifluoroacetic acid is preferably carried out in the presence of a cation scavenger such as anisole or phenol.

The reaction is usually carried out in water, an alcohol such as methanol or ethanol, a solvent such as methylene chloride, tetrahydronolane, or a mixture thereof, but the reaction may be carried out in any other solvent that does not adversely affect the reaction. Liquid bases or acids can also be used as solvents.

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

Production method B-■ Compound (IX) or a salt thereof can be produced by reacting compound (■) or a salt thereof with compound (I[) or a salt thereof.

This reaction can be carried out in the same manner as in Production Method 1 above,
Therefore, for the reagents to be used and reaction conditions such as solvent and reaction temperature, the explanation of Production Method 1 may be referred to.

Production method B-■ Compound (IV) or a salt thereof can be produced by subjecting compound (IX) or a salt thereof to an elimination reaction of the amine protecting group of R.

This reaction can be carried out in the same manner as in Production Method 3,
Therefore, for the reagents to be used and the reaction conditions such as solvent and reaction temperature, please refer to the explanation of Production Method 3.

Production method C-■ Compound (XI) or a salt thereof can be produced by subjecting compound (X) or a salt thereof to an elimination reaction of R's carboxine protecting group and R's amine protecting group.

This reaction can be carried out in the same manner as in the production method A-①.

149 = Production method C-■ Compound (IV) or a salt thereof can be produced by reacting compound (XI) or a salt thereof with compound (I) or a salt thereof.

This reaction can be carried out in the same manner as in the production method B-①.

The object compound (I>) of this invention and its pharmaceutically acceptable salts are novel compounds that exhibit strong antibacterial activity and inhibit the growth of pathogenic bacteria including Durum-positive and Durum-negative bacteria, and are antibacterial agents. It is especially useful as an antibacterial agent against pseudoμ strain.

For therapeutic purposes, the compounds of this invention may be mixed with pharmaceutically acceptable carriers such as organic or inorganic solid or liquid excipients suitable for oral, parenteral or topical administration to render the compounds effective. It can be used in the form of conventional pharmaceutical preparations containing it as an ingredient. Pharmaceutical preparations may be in solid form, such as capsules, tablets, dragees, ointments or suppositories, and may also be in the form of solutions, suspensions or emulsions.
It may also be in liquid form. If necessary - Section C In the preparation Auxiliary agents, stabilizers, wetting agents or emulsifiers, buffers and lactose, fumaric acid, citric acid, tartaric acid, stearic acid, maleic acid, succinic acid, phosphoric acid, magnesium stearate , white clay, sucrose, cornstarch, talc,
Other commonly used additives such as gelatin, agar, pectin, peanut oil, olive oil, cocoa butter, ethylene glycol, etc. may also be included.

Although the dosage of the compound varies depending on the age and condition of the patient, the compound according to the present invention has an average single dose of about 10 m
g, 50mg, 100mg・, 250mg, 500mg
, 1000mg was found to be effective in treating pathogenic bacterial infections. Generally, amounts between 1 mg/individual and about 6000 mg/individual or more may be administered per day.

In order to demonstrate the usefulness of the target compound (I), the results of in vitro antibacterial activity tests on representative compounds of the present invention are shown below.

Test compound 7-[2-(5-amino-1,2,4-thiareazol-3-yl)-2-methoxyiminoacetamide]-3
'-(8-methyl-8-asoniapinchlor[3,2,1
Cact-8-yl) methyl-3-cephem-4-carboxylate (synisomer).

The in vitro antibacterial activity of the test base was measured by the agar plate multiple dilution method described below.

The test strain was cultured overnight in Tributicase Soy Pross, and one platinum loop (106 viable bacteria/mQ) was placed on Heart Infuyeon Agar containing the test compound at each concentration level.
After culturing at 37°C for 20 hours, the minimum inhibitory concentration (MIC) was expressed as Pg/mQ.

Test results MIC(:斥/mQ) The invention will now be described in accordance with manufacturing examples and examples.

Production Example 1 3-hydroxy-8-methyl-8-azabicyclo[3,
2,1] octane (3'g) of acetonitrile (
21mQ)? Chlorosulponylisonane 1- (194 ma-) was added dropwise to 1ll at 5-10°C,
Stir the mixture at 35°Ct' for 2 hours□. Water ('1'
, 5 mQ) A mixture with acetonitrile (15 mQ) was added to the reaction mixture at room temperature and stirred for 1 hour. The mixture was adjusted to pH 9, s with sodium hydroxide, and then extracted with ethyl acetate. The organic layer was extracted with sulfuric acid. After drying with I-lium, the solvent was distilled off under reduced pressure to give 3-carbamoyloxydi-
8-Methyl-8-azabinclo[3,2,1]octane ('1.55 g) is obtained.

IR (Nujol) 1720 cm-1HMR
(DMso-d 8): 1.40-2.10
(8H, m), 2.206° (3! (,5), 3.00 (2H, m), 4.6
0 (IH, t, , J = 5Hz).

6.30 (2H,s) Mass: m/z 184 (M+) Production Example 2 1) To a suspension of sodium hydride (11.6 g) in N,N-dimethylformamide, thioacetic acid (22 mQ) was added with nitrogen gas. The mixture is added dropwise over 30 minutes at 5° C. under stirring in an atmosphere. After stirring for 15 minutes, the mixture -(28,4R)-2-
Hydroxymethyl-4-methanesulfonyloxy-1-
(4-nitrohensyloxycarbonyl)pyrrolidine (
li)Og) is added in three portions at 75-80°C with stirring.

Stirring is then continued for 4 hours at the same temperature. The reaction mixture was mixed with ethyl acetate (500 mQ) and cold water (800 mQ) (7).
Pour into the U mixture. The ethyl acetate layer is separated, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was triturated with ethyl ether to obtain (2S,4S)-4-acetylthio-2-hydroxymethyl-1-(4-nitrohensyloxycarbonyl)pyrrolidine (48.41 g).

NMR (DMSO-d6.S)' 1.802.3
8 (2H1m), 2.21 (3H,s) 2.86-
2.56 (2H, m>, 3.07-3.23 (L
H.

m), 3.20 (3H,s), 3.92-
4.10 (LH, m), '4.36 (2H, broad s), 5.30 (2H, s), 7.
69 (2H, d.

J-9Hz), 8.26 (2H, d, J=9Hz)
2) (2S,4S)-4-acetylthio-2-hydroxymethyl-1-(4-nitrohensyloxycarbonyl) pyrrolyne (48 g) in dichloromethane (480 m
Q) Methanesulfonyl chloride (115 mQ) and ethylamine (20.7 ml) were added dropwise to the solution at 5°C while stirring, and after stirring at the same temperature for 30 minutes, the reaction mixture was poured into cold water C400 mQ). The dichloromethane layer was separated and washed with water and a saturated aqueous solution of sodium chloride.
, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was triturated with diisopropyl ether (2S,
45) -4-Acetylthio-2-methanesulfonyloxydimethyl-1-(4-nitro-\n/loxycarbonyl)pyrrolidine (65.83 g) is obtained.

IR (Nujol) 1690. 1605. 1
520 cm-1HMR (DMSO-d6.8 >
'2.16-2.40 (2H7m)-2,33(3
H,s>, 346-3.40 (LH,m), 3.
40-3.76 (2H, m), 3.76-4.16
(IH, m), 4.65-5.00 (2H, m
), 5.23 (2H,s>, 7.63
(2H, d, J=9Hz>.

8.26 (2H, d, J=9Hz) 3) (,2S,4S)-4-acetylthio-2-methanesulfonyloxymethyl-1-(4-nitrohensyloxycarbonyl)pyrrolidine (65.5g) Tetrahydrofuran (200 mQ) and methanol (20
A 28% sodium methoxide solution in methanol (31.4 mQ) was added dropwise to the 0 mσ) solution at 5° C. with stirring. After continued stirring at the same temperature for 30 minutes, the reaction mixture was poured into a mixture of ethyl acetate/l-(4ooma), cold water (10100O) and concentrated hydrochloric acid (s, smQ). The organic layer is separated, washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue was triturated with diisopropyl ether to give 5-(4
-Nitrohensyloxycarbonyl-2-thia-5-azabicyclo[2,2,1 cohebutane (46,16g)
get.

NMR (DMSOd6,8)' L 632.23
(2H9m), 3.02 (2H,s), 3.33-
3.65'(2H,m>, 3.67-3.83(I
H, m);'4.58-4.80 (LH, m)y5
．． 23 (2H, s).

7.63 (2H, d, J=9Hz), 8.30
(2H, d, J=9Hz>4) Lithium aluminum hydride (6.35g) in tetrahydrofuran (320g)
mQ) 5-(4-nitrohensyloxycarbonyl)-2-der-5-azabicyclo['2,
．． A solution of butane (35&) to 2,11 in tetrahydrofuran (175mQ) was added to reflux F for 2 hours (7 times). After stirring for 30 minutes, ethyl acetate (73&) was added to the reaction solution.
) and methanol (73 mm ) are added dropwise at room temperature, and then a 70% aqueous solution of tetrahydrofuran (4 omQ) is added thereto at 5°C. The reaction mixture is filtered to remove inorganic materials, and the filtrate's solvent is distilled off under reduced pressure. Ethyl acetate (200mQ) and cold water (100mrL) were added to the residue.
) and then adjusted to pH 3 with IN hydrochloric acid. The ethyl acetate layer is separated, washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue was triturated with diisopropyl ether to give 5
-Methyl-2-thia-5-azabicyclo[221]hebutane (3.4 g) is obtained.

NMR (CDC13, δ): 2.05-2.18
<2)1. m>, 2.38 (3H, s), 3.0
5-3.15' (2H, m>, 3.15-3.25
(2H, m>t 3.26-3.40 (LH, m>,
3.50-3.65 (LH, m> Production Example 3 1) (2S, 4R)-2-Hydroxymethyl-4-methanesulfonylokidi-1-(penzyloquinecarbonyl)pyrrolidine (20 g) Tetrahydrofuran (2oo
mQ) Sodium hydride (2,8&') is added to the solution in three portions at room temperature under stirring in a nitrogen atmosphere. The reaction mixture is refluxed for 8 hours and then poured into a mixture of ethyl acetate (200 mQ) and cooled 0,3H salt m (3oc+...Q). The ethyl acetate layer is separated, washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to column chromatography using silica gel (100 g) and a mixture of ethyl acetate and diisopropyl ether (1:4, v/v).
Elutes with Fractions containing the target compound were collected, the solvent was distilled off under reduced pressure, and the 5-
(hensyloxycarbonyl compound) 5-azabicyclo[2.2.13 to obtain butane (tt.tg).

IR: 2960. 290
0.1700. 1450 cm-'NMR
<coCt3. δ): 1.83-1.90 (2H
, m), 3.35-3, 55 (2H.m>, 3.
70-4.0 <28,m>, 4.50-4.73(
2H. m), 5.20 (2H.s), 7.38
(5H.s>2) Lithium aluminum hydride (1.3
7g) of Ke1hesihydrofuran (68mQ) medium
Compound 2.2.1 Cohebutane (6 g
) in tetrahydrofuran (30 ml) under reflux over 2 hours. After stirring for an additional 30 minutes, the mixture was treated with ethyl acetate (15 mQ) and methanol (
1gmc) was added dropwise at room temperature, and then 70%
Tetrahydrofuran aqueous solution (s15mQ) at 5°C
Add with . The reaction mixture is filtered to remove inorganic materials.

The filtrate was dried over magnesium sulfate (15 g) and then distilled under atmospheric pressure to give 5-methyl-2-year-old xer-5-azabinculo[2.2.1]hebukun (bp. 65-6
8°C) (184 g) is obtained.

IR (Film)' 3950. 385
0, 1640. 1440 cm-1HMR
(CDC13,E)' 1. 50-2. O (
3H7m>, 2. 13-2. 63<2)1,m>,
2.43 (3H,s), 2.70-2.9
7 (LH.m).

3,50-4.10 (2)1,m), 4.25-4
．． 38 (LH.m) Production Example 4 1) In a mixed solvent of dichloromethane (tooomQ) and tetrahydrofuran (200mQ), 2-[2
-('5-amino-1.2.4-thiadiazole-3-
yl)-2-methoxyiminocoacetyl (syn isomer)
(64 g) and 7-amino-3-chloromethyl-3-
Cephem-4-carribonic acid henshydryl ester
Hydrochloride (100 g) is added at -15°C. The mixture is stirred at -15°C for 1 hour. The reaction mixture is poured into ice-cold water and neutralized with sodium hydrogen suboxide. Separate the organic layer,
Dry over magnesium sulfate and remove the solvent under reduced pressure.

The residue was triturated with diisopropyl ether to give 7-[2-
(5-Amino-1.2.4-thiaresol-3-yl)-2-methoxyiminoacetamide]-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (130.5 g) get.

NMR (oMso-d6.S>' 3. 2-3
．． 8 (2H, m), 3.93 (3) 1. s), 4
．． 43 (2)1. s), 5.27 (LH, d.J
=5)1z).

5, 97 (IH.dd.J=5Hz, 8)+z
>, 7.00 <iH;s).

7, 20-7.70 <108. m), 8.17 (
2H. s), 9.70(1)1. d, J=8Hz) 2) 7-[2-(5-amino-1.2.4-thiacyazol-3-yl)-2-methoxyiminoacetamide]
Add trifluoroacetic acid (5 mQ) to a solution of -3-chloromethyl-3-cephem-4-carribonic acid henshydryl ester (syn isomer) (3 g) in dichloromethane (smQ) and anisole dichloromethane (smQ) at 0°C. 'c/l
i down. The mixture is stirred at 0° C. for 2 hours. The mixture was dissolved in a cooled mixture of diisopropyl ether and hexane (
1:1, v/v). The precipitate was collected by filtration and dried under reduced pressure to give 7-[2-(5-amino-1.2.4-thiacyazol-3-yl)-2-methoxyiminoacetamide]-3-chloromethyl-3-cephem- 4-Carboxylic acid trifluoroacetate (syn isomer) (2.s.

g) is obtained.

IR (Nubuyor) 1770, 1630
．． 1600 cm-'NMR (DMSO-d6
,8)' 3.63 (2H,m), 3.93 (
3H.

s), 4.57 (2)1, s), 5.18 (1
)! ．． d, J = 5Hz).

5, 83 (LH, dd, J=5Hz, 8Hz>
, 8.10 (2H, broad s>, 9.5
5 (IH, d, J = 8 Hz>Production Example 5 In the same manner as in Production Example 4-2>, 7-[2-(5-amino-1,2.4-thiacyazol-3-yl)-2-ethoxy Iminoacetamido co-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (5 g) was reacted with trifluoroacetic acid (1omQ) and anisole (5mQ) to give 7-[2- (
5-Amino-1,2.

4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3-chloromethyl-3-cephem-4
-Carboxylic acid trifluoroacetate (syn isomer) (4
．． 10g).

NMR (DMSO-d6.δ): 1.25 (3
H. t. J=7Hz>, 3.48.

375 (2H, ABq, J=18Hz), 4.2
0 (2H, q.

J Near) 1z), 4.57 (2H,s>,
5.20 (LH, d, J=51(z).

5.85 (IH, del, J=5Hz, 8Hz
>, 9.58 (LH, d.

J=8Hz) Production Example 6 7-[2-(2-formamidothiazol-4-yl)
-2-ethoxyiminoacetamide]-3-chloromethyl-3-cephem-4-carboxylic acid henshydryl ester (syn isomer) <25.13 g) / mixture of chloromethane (50 mQ) and anisole (25 mQ) Add trifluoroacetic acid (somQ) to the suspension in
The solution is stirred for 2 hours at O''C. The solution is diisopropyl ether (IP) and hexane (2+2
) into the cooled mixture. The powdered product was filtered and washed with chilled hexane to give 7-[2-(2-porumamidothiazol-4-yl)-2-ethquiniminoacetamide]-3-chloromethyl-3- Cephem
Obtain 4-carboxylic acid (syn isomer) (19,88 g) -0 IR (Sujoor): 3230. 1780.
1670. 1540 cm-INMR (oMso
-d6. f; ) ' 1.26 (3H, t, J=
7Hz), 3. st and 3.78 (2H, ABq
, J=18Hz>, 4.19 (2H.

q, J-7Hz>, 4.58 (2H,s),
5.24 (IH, d.

J=5)1z), 5.90 (LH, dd, J=8 and 5Hz).

7.42 (LH,s),, 8.57 (1)1.
s), 9.76 (LH, d.

J=8)1z), 12,60 (LH,s) Production Example 7 1) 7-Amino-3-chloromethyl-3-cephem-4
-Carboxylic acid penshydryl ester hydrochloride (22,
6 g) of monotrimethylsilylacetamide (32.8 g) in tetrahydrofuran (230 mA).
Add at 18°C. The mixture is stirred at 1860 for 30 minutes and cooled to 5°C. Add 2=(5-amino-1,2,4-thiacyazol-3-yl)-2=(1
-Carboxy-1-methylethquinimino)acetic acid/methylsulfonic anhydride (syn isomer) (17.6g')
Add. The mixture is stirred for 1 hour at 5°C and poured into saturated aqueous sodium chloride solution. The organic layer is separated and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was triturated with vinyl ether to give 7-[2-(5-amino-1,2,4-thiacyazol-3-yl)-2-
(1-Carboxy-1-methylethoxyimino)acetamide]-3-chloromethyl-3-cephem-4-carboxylic acid henzhydryl ester (syn isomer) (33.60 g) was obtained.

IR (Sujoor): 3200. 1780.
1720. 1660. 1630°1520 cm
'-1 NMR (DMSO-d6.δ): 1.47 (6H
, s), 3.42.3.85 (2H, ABq, J=1
8Hz>, 4.32.4.62 (2H, A, Bq.

J-14Hz), 5.28 (IH, d, J-5Hz
>, 6.0 (18, dd.

J=5)1z, 8Hz>, 4.0 (IH,s),
7.20-7.70 (12H, m>, 9.53 (I
H, d', J=8Hz) 2) The following compound is obtained in the same manner as in Production Example 4-2).

7=[2-(5-amino-1,2,4-thiacyazol-3-yl)-2-('1-carboxy-1-methylethoxyimino)acetamide]-3-chloromethyl-3-cephem-4 -Carboxylic acid trifluoroacetate (syn isomer).

IR (Nujoor) ・3170. 1770. ．． 1
700. ．． 1630°1530 am"-' NMR (DMSO-9, l; )' 147 (6H
1s), 348.3-75(2t(, ABq, J=18
Hz>, 4.53 (2H, m), 5.20
(IH.

d, J-5) 1z),, 5.80 (LH, dd,,
c5Hz, 8Hz), 7.20 (2H, broad)
, 9.43 (LH, (1, J = 8) IZ) Production Example 8 7, -[2-(2-formamidothiazol-4-yl, ?-2-(1-tert-butoxyluponyl- 1-methylethoxyimino)acetamide]-3-chloromethyl-3-cephem-4-carboxylic acid henshydryl ester (syn isomer) (25&) in methylene chloride (50 ml
) and anisole (25 mQ), trifluoroacetic acid (5 omQ) is added under stirring at 5°C. Stirring is continued for 3 hours at the same temperature. The solution is added dropwise to a cooled mixture of diisopropylnial (1) and hexane (2P).

The powdered product was collected by filtration and washed with chilled hexane to give 7-[27(2-formamidothiazol-4-yl)-2-(1-tert-butinyl-1-methylethyl). quinimino)acetamitoco-3-chloromethyl-
3-cephem-4-carboxylic acid (syn isomer) (19
, 4g).

NMR(oMso-d6.S>'L'2
0-1.60 (15H, m), 3.48°3.
70 <28. ABq, J=18Hz), 4.5
3 (2H,s), 5.20<IH,d, J=5
Hz>, 5.86 (LH, dd, J=8Hz.

J=5)+z), 7.35 (LH,s>, 8.5
0 (LH, s), 9.55<IH, d, J=8Hz
) Production Example 9 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid henshydryl ester hydrochloride (2,1g
) and monotrimethylsilylacetamide (2,14
g) in tetrahydrofuran (4omQ), add chloride 2
-(5-amino-1,2,4-thialeazol-3-yl)-2-(1-tert-butinyl-1-methylethquinimino)acetyl hydrochloride (synisomer) (
2g) was added under water cooling. After stirring for 1 hour at 0° C., the reaction mixture is poured into a saturated aqueous solution of sodium chloride (20 mQ). The organic layer is separated, washed with a 10% aqueous solution of hydrogen carbonate, then a saturated aqueous solution of sodium chloride, and dried over red sea bream sulfate and sodium chloride. The residue obtained by distilling off the solvent was triturated with diisopropyl ether, collected by filtration, washed with diisopropyl ether, and dried in a pentoxide groove to give 7-[2
-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarponyl-1-methylethoxyimino)ace1-amide]-3-chloromethyl-3-cephem-4 -Carboxylic acid benz'hydryl ester isomer) (2.95 g) was obtained. 7-[2-(5
-amino-1.2.4-thiadiazol-3-yl)=
2-(1-tert-butoxycarbonyl-1-methyl"-
Toxiimino) acetamidoio 3-chloroI methyl-
To a suspension of 3-cephem-4-carboxylic acid henshydryl ester (syn isomer) (2.95 g) in dichloromethane (6 mB and anisole (15 mQ)) was added trifluoroacetic acid (2.95+nQ). 0-5
Add at °C. After stirring for 2 hours at −1 to 0° C., the reaction mixture is poured into a mixture of diisopropyl ether (60=67=mQ) and hexane (120 mQ) under water cooling. The precipitated powder was collected by filtration, washed with hexane, and dried in a pentoxide groove to give 7-[2-(5-amino-1,2.
4-thiaresol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethquinimino)acetamide]-3-chloromethyl-3-cephem-4-carboxylic acid trifluoroacetate (sin isomer) (2.41
g) is obtained.

NMR (DMso-d6.E) = 139 (9
)1. s), t. 40 (6)1.

s), 3.47. 3.75'(2H.ΔBq.J
-18Hz), 4.55 (2H.s), 5.2CI
(LH.d.J=5Hz), 5.85 (11(,d
d.

J-5Hz. 8Hz), 9.48 <IH. d. J
=8Hz) Production Example 10 In the same manner as in Production Example 4-2), 7-[2-'(2-triphenylmethylaminethiazol-4-yl)-2-difluoromethoxyiminoacetamide]-3-chloromethyl -3-cephem-4-carboxylic acid henzhydryl ester (syn isomer) (4.1 g) in trifluoroacetic acid (123 mQ) and 7=sol (4'.1 mQ)
7-[2-(2-aminothiazole-4
-yl)-2-cyfluoromethoxyiminoacetamidoco-3-chloromethyl-3-cephem-4-carboxylic acid trifluoroacetate (syn isomer) (2.73 g) is obtained.

IR (Nujol) 'L770. 16
66, 1540 cm-1HMR (DMSO-
d6, δ): 3. F+3 and 3.83 (2H.

ABq. J=17Hz>, 4.60 (2H.s),
5.30' (LH.d.

J-5Hz), 5.90 (IH, dd, J=514
z. 8Hz), 7.13(1)1,s), 7.1
6 (LH.t.J=72Hz), 10.10 (L
H.

d, J = 8Hz), 10.60 (28, Broad S) Production Example 11 In the same manner as in Production Example 4-2), 7-tertiary butoxycarbonylamino-3-chloromethyl-3-cephem-4-
Carboxylic acid henzhydryl ester C (15 g) was combined with trifluoroacetic acid (3QmQ) and anisole (1
5mu) to obtain 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid trifluoroacetate (7 g).

IR (Sujoor)' 1790. 16
90. 1620 cm'NMR (DMSO-d6
．． δ): 3.70 (2H, m>, 4.60 <
2H.

s), 5.20 (2H, m), 6.75
(2H, Broad S) Production Example 12 1) 7-Amino-3-chloromethyl-3-cephem-4
-Carboxylic acid hydryl ester hydrochloride (2,
3g) and monotrimethylsilylacetamide (2,
2-(2-aminothiazol-4-yl)-2-acetoquiniminoacetyl chloride hydrochloride (syn isomer) (1,9
Add g) all at once at 5°C while stirring. Continue stirring at the same temperature for 15 hours. The reaction mixture was diluted with ethyl acetate (100 mQ).
and cold water (100ml). The organic layer is separated, washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was triturated with diisopropyl ether to give 7-[2
-(2-aminothiazol-4-yl)-2-acetoxiimi, noacetamidoco-3-chloromethyl-3-cephem-4-carboxylic acid henzhydryl ester (gin isomer) (2,49 g) is obtained.

NMR (oMso-d6.8) ” 2.16 (3
H1s), 3.68 (2H1ABq, J=18)+z
), 4.42 (2H,s), 5.26 (
IH, d.

J-5)+z>, 5.90 (LH, dd, J=5
Hz, 8Hz), 6.93(LH,s),
7.05 (IH,s>, 7.15-7.60 (
IOH, m).

9.86 (IH, d, J=8Hz) 2) 7-[2-(2-aminothiazol-4-yl)-
2-acetoxyiminoacetamidoco-3-chloromethyl-3-cephem-4-carboxylic acid henshydryl ester (syn isomer) (2,4 g) and anisole (2
, 4 mQ) in dichloromethane (9.6 mQ) at 5°C with stirring.
Add with . Stirring is continued for 2 hours at the same temperature. The solution was mixed with diisopropyl ether (100 mQ) and hexane (zoo
mQ) dropwise into the cold mixture. The powdered product was collected by filtration and washed with cold hexane to give 7-[2-(2-aminothiazol-4-yl)-2-acetoxyiminoacetamide]-3=chloromethyl-3-cephem-4. -Carboxylic acid trifluoroacetate (syn isomer) (1.8g,
, ) is obtained.

NMR (, DMSO-da, 8)' 212 (3H
1s):, 3.53 (2H97l-ABq,,Cl8Hz), 4.46 (2H,s
), 5.13 (LH, d.

J=5Hz>, , 5.73. (LH, dd, J:
5Hz, 8Hz>, 6.98(LH,s), 9
．． 75 (LH, d, J = 8 Hz> (Ku Senbutsu) 72-Example 1 7-[2-(5-amino-1,2,4-thiacyasol-3-yl)-2-methoxyiminoacetamide] -3
-Chloromethyl-3-cephem-4-carboxylic acid trifluoroacetate (syn isomer) (1,16g) 0
') Tetrahydro7 run (20ml) solution, 3
-hydroxy-8-methyl-8-azabicyclo[3,2
,, 1 co-octane (1.5 g) is added at o''c. After stirring for 2 hours at room temperature 1. The reaction mixture is diluted with S ethyl acid (1 som
i) Pour inside. The precipitate is collected by filtration and dried under reduced pressure. The solid is dissolved in water (5Q mQ ) and chromatographed using the nonionic adsorption resin 1 Diaion HP 20 J (40 mQ ), eluting with 5% aqueous isopropyl alcohol. The desired fractions were collected and lyophilized to give 7-[2-(5-amino-1,2,4-thiacyazol-3-yl)-2-methquiniminoacetamitoco-
3-(3-Hydroquine-8-methyl-8-asoniabicyclo[3°21]oct-8-yl)methyl-3-cephem-4-carboxylate (syn isomer) (0,21
g) is obtained.

mp: 140″'C (disassembly) IR (nujol)' 1775. 1670.
1605 cm'NMR (DMSO-d 8;
)' 1.50-2.70 (8H, m>, 2.8
86゛ (3H, s), 3.10-4.00 (8H, m),
3.90 (3H, s).

505' (LH, m), 5.65 (IH, dd, J
=5Hz, 8Hz).

8.10 (2H,s)', '9.50 (IH,d,
J=8Hz) '7-[2-(5
-amino-1,2,4-thiacyazol-3-yl)-
2-Methoxyiminoacetamide]-3-chloromethyl-3-cephem-4-carboxylic acid trifluoroacetate (synisomer) was reacted with the corresponding bicyclo compound as described in Examples 2 to 9 below. Obtain the compound.

Example 2 7-[2-(5-amino-1,2,4-thiacyazol-3-yl)-2-methquiniminoacetamitoco-3
-[9-Methyl-4-year-old xo-3-aza-9-asoniabicyclo[4,2,1]non-9-yl]methyl-3-
Cephem-4-carboxylate (syn isomer).

mp: 140°C (decomposition) IR (nujol): 1775. 1650.
1610 c+n”NMR (oMso-d6.S
)' 1.40-240 (4H1m>, 2.80-
4.30 (10H, m>, 3.00-3.12 (
3H, m>, 3.90 (3H, s), 5.10 (
IH, d, J=5Hz), 5.67 (LH.

=75=dd, J=5Hz, 8Hz), 7.20-7.
80 (LH,m>,' 8.r3(2H,s),
9.50 (IH, d, J=8Hz>Mass
: m/z 551 (M+) Example 3 7-[2-(b-amino-1,2',,!-thiacyazol-3-yl)-2-methquiniminoacetamitoco-3'-(3, 6-cyhydroxy-8-methyl-8-asoniabicyclo[3',2.1]oct-8-yl)methyl-3-cephem-4-carboxylate (syn isomer).

mp: 140°C (decomposition) IR'
(Nujol)' 1770. 1660. 1
6'lO'cm-1 ''NM'R (DMSO-d
'8 > : 1.50'-2,3'O(6H, m
>, 2.70-6°5.00' (10H, in), "3.03' (3H, s
), 3.90 (3H,s>.

5.10 (IH, d', J=5H2), 5.65
(IH, dd, J=5Hz.

8Hz>, 8.13 (2)1. s), 9.5
0' (LH, d, J=8Hz) Mass: m/z
554 (M”) Example 4 7-[2-(5-amino-1,2,4-thiacyazol-3-yl)-2-methoxyiminoacetamide]-3
-(3-carbamoyloxy-methyl-8-asoniabicyclo[3.2.1]oct-8-yl)methyl-3-
Cephem-4-carboxylate (syn isomer).

mp: 140°C (decomposition) IR (nujol): 1770, 17
00, 1660. 1610 cm 'NM
R(DMSOda=8>'i, 50-2.7
0 (8H1m), 2.90 (3H, s), 3.1
0-4.00 (5H, m), 3.90, (,
3H,s),.

4.75 <28. m), 5.05 (IH, d
, J-5Hz>, 5.67<LH,d, J=5Hz
, 8Hz>, 6.55 (2H1S), 8.1
0 (2H, s), 9.47 (LH, d, J=8
Hz) Mass: m/z 579 (M+-1) Example 5 7-[2-(5-amino-1,2,4-thiacyasol-3-yl)-2-methoxyiminoacetamide]-3
-(3-Hydroquinimino-8-methyl-8-azoniabicyclo[3,2,,1-hydroxy-8-yl)methyl-
3-cephem-4-carboxylate (syn isomer).

mp: 140℃ IR '1780. 1670.
1620 cm-'NMR (DMSO-ds, E)
:' 1, 30-2.70 (8H1m>, 2.
97.

3.10 (3H,s), 3.20-4.20 (
6H, m), 5.10 (LH, m>, 5.67
(1)1. dd, J=5Hz, 8Hz), 8.13
(2H,s), 9.50 (1)1. d, J=8H
z) Mass: m/z 551 (M”) Example 6 7-[2-(5-amino-1,2,4-thiacyazol-3-yl)-2-methoxyiminoacetamide]-3
-(3-Methoxy-8-methyl-8-azoniabicyclo[3,2,1]oct-8-yl)methyl-3-cephem-4-carboxylate (zine isomer).

mp: 165°C (decomposition) IR (Nujol) 1770. 1660.
1610 cm-'NMR (DMSO-d6-8)
' 1.50-2.70 (8H1m>, 3.00 (3
H,s), 3.20-4.20 (7H,m>,
3.23 (3H,s).

3.90 (3H, s), 5.10 (LH, d,
J=5Hz), 5.68(IH, dd, J=5Hz,
8Hz), 8.15 (2H,s), 9.5
0(1)1. d, J=8Hz> Example η 7-[2-(5-amino-1,,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]=
3-(8-Methyl-3-xo-8-azoniabicyclo[3,2,1-xo-8-yl)methyl-3-cephem-4-carboxylate (syn isomer).

mp; 140℃ (decomposition) IR. (Sujoor)' 1770.1
720,, 1660, 1610 crnNM
R (D20.δ): 2.0-2.9 (8H, m
), 3.33, 3.52 (2H.ABq, J=17
)(z), 3.35 (3H,s), 4.02.

4, 82 (2H, ABq.J=15Hz), 4
．． 10 (3H.s).

4, 27 (2) 1, m>, 5.37 (IH.d.
J=5Hz>, 5.90 (11, d.J=5Hz) Example 8 7, - [2-(5-amino-1,2.4-thiadiazol-3-yl)-2-methoxyiminoacetamide] -3-(8-methyl-8-azoniabicyclo[3.
2.1'1oct-8-yl)methyl-3-cephem-
4-Carpoxyle-1- (syn isomer).

mp°160°C (decomposition) IR (Nujol) '1770. 1660.
1605 cm-1 MMR (DMSO-da, l;
) ' 1-20-2.70 (10H1m>, '
2.85゜3.00 (3H,5)y3.10-4.2
0 <6H, m>, 3.90 (3H, s), 5.0
8 (LH, m>, 5.65 (LH,, dd, J=
5Hz.

8Hz>, 8.17 (2H,s), 9.50 (
LH, d, J=8Hz>Example 9? -[2-(,,5-amino-1,2,4-thiacyazol-3-yl)-2-methquiniminoacetamidoco-3-(3-methyl-3-asoniabicyclo[3,2,
2] Non-3-ylcomethyl-3-cephem-4-carboxylate (syn isomer).

mp: 140°C (decomposition) IR (Nujol)' 1780. 167
0. 1610 cm-'NMR (D20.S):
1l50-240 (8H9>, 322 (3H9s),
3.30-4.20' (IOH, m), 4.10
(3H,'s).

535° (IH, d, J-5)! z>,' 5.8
'5 (IH, d, J=5Hz') Example 10 7-[2-(5-amino-1,2,4-thiacyazol-3-yl)-2-methoxyiminoacetamide]-3
-Chloromethyl-3-cephem-4-carboxylic acid trifluoroacetate (syn isomer) (0.55g) of N
, 2 in N-dimethylbormamide (5,5 mA) solution.
-Methyl-2-azabicyclo[3,3,0]octane.
Hydrochloride (0', 485 g) and sodium 2-ethylhexanoate (1 g) are added under ice cooling. After stirring the mixture at the same temperature for 1 hour, ethyl acetate (55 mQ) was poured into the reaction mixture and the solvent was decanted. The oily residue is dissolved in water, adjusted to pH 2 with IN hydrochloric acid and the insoluble matter is filtered off.

The filtrate was treated with nonionic adsorption resin (1 diamond ion) IF-20.
, and eluted with 5-10% aqueous isopropyl alcohol. Both desired fractions were collected, distilled to remove isopropyl alcohol, and lyophilized to yield 7-[2-(5-amino-1,2,4-thiacyazol-3-yl)-2-methquiniminoacetamide. ] -” 3- (2-Methyl-2-asoniapinchlor[330-co-2-yl)methyl-3-cephem-4-carboxylate (syn isomer) ('6.2
1 g').

Engineering R (X-a-IL): 3300. 1770
．． 1660. 1610 cm-'NMR (D 0
．． 8) + 1.30-2.60 (10H, m
>, 2.90°3.01 (3H,s), 3
．． 43 (1)1. d, J=18Hz),' 3.3
0-3.63 (LH, m), 3.87 (1)1
．． d,'J=18Hz), 3.92(IH,d,J
=14Hz'), 3.93-4.27 (4H, m
>, 4. '65 (LH, d, J-14Hz>,'
5.33 (LH, d, J=5Hz>, 5.87(
1M, d, J=5Hz) Example 11 In the same manner as in Example 10, ? -[2-(5-amino-1
, 2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-chloromethyl-3-cephem-4-carboxylic acid trifluoroacetate (syn isomer) (0.55 g), 7 -Nichiru 7-Azabicyclo [
7-[2-(5-amino-1,2,4-thiadiazol-3-yl)=2-methoxyiminoacetamide] by reacting with 2,2,1]hebutane hydrochloride (0.49 g) -3'-(7-nithil-7-azoniabicyclo[2,
2,1']hept-7-yl)methyl-3-cephem-
4-carboxylate (syn isomer) (0,145g
).

IR: 3300. 1770.
1660. 1610°1525 cm-1 NMR' (D20.8) '1, 28 (3H1t
, J=8Hz), 1, 60-2.50 (8H1m
), 3.07-3.43 (2H, m), 3.42
('1)1. d.

J-18Hz), 3.90 (LH, d, J-18H
z), 3.84 (IH.

d, J44Hz>, 4.07 (2H, s), 4.
47 (IH, d.

J44Hz), 5.31 (LH, d, J-5Hz)
, 5.87 (LH.

d, J = 5 Hz) In the same manner as in Example 1, 7-[,2-(5-amino-1
, 2,4-thiacyazol-3-yl)-2-ethoxyiminoacetamide]-3-chloromethyl-3-cephem-4-carboxylic acid triflic lambda acetate (syn isomer) is reacted with the corresponding bicyclo compound. This gives the compounds described in Examples 12 to 13 below.

Example 12 7-[2-(5-amino-1,2,4-thiacyazol-3-yl)-2-ethoxyiminoacetamide]=3
-(3-Hydroxy-8-methyl-8-asoniabicyclo[3,2,1-chot-8-yl)methyl-3-cephem-4-carboxylate (syn isomer).

mp: 140℃ (decomposition) IR (nujol) ゛ 1770. 1660.
1610 cm-1 HMR (DMSO-ds, l;
) ' 1.25 (3H1t, door) 1z), 1.5
0-2.70 (8H,m>, 2.88 (3H,s
>, 3.10-4.00 (8H, m), 4.15
(2H, q, J=7Hz), 5.05 (IH, d.

J=5Hz), 5.65 (IH, dd, J=5Hz
, 8)1z), 8.15(2H1s>, 9.'
47 (LH, d', J = 8 Hz> Example 13 7-, [2-(5-amino-1,2,4-thiacyazol-3-yl)-2-ethoxyiminoacetamide]
-3-(1',3,3.6-tetramethyl-6-asoniapinchloro[3,2,1]oct-6-yl)methyl-
3-cephem-4-carboxylate (syn isomer).

mp:, 140°C (decomposition) IR (nujol) = 1770. 1650.
1600 cm-1HMR (DMso-d6.E
>' 070-2-30 (17H, m), t,
23 (3H, t, J near Hz), 3.00 (3H,
s), 3.10-4.00 (5H, m>, 4.13
(2H, q, J=7Hz>, 5.05 (LH, m
>.

5.63 (IH, dd, J=5Hz, 8Hz)
, 8.08 (2H,s).

9.40 (IH, d, J=8Hz) Mass: m/z 578 (M”) Example 14 5-Methyl-2-thia-5-azabicyclo[2°21]
In a solution of heptane (580,5 mg) in N,N-dimethylformamide (6,7 inu),
5-amino-1,2,4-thiadiazol-3-yl)
-2-Ethoxyiminoacetamidoco-3-chloromethyl-3-cephem-4-carboxylic acid (syn isomer)'
(670 mg) was added in two portions at 8° C. under stirring, and stirring was then continued at the same temperature for 2 hours. The reaction mixture was poured into a mixture of ethyl acetate (20 mQ) and cold water (20' mQ) and adjusted to pH 3.0 with saturated aqueous sodium bicarbonate solution.
Adjust to. The aqueous layer is separated and subjected to chromatography using a nonionic adsorption resin 1Diaion HP-''20 and eluted with a 15% aqueous isopropyl alcohol solution. Both desired fractions are collected and freeze-dried. 7-12
-'(5-amino-1,2,4-thiareazole-3-
yl)-2-ethoxyiminoacetamidoco-3-(5
-Methyl-2-thia-5-azoniabicyclo[2,2,
1] Hept-5-yl)methyl-3-cephem-4-carboxylate (syn isomer) (520 mg) is obtained.

IR: 1770. 1660.
1610. 1520 cm-INMR (C20, &
)' 1.35 (3H1t, J=7Hz>, 3.
24 (3H1sn, 4.36 <28.q, J
=7Hz), 5.35 <IH, d.

J-5Hz), 5.87 (LH, d, J:5Hz>
Example 15 In the same manner as in Example 14, 7-C2-C2-form, amidothiazol-4-yl)-2-ethoxyiminoacetamide]-3-chloromethyl-3-cephem-4-carboxylic acid isomer) (948 mg) to 5-methyl-
2-thia-5-azabicyclo[221 cohebutane (77
7-[2-(2-formamidothiazol-4-yl)-2-ethoxyiminoacetamide]-3-(5-methyl-2-thea-5-azoniabicyclo[2,2,1 ]hept-5-yl)methyl-3
-cephem-4-carboxylate (syn isomer) (5
17 mg).

9l-IR (nuji→-ru)' 1770. 1660.
1610. 1525 cm-1 MMR (D 0-
NaHCO3,8) ' 1.30 (3H1t-J=
7Hz>.

3.21 (3H, s), 4.25 (2H,
q, J=7Hz>, 5.32 (LH, d, J=5H
z), 5.82 (LH, d, J=5Hz>, 6.
95(LH,s) Example 16 7-[2-(2-formamidothiazol-4-yl)
-2-Ethoxyiminoacetamidoco-3-(5-methyl-2-thia-5-azoniabicyclo[2,2,11hept-5-yl)methyl-3-cephem-4-carboxylate (syn isomer) (0 , 5g) of methanol (5g)
A) Add concentrated hydrochloric acid (0.37 mQ) to the middle suspension while stirring. Stirring is continued for 2 hours at 30°C. The reaction mixture is poured into a mixture of ethyl acetate (20 mQ) and cold water (20 mA) and then adjusted to pH 3.0 with saturated aqueous sodium bicarbonate solution. The aqueous layer is separated and subjected to chromatography using a nonionic adsorption resin "Diaion HP-20," and eluted with a 15% isopropyl alcohol aqueous solution. Both desired fractions are collected, freeze-dried, and
-[2,=(2-aminothiazol-4-yl)-2-
Ethoxyiminoacetamidoco-3-(5-methyl-2
-thea-5-azoniabicyclo[2,21]hept-5
-yl)methyl-3-cephem-4-carboxylate (syn isomer) (370 mg) is obtained.

IR (Nujol)' 1770. 1660.
1610. 1525 cm-'NMR (DzO-
NaHCO3, δ) ' 1.30 (3H, t, J=
7Hz>.

3.21 (3H, s), 4.25 (2M,
q, J = 7) 1z), 5.32 (1M, d, J-5
)+z), 5.82 (IH, d, J=5Hz),
6.95 (1B, s) Example 17 7-[2-(2-formamidothiazol-4-yl)
-2-ethoxyiminoacetamide]-3-chloromethyl-3-cephem-4-carvone # (syn isomer) (0
71g) of N,N-dimethylbormamide (7mQ), 7-nityl-7-azabicyclo[2,2,1:l
Heptane (0,57'g) in tetrahydrofuran (
Add the 1omQ) solution under water cooling. The mixture is stirred at the same temperature for 1 hour. Ethyl acetate (20 mQ) is poured into the reaction mixture and the solvent is decanted. Dissolve the oily residue in water,
The pH was adjusted to 2 with IN hydrochloric acid, and insoluble matter was filtered off. The filtrate is chromatographed using a 1Diaion HP-20 and eluted with 5-10% aqueous isopropyl alcohol. Both desired fractions were collected, distilled to remove isopropyl alcohol, and lyophilized to give 7-[2-(2-formamidothiazol-4-yl)-2-ethoxyiminoacetamidoco-3-(7-nityl- 7-Asoniabicyclo[2,2,11hept-7-yl)methyl-3-
Cephem-4-carboxylate (syn isomer) (0,
29g) is obtained.

NMR (D20.f; ) t, 34 (3H1t,
J=8Hz), 1.60-2.58(8H, m>, 3
．． 10-3.47 (2H, m), 3.46 (LH
,d.

J=18Hz＞,' 3.93 (IH, d, J=18
Hz>, 4.01 (LH.

d, J-14Hz>, 4. '05-4.23 (2H
, m), 4.72 (1) 1°d, J=14Hz>,
5.32 (IH, d, J=5Hz), 5.90 (
IH.

d, J=5Hz), 7.50 (LH,s), 8.
55 (IH,s) Inuho Koji 7-[2-1-formamidothiazol-4-yl)-
2-ethoxyiminoacetamide] = 3-(7-nityl-7-asoniabicyclo[221]hept-7-yl)
To a solution of methyl-3-cephem-4-carboxylate (syn isomer) (0.25 g) in methanol (10 mQ), add concentrated hydrochloric acid (-0.13 mQ) under water cooling. The mixture solution is stirred at room temperature for 3 hours. The reaction mixture is adjusted to pH 4 with saturated aqueous sodium bicarbonate solution and distilled to recover methanol.The residue is adjusted to pH 3 with IN hydrochloric acid.
Chromatography using a Diaion HP-20 was carried out and eluted with 5% aqueous isopropyl alcohol. The desired fractions were collected, distilled to remove the isopropyl alcohol, and lyophilized to give 7-[ 2-(2-
aminothiazol-4-yl)-2-ethoxyiminoacetamidoco-3-(7-nityl-7-asoniabicyclo[2,2,1]hept-7-yl)methyl-3-cephem-4-carboxylate (Syn isomer) (,0,
18g).

IR (nu9-le)' 3250. 1770.
1670. 1610 cm-'NMR (D20-8
) ' 1.27 (3H9t, J=8Hz >, 1
31 (3H, t, J=8Hz>, 1.63-2.53
(8H, m), 3.07-3.42 (2H, m),
3.43 (1)1. d, J=18Hz), 3
．． 84 (IH, d, J=14) (z), 3.90
(IH, d, J=18Hz>.

4.02-4.18 (28, m), 4.27 (
2H, q, J = 8Hz).

4.69 (LH, d, J=8Hz), 5.33
(1)1. d, J=5Hz).

5.86 (IH,'d,J:5)1z),,6.97
(1B, s) Example 19 In the same manner as in Example 10, 7-[2-(2-formamidothiazol-4-yl)-2-ethoxyiminoacetamide]-3-ri-tetramethyl-3-cephemu-4-carvone acid (syn isomer) (0.71 g) to 2-methyl-2
-Azabicyclo[3,s,0]octane hydrochloride (
0,728 g) to give 7-[2-(2-formamidothiazol-4-yl)-2-ethoxyiminoacetamide]-3-(2-methyl-2-azoniabicyclo[3,3,0]oct -2-ylmethyl-3-cephem-4-carboxylate (synisomer) (0.3g
).

Further, in the same manner as in Example 18, 7 obtained above
-[,2,-(,2-formamidothiazol-4-yl)-2-ethoxyiminoacetamide]-,3-(2
-Methyl-2-azoniabicyclo [330 years old Couteau 2
-yl) methyl-3-cephem-4-carboxylate (syn isomer) (0.3 g) in concentrated hydrochloric acid C0.15 mQ
) to form 7-[2-(2-aminothiazole-
4-yl)-2-ethoxyiminoacetamide]-,3
-(2-Methyl-2-azoniabicyclo[3,3,O-connect-2-yl)methyl-3-cephem-4-carboxylate (syn isomer) (o, t6 g) is obtained.

IR (Nujol)' 3300. 1775.
1670. 1610 cm-1HMR (D20.
8) River 34 (3)1. t, J=8Hz), 1.47
−2.60 (IOH, m>, 2.91.3.02 (
Total 3H1s), 3.23-3.63 (
2H,m>, 3.73-4.20 (2H,m>.

4.29 (2H, q, J=8Hz), 4.70
(LH, m), 5.35 (LH, d, J-5Hz)
, 5.86 (IH, d, J=5Hz>, 6.
99(1)1. s) Example 20 The following compound is obtained in the same manner as in Example 1.

7-[2-(5-amino-1,2,4-thiadiazol-3-yll-2-(1-carboxy-1-methylethoxyimino)acetamide]-3-(3-hydroxy-
8-Methyl-8-azoniabicyclo[3,2,1-cyclo-8-yl)methyl-3-hyphem-4-carboxylate (synisomer).

mp: 145°C (decomposition) IR: 1780. 1670.
1610 cm-'NMR (DMSO-9, f;
): 1.50 (6H, s), 1.60-2.7
0 (8H, m), 2.90 (3H, s), 3.0
0-5. oo (81(,'m).

5.10 (1)1. d, J=5Hz), 5.72
(IH, dd, J=5Hz.

8Hz>, 8.18 (2H,s), 9.43'(
LH, 9, J = 8 Hz) (hereinafter referred to as "F Kuraji") (0'O- Example 21 In the same manner as in Example 14, 7-[2-(2-formamidothiazol-4-yl)-2' ll-methyl-1-(
Tert-butoxycarbonyl)ethoxyimino)acetamide]-3-chloromethyl-3-cephem-4-carboxylic acid (syn isomer) (1,15 g) was converted into 5-methyl-2-
-thia-5-azabicyclo[2,2,1]hebutane (7
74mg) to give 7-[2-(2-formamidothiazol-4-yl)-2-(1-methyl-1-
(Tertiary butoxycarbonylmide].-37[5-methyl-2-thia-5-azoniabicyclo[2,2,1]hept-5-yl)methyl-3
-cephem-4-carboxinerate (syn isomer) (
590 mg).

IR (Nujol) + 1770. 1720.
1670. 1610°1540 cm-1 NMR (DMSO-d6.l; )' 148
(9H,s),, t,58 (6H1s),
3. '24 (3H,s), 5.35 (LH,d
, J=5Hz).

5. 87 (LH, d, J=5Hz>, 7.50
(IH,s), 8.52(IH,s> Example 22 7-42.-(2-formamidothiazol-4-yl)-2-+ 1-methyl-1-(tert-butoxycarbonyl)ethoxy imino)acetamido]-3-(5-methyl-2-thia-5-azoniabicyclo[2,2,1]
Hept-5-yl) methyl-3-cephem-4-carboxylate (syn isomer) (,570 mg) was added to a suspension of concentrated hydrochloric acid (025 mQ) in methanol (5,7 mQ).
Add under stirring. Continue stirring at 30°C for 2 hours. The reaction mixture was poured into leisoprobil ether, the resulting precipitate was collected by filtration, and 7-[2-(2-aminothiazole-
4-yl)-2-(1-methyl-1-(tert-butoxycarbonyl)ethquinimino)acetamide]-3-(
5-Methyl-2-thia-5-azoniabicyclo[2,2
,1]hep-1-5-yl)methyl-3-cephem-4
-Carboxylate dihydrochloride (syn isomer) (46
7 mg).

IR (Nujol): 1780. 1710.
1670. 1620 cm-INMR (D20-
NaHCO3+[1M5O-d6. f; ) = L
48 (9H, s).

1.60 (6H, s), 3.28 (3H, s),
5.39 (18, d.

, C3Hz>, 6.91 (LH, d, J25H
z>, 7.06 (IH,s)103-Example 23 7-[2-(2-aminothiazol-4-yl)-2-
(1-methyl-1-(tert-butoxycarbonyl)ethoxyimino)acetamitoco-3-(5-methyl-2-
Thia-5-azoniabicyclo[2,2,1]hept-5
-yl) methyl-3-hyphem-4-carboxylate dihydrochloride (syn isomer) (447 mg) in dichloromethane (1.8 mQ) and anisole (0.5 m). ) was added dropwise at 5°C. Stirring was continued for 3 hours at 15°C. The reaction mixture was poured into a mixture of ethyl acetate (20 mQ) and cold water (20 mQ) and then brought to pH 5.0 with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was separated and subjected to chromatography using 1 Diamond Ion HP-20J.
Elute with 5% isopropyl alcohol aqueous solution. Both desired fractions were collected and lyophilized to yield 7-[2! , 7 (2-
aminothiazol-4-yl)-2-7(1-carboxy-1-methylethoxyimino)acetamide]-3-
(5-methyl-2-thia-5-azoniabicyclo[2,
2,1]hept-5-yl)methyl-3-cephem-4
-carboxylate (syn isomer) (250 mg) is obtained.

IR (Nujol)' 1760. 1640.
1610 cm-'NMR (DO,f;')
: 1.51 (6H,s), 3.25 (3H,s
).

5.35 (LH, d,'J=5+)Iz), 5.85
(IH, d, J-5Hz>.

6.97 (LH,s) Example 24 In the same manner as in Example 10, 7-['2- (5-amino-1,2,4-thiacyazol-3-yl)-2-(1
-Methyl-1-(tert-butoxycarbonyl)ethoxyimino)acetamide]-3-(7-nityl-7-asoniabicyclo[2,2,1]hept-7-yl)methyl-3-cephem-4- Carboxylate (syn isomer)
get.

? -[2=, (5-amino-1,2,4-thiacyazol-3-yl)"-2-fl-methyl-1-(tert-butoxycarbonyl)ethquinimino)acetamide]-3-(7-nityl 7-Asoniapinkuro [2,2
,1]hept-7-yl)methyl-3-cephem-4-
To a suspension of carboxylate (syn isomer) (0.2 g) in dichloromethane is added anisole (o2mB, then trifluoroacetic acid (06mQ) under water cooling. The mixture is stirred at room temperature for 4 hours. The reaction mixture is diisopropyl Pour into ether (2omQ), collect the resulting powder by filtration and dissolve in saturated aqueous sodium bicarbonate solution.Wash this aqueous solution with L-ethyl acetate.The aqueous layer is adjusted to pH 3 with IN hydrochloric acid.
The sample was subjected to chromatography using 1 Diamond Ion HP-20J and eluted with a 5-10% aqueous isopropyl alcohol solution. Both desired fractions are collected, distilled to recover isopropyl alcohol, and lyophilized to give 7-
['2-(5-amino-1,2,,4-thiacyazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamide]-3-(7-nityl-7-
Azoniapinchloro[2,2,11hept-7-yl)methyl-3-cephem-4-carboxylate
1 (1,7-mer)' (o, 12.g) is obtained.

IR"<i shawl) 3300.' 177
f), '1660. 1610 c'm"NMR (D
O, δ)'1.28 (31(,t, J=8)1z>,
157 (6H.

S) 73-2.53' (8H, m>, 3.07-
3.43 (2H, m), '3.4'3 (IH, d,
'J=18Hz'), 3. (Jl”(IH, d', J
= 18Hz).

4.0 (1)1. d, J=8Hz), 4.03-4
．． 2'7 (2H, m>.

4.72'<LH, d, J-8Hz), 5.33 (
IH,d,,T=5Hz).

5.88'(IH, d, J=5Hz>Example 25 The following compound is obtained in the same manner as in Example 1.

? -[2-(2-aminothiazol-4-yl)-2-
cyfluoromethoxyiminoacetamide]-3-C3-
Hydroxy-8-methyl-8-asoniabicyclo[3,
2,1]oct-8-yl)methyl-3-cephem-4
- Carboxylate (syn isomer).

mp: 140°C (decomposition) 1R (nucle): 1770. 1670.
1610 cm NMR (DB, 5o-d6.S)
: 150-2.75 (8H, m>, 2.90 (3
H,s), 3.1074.50 (8H,m>, 5
．． 15 (IH, m>.

5.67 ('IH, dd, J=5Hz, 8Hz),
6.98 (LH,s).

7.1.0 (LH, t, J=72Hz>, 7.37
(2H, s), 9.90 (4H, d, J=8)1
z') Mass: m/z 57'3 (M") Example 26 1) Tetrahydrofuran (4HmQ) solution of 7-hengamido-3-chloromethyl-3-cephem-4-katsubonic acid (2.0 g) A solution of 7-nity-7-azabinclo[2,2,1]hebutane (3.57 g) in tetrahydrofura:' (20 mQ) was added to the solution under water cooling.

After stirring at room temperature for 2 hours, ethyl acetate was added to the reaction mixture,
Then diisopropyl ether is added.

The precipitate is filtered off, washed with diisopropyl ether and dried in a pentoxide groove. This powder is dissolved in water, the solution is adjusted to pH 3 with IN hydrochloric acid, and the insoluble matter is filtered off. The filtrate was subjected to chromatography using a nonionic adsorbent willow fat 1 Diaion HP-20 (trademark, manufactured by Mitsubishi Chemical Industries, Ltd.) and eluted with a 10% aqueous isopropyl alcohol solution. The desired fractions were collected and distilled to remove isopropyl alcohol, and the resulting aqueous solution was lyophilized to give 7-hensamido-3-(7-nityl-7-asoniabicyclo[221
Cohept-7-yl)methyl-3-cephem-4-carboxylate (035 g) is obtained.

NMR, (D20.l; ) 1-28 (3H1j
, J-8Hz>, 1.03-2.60 (8H, m>,
3.31 (2H,'q, J=8Hz>, 3.
40 (1)1. d.

J-18Hz), 3.89 (, IH, d, J=18
Hz), 4.11 (2H.

s), 4.06 (LH, d, J=14Hz>,
4.72 (LH, d.

J=14Hz), 5. ．． 34 (LH, d, J=5
Hz>, 5.92 (LH.

d, J=5Hz), 7.43-7.97 (5H
, m) 2) 7-Penceamido 3-(7-Nityru 7-
Asoniabicyclo[2,2,1]hept-7-yl)methyl-3-cephem-4-carboxylate (0,3g
) in dichloromethane (5 mQ), N, N-
Dimethylaniline (0.99 g) and then trimethylchlorosilane (0; 74 g) are added under water cooling. 5°
After stirring for 1 hour at -10°C, the mixture is cooled to -30°C. To this is added pentachloride (0.28 g) and the mixture is stirred at -20°C to -30°C for 1 hour.

Inbutanol (0.5 g) and 1°3 were added to the reaction mixture.
-propanediol (0,52 g) in dichloromethane (
3, smi+) Add the medium temperature mixture at -30°C. The precipitate was collected by filtration and washed sequentially with dichloromethane, acetone and diisopropyl ether to give 7-amino-3-(7-
Nichiru 7-asoniabicyclo [22゜1 cohebuto-7
-yl)methyl-3-cephem-4-carboxylate hydrochloride is obtained.

This product was mixed with water (3 mQ) and tetrahydrofuran (
Dissolve in 1 mQ). This solution is adjusted to pH 5 with a saturated aqueous solution of hydrogen carbonate. In the solution, 2-(2-ami,nothiazol-4-yl)-2-7doroquinimide, noacetic acid succinimide hydrochloride (syn isomer), (0,
22g,) was adjusted to pH with a saturated aqueous solution of sodium bicarbonate.
Add at room temperature while keeping the temperature at 5. After stirring overnight at the same temperature, the reaction mixture was adjusted to pH 3 with IN hydrochloric acid, and insoluble matter was filtered off. The filtrate was chromatographed using 1Diaion HP-20 and eluted with 5-10% isopropyl alcohol aqueous solution. Both desired fractions are collected, distilled to recover isopropyl alcohol, freeze-dried, and...
-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamyl]-3-(7-nityl-7
-Asonia Bisikdai”[2,”’2. , 1-cohept-7-yl) methoxy-3-cephemu-4-carboxylate (syn isomer) (75 mg).

IR (Sujoor): 1770. 1650.
1610 cmNMR (D20.E) 1.2
1 (3)1. t, J=8Hz), 1.60-2.47
(8M, m), 3.07-3.37 (2H, m)
, 3.40 (IH, cl,, J=18Hz),
3.90 (LH, d, J=18)1z), 3.
97 (LH.

d, J=8Hz), 4.02-4.25 (2H,
m>, 4.53-4.83 (LH, m>, 5.34
(LH, d, J=5Hz), 5.90 (IH,
d.

J=5Hz,),,',7',O(LH,s),
7.61 (IH,s) Example 27 0H 1>7-amino-3-chloromethyl-3,-cephem-
3-Hydroxy-8,-methyl-8-azabicyclo[
3,2,1]octane (14,49 g) is added at 0°C. After stirring for 2 hours at room temperature, the reaction mixture is poured into ethyl acetate. The precipitate is filtered and dried under reduced pressure. The solid was dissolved in water and subjected to chromatography using a nonionic adsorption resin 1 Diaion HP-20, eluting with 5% aqueous isopropyl alcohol. The desired fractions were collected and lyophilized. 7-ami, no 3-(3-hydroxy-8
-Methyl-8-asoniapinchloro[3,2,1]oct-8-yl)methyl-3-cephem-4-carboxylate (7,50'g) is obtained.

IR' (Sno Seal): 1775. 16
60 cm-1HMR (D'MSO-d6.δ):
1.50-2.70 (8H, m), 2.83 (3
H, s), 3.30=4.80 (10)1. m),
4.80-5.20 (2H, m) Mass: m/z 354 (M”) 2) Tetrahuman O7 run (27mQ) and water (6Hm1F)
2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetic acid succinimide hydrochloride (syn isomer) (34 tg) and 7-amino-3-
(3-hydroxy-8-methyl-8-asoniabicyclo[:3.2.1]-1--8-yl)methyl-3-cephem-4-carboxylate (3,Og) Add with . The reaction solution was adjusted to pH 5.0 and stirred overnight at room temperature. After adjusting the reaction mixture to pH 20, it is washed with ethyl acetate and the precipitate is filtered off. The filtrate was diluted with water and subjected to chromatography using 1Diaion HP-20, eluting with 5% aqueous isozolobilalfur.

Both desired fractions were collected and lyophilized to yield 7-C2-C2-aminothiazol-4-yl)-2-hydroxyiminoacetamide]-3-(3-hydroxy-8-methyl-8
-asoniabicyclo[3,2,11oct-8-yl]
Mebul-3-cephemu-4-carboxylene-1.(syn isomer) (237.4 mg) is obtained.

mp: 140"C (disassembly) IR (nujol) 1770. 1660.
1605 cm-1HMR(-DMSO-d6.δ)
River 50-2.70 (8H, m>, 2.87 (3H,
s), 3.20-4.90 (8H, m>, 5.1
0 (IH, m>.

5.68 (LH, dd, J=5Hz, 8Hz),
6.63 (LH,s).

7.07 (2H, s), 9.37 (IH, d, J
=8Hz), 11.43-11' 5- (LH,s) Mass: m/z 522 (M'') Example 28 0CH3 In the same manner as Example 27, 7-amino-3-(3-hydroxy- 8-Methyl-8-asoniabi, cyclo[3,2
,1]oct-8-yl)methyl-3-cephem-4-
Carboxylate (1,5 g) and 1-[2-(2--
aminothiazol-4-yl)-2-methoxyiminoacetyl]hensotriazole-3-oxide (N,
7-'['2-(2
-aminothiazol-4-yl)-2-methquiniminoacetamidoco-3-(3-hydroquine-8-methyl-
8-Asonia Pinguero [3,'2.1]Oc1--8-
Nobu-ru 3-cephem-4-carboxylate (syn isomer) (67, 1 mg) is obtained.

mp・140℃ IR (Nujol): 1770. 1660.
'1620 cm-'NMR (DMSO-dS)
, : 1.70-2.7'O(8H,m>, 2.88
6'' (3H, s), 3 20=4. '80
(8H, +rI), 3.90 (3H, s).

5.30 (IH, d, J=5Hz), 5.85 (
LH, dd, J = 5Hz.

8Hz), 6.73(LH,s), -7,28(2H
.
1,] in a solution of heptane (620 mg) in N,N-dimethylformamide (Iomq), ? Stir -42-(2-aminothiazol-4-yl)-2-acetoxyiminoacetamide]-3-chloromethyl-3-cephem-4-carboxylic acid trifluoroacetate (syn isomer) (Ig) Add in 2 portions at 10°C and stir for 2 times at the same temperature.
Lasts for a period of time (-). The reaction mixture was poured into physobrobyl ether to form a precipitate, which was then poured into water (lom
Q) and methanol (2omQ).

Ammonium chloride (239 mg) is added to the solution, and then a 10% aqueous potassium subacid solution is added dropwise at room temperature with stirring until the reaction mixture reaches p)lB,0. After adding 10% potassium carbonate and keeping the pH at 8.0, stirring was continued for 15 hours at the same temperature. Add IN hydrochloric acid to the reaction mixture to adjust the pH.
After adjusting to 3.0, methanol is distilled off under reduced pressure. This solution was subjected to chromatography using R-Diaion HP-20 and eluted with a 15% aqueous isopropyl alcohol solution. Freeze-dry both parts containing the target compound,
7-[2-(2-aminothiazol-4-yl)-2-
Hydroxyiminoacetamide]-3-(5-methyl-
2-year-old xar-5-azoniavinclo[2,2,1]hept-5-yl)methyl-3-cephem-4-carboxylate (syn isomer) (120 mg) is obtained.

IR (X-a-R): 1770. 1650.
1600. 1520 cm-'NMR (DMSO
-d6. δ＞: 3.10 (3Ls), 5.10
(1) 1°d, J-5Hz), 5.68 (LH,
dd, J=5Hz, 8Hz>, 6.63(LH,s
), 7.08 <28. broad s), 9
．． 37 (LH.

d, J = 8 Hz) Example 30 5-Methyl-2-year-old xer-5-azabicyclo[221 In a solution of cohebutane (500 mg) in N,N-dimethylpolamide (8 Hz), 7-[2-(5-amino -1, 2,
4-thiacyazol-3-yl)-2-methoxyiminoacetamide]-3-chloro-comethyl-3-cephem-
4-Carboxylic acid trifluoroacetate (syn isomer)
(805 mg) was added in two portions at 8°C with stirring.
Stirring is then continued for 2 hours at the same temperature. The reaction mixture is poured into a diisopropyl needle to generate a precipitate, and the precipitate is then filtered to obtain a powder, which is added to water and adjusted to pH 3.0 with a saturated aqueous solution of sodium bicarbonate. This solution was subjected to chromatography using "Diaion HF'-20" and 15% isopropyl alcohol water 71%
# Elute with solution, freeze-dry both parts containing the target compound,
7-[2-(5-Amino-1,2,4-thiaresol-3-yl)-2-methoxyiminoacetamide':l
-3-(5-Methyl-2-year-old xar-5-azoniavinclo[2,2,1]hept-5-yl)methyl-3-cephem-4-carboxylate (syn isomer) (2,6
7 mg).

IR (x9-ru): 1760. 1650.
1600. 1510 cm-INMR (DMSO-
d6. δ) : 3.13 <3H,s),
3.93 <3H.

s>, 5.09 (LH, d, J=5Hz),
5.68 (LH, dd.

J=5Hz, 8)1z), 8.15 (2H
, broad s), 9.53<LH, d, J=8H
2) Example 31 5-Methyl-2-oxa-5-azabicyclo[221 7-[2-(5-amino-
1,2,4-thiaresol-3-yl)-2-(1-
Carboxy-1-methylethoxyimino)acetamido-3-chloromethyl-3-cephem-4-carboxylic acid trifluoroacetate (syn isomer) (1.1 g) was prepared in two portions at 8°C with stirring. Add and continue stirring at the same temperature for 2 hours. Pour the reaction mixture into diisopropyl ether,
The resulting precipitate is collected by filtration, the powder obtained is dissolved in water, and then C
Adjust p) to 13.0 with a saturated aqueous solution of sodium hydrogen carbonate. This solution was subjected to chromatography using 1Diaion HP-20', eluted with 15% isopropyl alcohol aqueous solution, and both fractions containing the target compound were lyophilized. -1,2,4-thiareazol-3-yl)-2-
methylethoxyimino)acetamide]-3-(5-methyl-2-oxa-5-asoniabicyclo[2,2,1
]hept-5-yl)methyl-3-cephem-4-carboxylate (syn isomer) (250 mg) is obtained.

IR (Nujol): 1765. 1660.
1610. 1510 cm-INMR (DMSO
-d6,8) 148 (6H1s), 3.13
(3H1s), 5.13 (LH, d, J=5H
z>, 5.70 (i)1. dd.

-1'23- J=5H2,8)IZ), 8.16 (2H, broad s), 9.47 (LH, d, J=8Hz) Patent applicant Fujisawa Pharmaceutical Co., Ltd.

Claims (1)

[Claims] 1) Formula: ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is an amino group or a protected amino group; R^2 is hydrogen, a hydroxy protecting group, or an appropriate substitution a lower alkyl group which may have a group; R^3 is a lower alkyl group; R^4 is hydrogen, a lower alkyl group or a hydroxy group; n is an integer from 1 to 3; A has a suitable substituent; optionally interrupted by a heteroatom; Y means CH or N) and pharmaceutically acceptable salts thereof. 2) Formula (1): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 is an amino group or a protected amino group; R^2 is hydrogen, a hydroxy protecting group, or a suitable substituent a lower alkyl group that may be substituted; Y is CH or N; Q means a suitable leaving group) or a salt thereof, represented by the formula; , R^3 is a lower alkyl group; R^4 is hydrogen, a lower alkyl group or a hydroxy group; n is an integer from 1 to 3; A may have a suitable substituent and is optionally interrupted by a heteroatom; (meaning a lower alkylene group) or a salt thereof; or, formula (2); ▲There are numerical formulas, chemical formulas, tables, etc.▼ and A have the same meanings as above), or its reactive derivative at the amino group, or its salt;
(3) Reacting with a compound represented by the formula (in which Y, R^1 and R^2 each have the same meaning as before) or a reactive derivative thereof or a salt thereof at the carboxy group; or (3) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, Y, R^2, R^3, R^4, n and A each have the same meaning as before, and R^1_a is a protected amino When a compound represented by (meaning a group) or a salt thereof is subjected to an amino-protecting group elimination reaction, the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, Y, R^2, R^3 , R^4, n and A each have the same meaning as before); or, formula (4): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, Y, R ^1, R^3, R^4, n and A each have the same meaning as before, and R^2_a means a protected carboxy (lower) alkyl group) or its salt is carboxy-protected. For the elimination reaction of groups, there are formulas: ▲Mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, Y, R^1, R^3, R^4, n and A each have the same meaning as before. and R^2_b means a carboxy (lower) alkyl group) or a salt thereof; and (5
) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, Y, R^1, R^3, R^4, n and A each have the same meaning as before, and R^2_c is a hydroxy protecting group ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, Y, R^1, R^2, R^3, R^4, n and A each have the same meanings as before) Formulas characterized by obtaining compounds or salts thereof: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R ^1, R^2, R^3, R^4, n, A and Y each have the same meanings as above) or a method for producing a pharmaceutically acceptable salt thereof. 3) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^3 is a lower alkyl group; R^4 is hydrogen, lower alkyl group, or hydroxy group; R^7 is an amino group or protected amino a group; n is an integer from 1 to 3; A means a lower alkylene group optionally interrupted by a heteroatom, which may have a suitable substituent; or a group thereof.