JPS60231682A - Novel cephalosporin antimicrobial compound and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [R<1> is amino, or protected amino; R<2> is CH2, O, S, or group shown by the formula II (R<5> is lower alkyl which may be substituted, or H); R<3> is H, halogen, lower alkylthio, lower alkoxy, etc.; R<4> is carboxyl, or protected carboxyl; X is H, or O] and its salt. EXAMPLE:7-[2-( 2-Aminothiazol-4-yl )-2-(4-ethyl-2,3-diketopiperazinylcarboxylmethoxyimino )acetamido]-3-( 1-methyltetrazol-5-ylthiomethyl )-3-cephem-4-carboxylic acid. USE:A cephalosporin antimicrobial agent. PREPARATION:A compound shown by the formula III is reacted with a compound shown by the formula IV in an organic solvent under cooling - under heating to give a compound shown by the formula I. When the compound shown by the formula IV is used in the form of a free acid or a salt, the reaction is preferably carried out in the presence of a condensation agent such as N,N'-dicyclohexylcarbodiimide, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to pharmaceutically acceptable salts thereof. More specifically, the present invention relates to a novel cephem compound having antibacterial activity, a medically acceptable base thereof, and a method for producing the same.
．． SOe. , i 8 4 volumes. J3400 pages (19
It was named in reference to "cepham" in 1962) and refers to the basic cepham structure with one double bond.

BACKGROUND ART As cephalosporin compounds closely related to the compound of the present invention, the compounds described in, for example, JP-A-55-19267 and JP-A-58-210093 are known. The compound of the present invention is
The side chain at the ldB position or the 7th position is different from the above.

Summary of the Invention The compound according to the present invention has the following formula (I) [wherein R1 is an amino group or a protected amino or hydrogen atom]; R3 is a water bulk atom, -logen atom, lower alkylthio group, lower alkyl Musi base.

Vinyl group or group -Cm(2Y (wherein, Y is a hydrogen atom.

R' is a carboxyl group) or a protected carboxyl group; X represents R2 or 0, respectively] and pharmaceutically acceptable salts thereof. Examples are common non-toxic salts, such as alkali metal salts (e.g. sodium salts, potassium salts, etc.) and alkaline earth metal salts (e.g. calcium salts, magnesium salts, etc.). Gold maple salt, ammonium salt, salt with organic base (file is trimethylamine salt,
salts with organic acids (e.g. acetate, trifluoroacetate, maleate, tartrate, methanesulfone) acid salt, benzene sulfonate, formate.

toluenesulfonate, etc.), salts with inorganic acids (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.) or salts with amino acids (e.g. arginine salt).

aspartate, glutamate, etc.).

In the above and below descriptions, suitable examples included in the various definitions will be explained in detail as follows.

The term "lower" shall mean 1 to 6 carbon atoms unless otherwise specified. A "protected amino group" may include acylamino or at least one suitable substituent. Good examples include amino groups substituted with conventional protecting groups such as alkyl (eg, benzyl, trityl, etc.).

Suitable examples of the acyl moiety in "acylamino" include aliphatic acyl groups and acyl groups containing aromatic or heterocycles, more specifically, lower alkanoyl (
For example, formyl and acetyl.

propionyl, butyryl, imbutyryl, valeryl, invaleryl, oxalyl, succinyl, pivaloyl, etc.); lower alkoxycarbonyl (e.g. evamethoxycarbonyl, ethoxycarbonyl).

Propoxycarbonyl, 1-cyclopropylethoxycarbonyl, impropoxycarbonyl, phthoxycarbonyl, tert-phthoxycarbonyl.

lower alkanesulfonyl (eg mesyl, ethanesulfonyl, furo/nansulfonyl);

InproΔnesulfonyl, butanesulfonyl); Ryolanesulfonyl C examples, benzenesulfonyl, tosyl, etc.); Aroyl (e.g. benzoyl, toluoyl,
(xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc.); Al (lower) furucyl (II, t-phenylacetyl, phenylpropionyl, etc.); Al (lower) dicarbonyl in alkyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.) Furthermore, such acyl moieties include halogen (m
l.

It may contain at least one suitable substituent group such as bromine, fluorine and iodine.

Preferred examples of the acylamino group defined above include lower alkanoylamino, and the most preferred group includes formamide.

"Protected carboxyl group" includes esterified carboxyl, etc. Suitable examples of the ester moiety of such esterified carboxyl group include allyl ester; lower alkyl ester (e.g. evamethyl ester, ethyl ester) .

propyl ester, inpropyl ester, phthyl ester, isobutyl ester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.)
;Lower alkanoyloxy (lower) alkyl ester (
For example, acetoxymethyl ester, peropionyloxymethyl ester.

Petitilol dimethyl ester, valeryloxymethyl ester, hyhaloyl dimethyl ester, 1- or 2-acetoxymethyl ester.

1-MoL<ha 2-Fropionyloxymethyl ester,
lower alkanesulfonyl (lower) alkyl esters (such as 2-methylethyl ester) or mono-(or di- or tri)ac2(lower) alkyl esters (such as 2-iodoethyl) lower alkyl esters having at least one suitable substituent such as esters, 2,2,2-trichloroethyl esters, etc.; lower alkenyl esters (111, vinyl esters, allyl esters, etc.); lower alkynyl esters; (e.g. ethynyl ester, flobinyl ester nato); al(lower) alkyl ester which may be I-carrying with at least one suitable substituent (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitro Benzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(diphenyl in meth) methyl ester, 3.
4-dimethoxybenzyl ester, 4-hydroxy 3
．． 5-diLerL-butylbandyl ester, etc.):
Aryl esters C which may have at least one substituent, such as phenyl esters, 4-LffG phenyl esters, tolyl esters, tert-butylphenyl esters, xylyl esters.

Examples include mesityl ester, cumenyl ester; and (2-oxo-1,3-dioxolen-4-yl)methyl ester which may have a 1-substituent.

Preferred examples of the above-mentioned esterified carboxyl groups include lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, impropoxycarbonyl, butoxycarbonyl, imbutoxycarbonyl + terE-))oxycarbonyl, pentyl oxycarbonyl, terL-hentyloxycarbonyl, hexyloxycarbonyl, I
mono- or di- or triphenyl (lower) alkoxycarbonyl (e.g. dicarbonyl 2-benzhydryloxycarbonyl, etc.) and their nitro-substituted products (e.g. 4-nitrobenzyloxycarbonyl) ) and lower alkanoyloxy(lower)alkoxycarbonyl (e.g. acetoxymethoxycarbonyl, 1
- or 2-fropionyloxyethoxycarbonyl, 1- or 2-clonyloxyethoxycarbonyl, 1
- or 2- or 3-acetoxycarbonyl, bivaloxymethoxycarbonyl, dimethoxycarbonyl hexanoyl, etc.), and the most preferred examples include 4-nitrobenzyloxycarbonyl and piparoyloxymethoxycarbonyl. Can be mentioned.

Suitable examples of the "lower alkylthio group" include C1 to C4 lower alkylthio groups such as methylthio and ethylthio.

Suitable examples of "lower alkoxy groups" include methoxy, nidoxy, probogyoxy, and impropoxy.

Examples include butoxy, ethyloxy, hegysyloxy, and the like, and methoxy is most preferred.

Suitable examples of "hegulin" include chlorine, bromine or iodine, preferably chlorine or bromine, most preferably chlorine in the O group -CM2Y group.
Examples of the "acyloxy group" include a lower alkanoyloxy group (especially an acetoxy group), a lower alkanoyl group (e.g., a methoxycarbonyloxy group), an N-
Examples include acyl groups of carbazic acid which may be substituted with f (for example, carbamoyloxy group, N-methylcarbamoyloxy group), and the like.

In addition, the "optionally substituted heterocyclic thio group" of Y in the group -CH2Y means the following formula (■): 6 [wherein R and R may be the same or different, hydrogen or each represents a lower alkyl group which may have a substituent], or 1 to 4 ring nitrogen atoms and optionally another ring heteroatom selected from oxygen and sulfur. is a substituted or unsubstituted heterocyclic group having a ring carbon atom and bonding to a thio group via a ring carbon atom.

Such heterocyclic groups are in particular optionally substituted 5- or 6-membered monocyclic diaza-, triaza-, aromatic or partially saturated nature containing, for example, the substituents listed below. Tetrazer, Chiryozer.

It is a thiadiaza, thiatriaza, oxaza or oxadiaza-cyclic group.

Preferred heterocyclic thio groups in which the heterocyclic group is a corresponding 5-membered monocyclic group are in particular imidazolylthio groups, such as 2-imidazolylthio groups; triazolylthio groups optionally substituted with lower alkyl groups and/or phenyl groups 1 For example, IH
-1,2,3-)riazol-4-ylthio group, 1-methyl-1)'I-1,2,3-triazol-4-ylthio group, IH-1,2,4-triazol-3-ylthio group basis,
5-Methyl-IH-1,2,4-)riazol-3-yl? o group, 3-methyl-1-phenyl-11(-1,2,
4-1-resol-5-ylthio group, 4,5-dimethyl-4H-1,2,4-triazol-3-ylthio group or 4-carboxyethyl- or 4-phenyl-4H-
1,2,4-) lyazol-3-ylthio group; or especially a tetrazolylthio group optionally substituted as described above.

For example, 1■-tetrazol-5-ylthio group, 1-methyl-IH-tetrazol-5-ylthio group, 1-carboxymethyl-IH-tetrazol-5-ylthio group, 1-(2
-carboxyethyl)-1H-tetrazol-5-ylthio group, 1-sulfomethyl-IH-tetrazol-5-ylthio group, I-(2-sulfoethyl)-1H-tetrazol-5-ylthio group, l-(,2-dimethylaminoethyl )-1H-tetrazol-5-ylthio group, 1-phenyl-IH-tetrazol-5-ylthio group or ha-(4-
chlorophenyl)-11-te)rubr-5-ylthio group; dichozolylthio or isothiazolylthio group optionally substituted with a lower alkyl group or chenyl group, e.g. 2-thiazolylthio group, 4-(2-chenyl) -2
-thiazolylthio group, 4,5-dimethyl-2-thiazolylthio group, 3-inchazolylthio group, 4-inchazolylthio group or 5-inchazolylthio group; especially also,
A thiadiazolylthio group optionally prepared and substituted as described above, such as a 1°2.3-thiadiazol-4-ylthio group, l.

2.3-thiadiazol-5-ylthio l,l.

3.4-thiadiazol-2-ylthio group, 2-methyl-
1,3,4-thiadiazol-5-ylthio group, 2-(3
-carboxypropionylamino)-1,3,4-thiadiazol-5-ylthio group, 1,2.4-thiadiazol-5-ylthio group, 3-methyl-1', 2.4-thiadiazol-5-ylthio group ylthio group or 1.2.5-thiadiazol-3-ylthio group; thiatriazolylthio group, such as l, 2.3.4-thiatriazol-5-ylthio group;
oxazinorthio or inxazolylthio optionally substituted as above, such as 5-oxazinorthio, 4-methyl-5-oxazinorthio, 2-oxazinorthio, 4,5-diphenyl-2-oxazinorthio, or 3-methyl-5-yneoxadinorthio group; or an oxadiazolylthio group optionally substituted as described above, such as 1.2.4-, oxadiazol-5-ylthio group, 2-methyl-1°3. 4-oxadiazol-5-ylthio group, 2-phenyl-1,3,
4-oxadiazol-5-ylthio group, 5-(4-nitrophenyl)-1゜3.4-oxadiazol-2-ylthio group or 2-(2-chenyl)-1,3,4-o-thadiazol-5- ylthio group・In addition, "pyridinio group which may have a substituent" is the following formula (■): [In the formula, R and R may be the same or different, and each hydrogen atom; methyl Lower alkyl i (C, ~C4) such as groups
; carbamoyl group; carboxyl group; sulfonic acid; or lower alkoxy group (C1-c4) such as methoxy group; quaternary ammonium group; or the following formula (vi)
:6 [In the formula, R6 and R7 have the same meanings as above: A is -CH
Examples include quaternary ammonium groups represented by 2-, '-5-1-〇-, or -Nl (representing -).

Representative examples of compounds of the invention include the following.

■ 7-C2-C2-aminothiazol-4-yl)-
7-[:2 -(2-aminothiazol-4-yl)
-2-(4-benzyl-2,3-diketobiberazinyl-lponylmethquinimino)acetamide)-3-(+-
Methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid 7-C2-C2-aminothiazol-4-yl)-
2-(4-(2-chenylmethyl)-2゜3-diketo-
1-Piperazinylcarbonylmethoxyimino)acetamide]-3-(+-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid■ 7-[2-C2-aminothiazol-4-yl)-
2-(2,3-diketo-1-biradinylluponylmethoxyimino)acetamide]-3-(+-methyltetrazol-5-ylthiomethyl)-3-cephem-4-
Carboxylic acid ■ 7=(2-(2-aminothiazole-4
7-[2-(2-aminothiazol-4-yl)-
2-(4-ethyl-2,3-diketo-1-piperazinylcarboxymethoxyimino)acetamide]-3-(1
-Methylpyridinium-4-ylthiomethyl)-3-cephem-4-carboxylic acid 7-[2-(2-aminothiazol-4-yl)-
2-(N-piperidiniocarbonylmethodiimino)acetamide)-3-(+-methylpyridinium-4-
ylthiomethyl)-3-cephem-4-carboxylic acid 7-C2-(2-aminothiazol-4-yl)-
2-(4-ethyl-2,3-diketo-1-piperazinylcarbonylmethoxyimino)acetamide, 1-3-
(5-Methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid 7-C2-' (2-aminothiazol-4-yl)-2-(4-ethyl -2,3-diketo-1-biradinyl methoxyimino)acetamide)-3
-(1-methylpyridinium-2-ylthiomethyl)-
3-cephem-4-carboxylic acid @ 1-C2'-C2-aminothiazol-4-yl)
-2-(N-piperidiniocarbonylmethodiimino)
acetamido]-3-(+-methylpyridinium-2-
ylthiomethyl)-3-cephem-4-carboxylic acid 7-[2-(2-aminothiazol-4-yl)-
2-(4-carboxymethyl-2,3-diketobiperazinyl methoxyimino)acetamide)-3-
(5-Methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid 07-[2-(2-aminothiazol-4-yl)-2
-(N-piperidiniocarbonylmethodiimino)acetamyl')-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-
Carboxylic acid hyvaloyloxymethyl ester The compound of the present invention can be prepared by the following method.

Method 1 The following formula (■): 4 [In the formula, R is a hydrogen atom, a -rogane atom, a lower alkylthio group, a lower alkoxy group, a vinyl group, or a group -CI]
(2Y (wherein, Y is a hydrogen atom, -.rogen atom,
-R4 represents a carboxyl group, a protected carboxyl group, an acyloxy group, a heterocyclic thio group which may have a substituent, or a pyridinio group which may have a substituted &'; [representing a carboxyl group] or a reactive derivative thereof at the amino group or a salt thereof, the following formula (III)
[In the formula, R1 is an amine group or a protected amino group; R2
is a compound represented by CH2, O, S or a group '>N-R5 (in the formula, 85 is a lower alkyl group or a hydrogen atom which may have a substituent): x represents R2 or O, respectively] Alternatively, it can be produced by reacting reactive derivatives or salts thereof at the carboxyl group.

Suitable examples of reactive derivatives at the amino group of compound (II) are ship base-type iminos or tautomers thereof produced by the reaction of compound (II) with carbonyl compounds such as aldehydes, ketones, etc. Enamine type isomer; compound (II) and bis(trimethylsilyl)
Silyl derivatives obtained by reaction with silyl compounds such as acetamide; derivatives produced by reaction of compound (n) with phosphorus trichloride or phosgene, etc. 0 Suitable compounds of compound (II) and (■) Salts include salts with organic acids (e.g. acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate, etc.) or salts with inorganic acids (e.g. hydrochloride, hydrobromide, sulfuric acid). acid addition salts such as salts, phosphates, etc.; alkali metal salts or alkaline earth metal salts (e.g.
Examples include metal salts such as aluminum salts, potassium salts, calcium salts, magnesium salts, etc.; ammonium salts; and nucleated amine salts (eg triethylamine salts, dicyclohexylamine salts, etc.).

Suitable examples of reactive derivatives at the carboxyl group of compound (■) include acid-rokenides, acid azides,
Examples include acid anhydrides, active amides and active esters, and more specifically acid chlorides, modified bromides; substituted phosphoric acids (e.g. dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, -logenated phosphorus). acids, etc.), phosphorous acid, sulfite, thiosulfate,
Sulfuric acid, alkyl carbonates (e.g. methyl carbonate, ethyl carbonate, etc.), aliphatic carboxylic acids (e.g. pivalic acid, valeric acid, invaleric acid, 2-ethyl acetate, tri-20-acetic acid, etc.) or aromatic carboxylic acids (e.g. benzoic acid) mixed acid anhydrides with acids such as); symmetrical acid anhydrides; imidazole, 4-substituted imidazole, dimethylpyrazole,
activated amides with triazoles or tetrazoles; or activated esters (e.g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH3)
2N = CH-] ester, vinyl ester, propargyl ester-p-nitrophenyl ester,
2.4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester,
Phenylthioester3. p-nitrophenyl thioester, p-cresyl thioester, carboxyl dimethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.), or UN-hydroxy compounds (e.g., N
, N-dimethylhydroxylamine, 1-hydroxy-
Examples include esters with 2-(II()-pyridone, N-hyPc1xysuccinimide, N-hypxysuccinimide, 1-hydroxy-6=chloro-IH-benzotriazole, etc.).

These reactive derivatives are appropriately selected depending on the type of compound (III) to be used.

This reaction typically involves water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, 'N,N
- carried out in conventional solvents such as dimethylformamide, pyridine or other organic solvents that do not adversely affect the reaction.

These solvents may be used in combination with water.

In this reaction, when the compound (in) 'e is used in the form of a free acid or a salt, it is preferable to carry out the reaction in the presence of a condensing agent, and such condensing agents include, for example, N
, N7-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide;
N-Schifa hexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;N,N'-diethylcarbodiimide:N,N'-diisopropylcarbodiimide;N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;N,N-carbonylbis(2-methylimidazole); pentamethyleneketene-
N-cyclohexylimine: diphenylketene-N-cyclohexylimine: ethoxyacetylene; 1-alkoxy-1-chloroethylene; phosphorous acid) rifurkyl;
Ethyl polyphosphate; Impropyl polyphosphate; Phosphorus oxychloride; Phosphorus trichloride; Thionyl chloride; Oxalyl chloride;
Triphenylphosphine; 2-ethyl-7-hydroxybenziisosolium salt; 2-ethyl-5(m-sulfophenyl)isoxazolium hydroxide intramolecular m:
1-(p-chlorobenzenesulfonyloxy)-6-chloro-+amybenzotriazole; Examples include the so-called Wilsmeier reagent obtained by reacting dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride, etc.@This reaction is It may also be carried out in the presence of an inorganic or organic base, and examples of such bases include alkali metal hydrogen carbonates (e.g. aqueous sodium carbonate, potassium hydrogen carbonate, etc.), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.). potassium, etc.), alkaline earth metal carbonates (e.g. calcium carbonate), tri(lower)alkylamines (
11FILt trimethylamine, triethylamine, etc.), pyridine, N-(lower) alkylmorpholine,
Examples include N,N-di(lower)alkylbenzylamine.@The reaction temperature is not particularly limited.The reaction is usually carried out under cooling or heating.

Method 2 A nuclear compound is added to the compound represented by the following formula ((V) [wherein R, R, R and X have the same meanings as above, and 2 is a substitutable residue of the nuclear compound]. For example, in the general formula CI), R3 is a group CH2Y' (wherein, Y' is a pyridinio group which may have a substituent or an N-substituent). The compound (■') represented by a lower alkylviridioniothio group (which may be a lower alkylviridioniothio group) is represented by (IT) as the following formula % () [wherein R, R and A have the same meanings as above] G produced by reacting with pyridines (IX), (X) and/or pyridothiones (XI) represented by, for example, R3 in general formula (I) is a group -CH2Y and Y is Compound (I) representing a nuclear compound residue such as a nitrogen-containing heterocyclic thio group can be prepared by converting the corresponding compound (IV) into the following formula % (wherein R represents the above-mentioned nitrogen-containing heterocyclic group) It is produced by reacting with a nuclear compound such as a nitrogen-containing heterocyclic thiol represented by As a nuclear substitution reaction, various prior documents and patents (e.g. RH・FLynn U, Cephalosporin Ant 1 Penicillin, Chapter 4, Part 5, pp. 151, 197
2nd year, published by Academic Press: Tokuko Sho 39-17
No. 936; Special Publication No. 39-26972; Special Publication No. 43-1
This method is essentially the same as that disclosed in Japanese Patent Publication No. 1283), and therefore can be carried out using the same or similar procedures.

Among the nucleophilic compounds, nitrogen-containing heterocyclic thiols may be used in free form, but are advantageously used in the form of alkali metal salts such as sodium or potassium.

This reaction is preferably carried out in a solvent, such as an organic solvent that does not react with water or the raw materials, such as dimethylformamide, dimethylacetamide, dioxane, acetone, alcohol, acetonitrile, dimethyl sulfoxide, tetrahtomifuran, etc. alone or as a mixed solvent. The reaction temperature and time used as the reaction time depend on the raw materials, solvent, etc. used, but are generally appropriately selected within the 8δ range of 0 to 100°C and several hours to several days. The reaction is near neutral,
It is preferable to carry out the reaction at a pH of 2 to 8, preferably 5 to 8. A quaternary ammonium salt having a surfactant action such as trimethylbenzylammonium bromide, triethylbenzylammonium bromide, or triethylbenzylammonium hydroxide is added to the reaction system. Advantageous results can also be obtained by carrying out the reaction under an inert gas atmosphere such as nitrogen to prevent air oxidation.

Nitrogen-containing heterocyclic thiols are, for example,
/1. Rogowski, John Wiley & Sons, 1960), Chapter 5, Heterocyclic
Con A Uns, Vol.
Chapter 1 of Advances in Heterocyclic Chemistry, Volume 9 (In, R. Katlicki and A.
, edited by J. Bruton, Academic Press, 196.
8), pp. 165-209 or Dai Organic Chemistry (edited by Munio Kotake, Asakura Shoten), vol. Alternatively, it can be produced by subjecting a functional group other than thiol in the heterocyclic thiol obtained by method 1) to a chemical conversion reaction known per se.

Method 3 The following formula (V) (wherein, R,, R3 and R4 have the same meanings as above, and B
represents a carboxyl group or a reactive derivative thereof) with a compound represented by the general formula % (wherein R2 and v
Suitable examples of reactive derivatives at the carboxyl group in ) are based on the reactive derivatives of compound (m) in method 1 described above, and the acylation reaction thereof can also be based on method 1. Also, among the compounds of the general formula, XkaO, R2ka'';N-
The 2,3-diketobiradine derivative of R6 (wherein R5 is a lower alkyl group which may have a substituent) is the N-
It can be synthesized according to the method for synthesizing ethyl-2,3-diketopiperazine.

In addition, in the compound (I) of the present invention obtained by the above reaction, if necessary, the carboxyl protecting group and/or amino protecting group may be removed according to a conventional method, or the carboxyl group may be metabolically unstable and harmless. Conversion to an ester group may also be performed. The method for removing the carboxyl protecting group and/or amino protecting group is appropriately selected depending on the type of protecting group to be removed. - The removal reaction of the amino protecting group involves hydrolysis, reduction, and when the protecting group is an acyl group. After treating a certain compound with an iminologenating agent and then with an iminoetherifying agent,
If necessary, any commonly used method such as hydrolysis can be applied. Hydrolysis using an acid is one of the common methods, for example, alkoxycarbonyl group,
Acids that can be used to remove groups such as formyl and trityl groups include formic acid, trifluoroacetic acid,
Organic and inorganic acids such as p-toluenesulfonic acid and hydrochloric acid, preferably formic acid, trifluoroacetic acid, hydrochloric acid, etc., which are easily post-treated, are appropriately selected depending on the type of amino protecting group.The reaction is carried out without a solvent. The reaction can be carried out either in the presence of water, a hydrophilic organic solvent, or a mixed solvent thereof. Furthermore, when trifluoroacetic acid is used, the reaction may be carried out in the presence of anisole. Any commonly used method such as hydrolysis or reduction can be applied to the elimination reaction of carboxyl protecting groups. Hydrolysis using acid is one of the common methods, for example, Applies to the detachment of

In addition, in the present invention, when the target compound (■) is obtained in the form of a free acid at the 4-position and/or the oxime position, and/or when the compound (I) has a free amino group,
This compound is converted into a pharmaceutically acceptable salt by conventional methods.

The compounds of the present invention (It and starting compounds (III) and [3]) exist in syn and anti isomers, tautomers, aminothiazole type and iminothiazoline type,
In the present invention, any one may be used or a mixture thereof may be used.

The compounds of the present invention are all new compounds, and the minimum inhibitory concentrations of some of them are shown in Table 1 (measured by the agar dilution method).As a result, all of the tested compounds Possessing broad-spectrum and potent antibacterial activity, the compounds of the present invention are useful as medicines.

When administering the object compound (tI) of the present invention or a pharmaceutically acceptable salt thereof for therapeutic purposes, an organic or They can be administered in the form of conventional formulations mixed with pharmaceutically acceptable carriers such as inorganic, solid or liquid excipients. Examples of such preparations include capsules, tablets, sugar-coated tablets, ointments, suppositories, solutions, suspensions, and emulsions.Additionally, if necessary, supplements, stabilizers, wetting agents, emulsifiers, buffers, etc. may be added to the preparations. Commonly used additives may be included.

EXAMPLES Next, the present invention will be explained by reference examples (production of raw material compounds) and Example 11 (production of compounds of the present invention).

1flJI N-benzylethylenediamine 50t of benzyl chloride was added dropwise to 200td of ethylenediamine while stirring under water cooling for 30 minutes, and the solution was then heated under reflux for 1 hour @The reaction mixture was ice-cooled and dissolved in methanol containing 301m of potassium hydroxide. The solution was added and left to stand ◇ The precipitated salt was removed, the p solution was concentrated under reduced pressure, water and potassium hydroxide were added to the resulting residue, and the organic layer extracted with benzene was dried over potassium hydroxide. The solvent was distilled off under reduced pressure,
The obtained residue was distilled under reduced pressure to obtain 42.7ff of the target product. bp, 91-94℃/l mmHg 0 Reference P12 N-2-f enylmethylene ethylenediamine 2-thiophene aldehyde 20t7 and dioxysan 25-
The solution was added dropwise to 100% ethylenediamine at room temperature with stirring over 30 minutes. Subsequently, after heating under reflux for 1 hour, a portion of the solvent was distilled off under reduced pressure. The residue was diluted with methanol, sodium borohydride was added little by little at o Da, and the mixture was left overnight at room temperature. After the solvent was distilled off under reduced pressure, water 100- and potassium hydroxide were added to the residue. After drying the extracted solution with potassium hydroxide, the solvent was distilled off under reduced pressure, and the resulting residue was distilled under reduced pressure to obtain the target product 19.22 b
p-124~130''C/9~10 mmHg.

Reference 9i1J3 N-2-Furfurylethylenediamine Obtained from 22.7 t of furfural in the same manner as in Reference Example 2. Collection @229. bp, 112~+14't:
/+5rrtnug a Reference % JAN-furfuryl 2.3-diketopiperazine N-furfuryl ethylenediamine 14 ft-1-Tanol 50g solution soaked in diethyl oxalate 14
．． 250 ml of ethanol containing 6F! It was added dropwise to the mixed solution under stirring and water cooling for 30 minutes.

After the dropwise addition, the solution was heated under reflux for 6 hours, and then half of the solvent was distilled off.The target product was left overnight at room temperature.The desired product precipitated out as crystals. I got crystal. Contraction i14.9f: mp, 19
0-191°C (recrystallized from ethanol) IR (Nujol): 3210.705.1660 cm.

Reference Example s N-(2-chenylmethyl)-2,3-diketopiperazine was obtained from N-2-chenylmethylenediamine in the same manner as in Reference Example 4. Yield 452%: mp, 219-220℃ (
Recrystallized from ethanol); IR (Nujol): 3210.1720.1695
．． 1670 mouths.

Reference Example 6 N-benzyl-2,3-diketopiperazine was obtained from N-benzylethylenediamine in the same manner as in Reference Example 4. Yield bore 7%; mp, 219-223°C (recrystallized from ethanol); IR (Nujol): 3210. l"718..
1695.1670I MO Reference Example 7 Allyl 2-(4-ethyl-2,3-diketopiperazinylcarbolydimethoxyimino)-2-(2-)ditylaminothiazol-4-yl)acetate (syn isomer) 710+y of N-ethyl-2,3-diketopiperazine and 0.65% of pyridine were completely dissolved in dry tetrahydrofuran, cooled on ice, and 1.1fi of bromoacetyl bromide was added to the solution.
Drop in 10 minutes. Concentrate under reduced pressure to 50% ethyl acetate.
− dissolves. Wash sequentially with water and saturated bicarbonate of soda water,
Dry over magnesium sulfate and concentrate under reduced pressure. -10,000 allyl 2-hydroxyimino-2-(2-tritylaminothiazol-4-yl) acetate (synso form) 2
．． 39f dry D MF 30 tne K m Dissolve, add 1.3f of silver carbonate, add 4-bromoacetyl-2,3-diketobi obtained earlier, add radin, and stir at room temperature for 4 hours. Remove insoluble matter. Concentrate the P solution under reduced pressure. Dissolve in ethyl acetate 50- and wash sequentially with water, sqb MCI, saturated aqueous sodium bicarbonate, water, and dry over magnesium sulfate. Concentrate under reduced pressure, and purify the residue using Wako Gel C-200 using toluene-ethyl acetate as a developing solvent.0 Yield: 2.O? ; NMR (80MHz', δ value, ppm CDCl5
)1.20(3f(,tJ=9'EIZ)3.5(4I
(, m) 4.0 (2H, m ) 4.80 (2H, b
d) 5-3 (3H,m)5・9(IT(,m)
6.5 (IH, El ) 7.3 (16H, 11) Reference Example 8 2-(2-1-cutylaminothiazol-4-yl)-2-(4-ethyl-2,3-digutobiperazini Alcarponylmethoxyiminoacetic acid (synisomer) Allyl 2-(2-tritylaminothiazol-4-yl)-2-(4-ethyl-2,3-diketobiberazinylcarponylmethoxyimino)acetate (Syn isomer)
1.2t was dissolved in 20 vJ of ethyl acetate and 2-
Add and dissolve 305 μl of ethylhexanoic acid sodium salt. Triphenylphosphine 7200”!, Tetrakistriphenylphosphine Palladium (0) 2001q
were added at the same time and stirred for 30 minutes to precipitate crystals. Add 20-isopropyl ether to collect 1kF of precipitate and dry. imino) acetic acid sodium salt 820
■ is obtained. The obtained sodium salt was dissolved in ethyl acetate (30) and water (10) under water cooling, and the solution was adjusted to pH 2 with 5% hydrochloric acid.
Adjust to 0. Wash with saturated saline to obtain 7g0 of the target compound.
O N M R (F!; OMH δ value * ppm, cD
cz3) 1.20 (3H, td, J=9.2Hz)3
,5(2H,m)4,o(2H,rn) 4.9
(2H, ba ) 6.6 (I H, s) 7.2 (
+6)1. 8).

Reference Example 9 Allyl 2-(piperidiniocarbonyl, methoxyimino)-2-(2-tritylaminothiazol-4-yl)acetate (syn isomer) Pi is 1.2πi of lysine and 0.97 m/i of pyridine dry chloride Dissolve in 20 ml of methylene and cool to -30°C. Add 0.86 ml of bromoacetyl bromide dropwise to this and stir at -30° to 0°C for 30 minutes. Pour the mixture into 200 ml of ethyl chloride and 50 ml of water. Add to the mixture, add water,
Wash sequentially with 5% HCl and water. After drying with magnesium sulfate, concentrate under reduced pressure. Oily bromoacetylpiperidine was quantitatively obtained. ◎ NMR (g OMHz, δ value,
ppm, CDC/3) 1・60 (61(,ba)
3.40 (4H,ba) 3.85 (2Tf.

S).

Allyl 2-(hydroxyimino)-2-(2-tritylaminothiazol-4-yl)acetate (cyJ%
2.3 t in dry dimethylformamide 15-
Ni Numa Hiroshi, Tansai Gin T, 6? and add the previously obtained bromoacetylpiperidine.Stir at room temperature for 5 hours, remove insoluble matter, and pour rPi into a mixture of 200 parts of ethyl acetate and 100 parts of water. It is washed successively with water, 5 fat (Cl/water) and a saturated sodium bicarbonate aqueous solution, and dried over magnesium sulfate. It is condensed and dried under reduced pressure to obtain a target compound containing the target compound.

Wako gel C-200100? (purification and development with benzene-ethyl acetate) to obtain the desired product 1.6f.

NMR (80MHz, δ value, , ppm, CDC
l ) 1・6 (6H, bs ) 3.4 (4H,'
bs) 5.7 (2H.

bd ) 5.8 (2H,s) 5-3 (21(
, m) 5.9 (IH, m) 7-55 (l
H,s) 6-9 (IT(,bs)'I,3
(15H,s) Reference example +o 2-(2-tritylaminothichozole-4
-yl)-2-(piperidiniocarbonylmethoxyimino)acetic acid (syn isomer) 2-(2-)rithylaminothiazol-4-yl)-2
-(Bisridinioluponylmethoxyimino)acetic acid allyl ester (synisomer) 1.68f to ethyl acetate 1
Sodium 2-ethylhexanoate dissolved in 0-470
Cape is bath-dissolved at room temperature and triphenylphosphine 320
■, Tetrakis triphenylphosphine Δradium (o
) 320 wryt was added at the same time and stirred at room temperature rM for 1 hour to precipitate crystals. Add 50% of isopropyl ether, separate the crystals, and dry. 2-(2-1-'J thylaminothiazol-4-yl)-2-(piperidiniocarbonylmethoxyimino)acetic acid sodium salt 1.3f
get. The obtained sodium salt was dissolved in 50 ml of ethyl acetate.
Water 10++rl! Dissolved in a mixture of under ice-cooling and diluted with 5% hydrochloric acid.
Train to H2,0. Wash the organic layer with saturated brine and dry with magnesium sulfate. Concentrate under reduced pressure to obtain 1t of the target compound. O NMR (80 MHz, δ value, ppm, CDCl)
1.6 (6H, ba) 3.3.3.5 (4H,
each bs) 4.9 (2L s) 6,9 (l)
t, bs) 7.3 (15H,s) for reference ji
ll The following compound was synthesized according to Diagnostic Example 7~lo&l $ ◎ 2-(2-tritylaminothiazol-4-yl)
-2-(4-<Fujiru-2,3-diketo 1-piperaziniocarbonylmethoxyimino)acetic acid (syn isomer) ◎ 2-(2-)ditylaminothiazol-4-yl)
-2-(4-(2-thenylmethyl)-2,3-diketo-1-piperaziniocarbonylmethoxyimino)acetic acid (
syn isomer) ◎ 2-(2-)ditylaminothiazol-4-yl)
-2-(4-furifuryl-2,3-diketo-1-piperaziniocarbonylmethoxyimino)acetic acid (syn isomer) ◎ 2-(2-)ditylaminothiazol-4-yl)
-2-(4-tert-butoxycarbonylmethyl-2,3-diketo-1-piperaziniocarbonylmethoxyimino)acetic acid (syn isomer) (J2-(2-tritylaminothiazol-4-yl)
-2-(4-tert-butoxycarbonyl-1-piperaziniocarbonylmethoxyimino)acetic acid (syn isomer) ◎ 2-(2-tritylami/thiazol-4-yl)
-2-(morpholiniocarponylmethoxyimino)acetic acid (syn isomer) Example 1 7-[22-(2-)ditylaminothiazol-4-yl)-2-(4-ethyl-2,3-diketo -1-Radiniolponylmethoxyi))acetamide) -3-Cl-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester (synisomer) 2-(2- ) dithylaminothiazol-4-yl)-2
-(4-ethyl-2,3-diketo-1-piperaziniocarbonylmethoxyimino) vinegar! (j-sho, Ta-ku t-b-S
＋tsu＾憫
and 7-amino-3-(1-methyltetrazole-5-
ylthiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester (100 μ) was dried with 20 tons of ethyl acetate.
rd! , cool on ice, add 42 kg of dicyclohexylcarbodiimide, and stir at 5°C for 15 hours. Remove the precipitated urea derivative, add 30-ethyl acetate,
Wash sequentially with water, 2.5 cm cold hydrochloric acid, 5-sodium bicarbonate aqueous solution, and water, dry over magnesium sulfate, and concentrate to dryness. The residue was purified using Wako Kel C-2001Of to obtain the target compound 40.O NMR (8QMI (z, δ value, pp (11, CDC
1:2 C3I (, tr J=6Hz) 3.6
(4H, l1l) 3.67 (2H, be ) 3-8
(3H,s) 4.0 (2H,m)4.3(2
H, ba) 5.05 (IH, d, J=4.8) 5.40
(l T(, ba ) 5.95 (l H, d,
d, J = 4.8I (z + 9.6 Hz) 6
．． 8 (l H, a ) 6-81 (l H, a )
7.20 (26H, bs) 8.4 (IH, d, J = 9°6Hz) ■R (nujol): 3300.3200
．． +q75cm.

Implemented l 2 7- (2-(2-aminothiazole-
4-yl) -2-(4-ethyl-2,3-diketo-1
-piperaziniocarbonylmethoxyimino)acetamide]-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (synisomer) trifluoroacetate 7-[2-(2-tritylamino thiazol-4-yl) -2-(4-ethyl-2,3-diketo-1-piperaziniocarbonylmethoxyimino)acetamide)-3
-(1-methyltetrazol-5-ylthiomethyl)-
Dissolve 40η of 3-cephem-4-carboxylic acid diphenylmethyl ester (syn isomer) in 0.5-anisole. Add trifluoroacetic acid while cooling with water. Stir at 5DC for 1 hour.

This solution was added to isopropyl ether 5C), and the precipitated crystals were separated and dried to obtain the desired compound 12.

N 11.4 R (DMSO-d, δ value + ppm
) 1.20 (3H, L, J=6Hz ) 3.5 (4H
, m) 3=7 (2F[, bs ) 4.0 (2H,
m ) 3.8 (3Il, s) 4.3 (2H, s)
5・O(lH,d,J=44Hz)5.4(2T(,
5) 5-9 (lH, d, d, J = 4.8Hz.

9.6Hz) 6.8 (II(,8)Example 3 7-(:2-(2-)ditylaminothiazol-4-yl)-2-(4-ethyl-2,3-diketo-+ -Hyheraziniorponylmethoxyimino)acetamidocou 3
-Chloamethyl-3-cephem-4-carboxylic acid diphenylmethyl ester 2-(2-)ditylaminothiazol-4-yl)-2-(4-ethyl-2,3-diketo-
1-Piperaziniocarbonylmethoxyimino)acetic acid (syn isomer) 6 ooq and 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester 416 Wt dissolved in dry methylene chloride 25@-
Cool to 20°C, add 0.323d't'' of irisine,
Next, 0.129 grams of phosphorous chloride was slowly added dropwise to the reaction solution, stirred at 200 C for 20 minutes, and poured into 200 grams of ethyl acetate and 2 grams of cold 25% hydrochloric acid. Wash the organic layer with water and cool with water. Adjust the pH to 7 with sodium bicarbonate and wash with water. After drying with magnesium sulfate, concentrate to dryness. Purify the residue with Wako Gel C-200, 15F (developing solvent benzene-ethyl acetate) to obtain 260v of the target compound. ONM R (80MHz, δ value, ppm, CDC1
3) 1.2(3H,t, J=6T(z)3.5(6
H, m) 4.0 (2H, m) 4・35' (2H,
a) 5.05 (IH, d, J= 4.8)
IZ) 5.45 (2H, 11> 5.95 (l
H, d, d.

J=4.8Hz, 9.6H7) b, g (l H,
8) 6.92 (I I(,a) 6.96 (l
H, bs ) 7.3 (25H, be ) 8.45
(l H, d, J = 9.6 Hz) IR (3C
``I''): 3200.1770 crn.

Example 4 7-C2-C2-tritylminothiazol-4-yl)-2-(4-ethyl-2,3-diketo-1-piperaziniocarbonylmethoxyimino)acetamide)-3-(+-methylpyridinium- 4-ylthiomethyl)-3-cepheA-4-carboxylic acid diphenylmethyl ester (syn isomer) chloride 7-C27(2-)ditylaminothiazol-4-yl)-2-(4-ethyl-2,3- Diketo-1-piperaziniocarbonylmethoxyimino)acetolimide]-3-
250 μl of chloromethyl-3-cephem-4-carboxylic acid diphenylmethyl ester (syn isomer) was dissolved in dry tetrahydrofuran, and N-mesol-4-4-carboxylic acid was dissolved under stirring.
Stir for 3 hours. Add this solution to 100% ether.
1 The precipitated 7. salt is washed with ethyl acetate in a furnace W eggplant and dried and the target compound 270 *9 is obtained.
Cl)1=2(3H,t, J=6Hz)3.5(
6H, m) 4.0 (2H, m) 4.3 (5H, b
a) 5.05 (l H, d, J= 4.B T
(z, ) 5.35 (2H,a) 5-9 (l
H, d, d.

J = 4-8 Hz, 9.6 Hz) 6.8(
lH,8) 6.65(lH,'s)7.3(25H
,a)7-7(2T(,d,J=7Hz)8・45(l
H, d, J = 9.6Hz) 8.7 (2H, d, J =
7 I(z) IR (Nujol): 1790m.

Example 5 7-(2-(2-aminothiazol-4-yl)-2-(4-ethyl-2,3-diketo-1-piperaziniocarbonylmethoxyimino)acetamide]-3-(1-methyl Pyridinium-4-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer)) lifluoroacetate 7-C2'-(2-tritylaminothiazole-4-
yl), -2-(4-ethyl-2,3-diketo-1-piperaziniocarbonylmethoxyimino)acetamide)
-,3-(+-Methylpyridinium-4-ylthiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester chloride (synisomer F4') was dissolved in anisole 1-, and trifluoroacetic acid 5- was cooled with water. Pour this into isopropyl ether, wash the precipitated salt with lots of lotitrahydrofuran, and dry to obtain the desired compound. R (400MHz, δ value, ppm, DMS
O-d6) 1.12 (3H, t, J=6H7) 3
．． 4 (4H, m) 3.55 (2H, m) 3.9
(2i(, bs ) 4.15 (31(.

s ) 4.45 (2I(, a) 5.1 (3H, bs
) 5.7 CIH, d, d, J = 4.8 Hz, 9.
6Hz) 6-75 (I H,s)g, oε(2H
,d, J=7Hz)8.65(2I(,d,J=7Hz
) 9.42 (l H, d, J = 9.6 Hz) Implementation v116 7- C2-(2-tritylaminothiazol-4-yl)-2-(pyridinioluponylmethoxyimino)acetamide,]- 3-(5-methyl-1゜3.4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester (syn isomer) 2-(2-)ditylaminothiazol-4-yl) -2
-(piveridinioluponylmethoxyimi/)acetic acid (syn isomer)llomy, 7-'γminor 3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carvone Acid diphenyl methyl ester I02■'t'' Dissolve in dry methylene chloride 10-.After cooling to -20°C, add 0.065 d1 of pyridine, then add 0.025 d? of phosphorus oxychloride at the same temperature.030 at the same temperature. After stirring for a minute, 1 ootnt of ethyl acetate
, in water 50-, 7-, Yiyi under cooling r) H2, O
f □ 4 horses 11 mouths, selling price 1 log ・The organic layer was washed with water ・pH 7 with 5% sodium carbonate aqueous solution
Maintain VC and stir for 10 minutes under water cooling. After washing the organic layer with water f
Dry over magnesium ittate, concentrate to dryness under reduced pressure,
Made of silk with Wako Gel C-2001Of (developing solvent: benzene)
(ethyl acetate) to obtain the target compound 1021r4.

NMR (80MHz, δ value, ppm, coc7!
3) 1.5 (6H, ba) 2.6 (3H, s ) 3.2
~3.4 (4H, bs) 3.55 (2H, s)
4.2.4.55 (2H.

ABq, J = 16 Hz) 4,92 (2H
,s) 5.00 (IH.

d, J=5 Hz)5.85 (l H, d, d,
J=5Hz.

'1.6Hz)6-78 (IH,a)6.85
(IH,s)7.3 (25H) IR (Nujol): 3300.1770Crn0
7-[2-(2-minothiazol-4-yl)-2-(piperidiniocarbonylmethoxyimino)acetamide p3-3-(5-methyl-1,3,4-thiadiazole-2) -ylthiomethyl) -3-cephem-4-carboxylic acid (syn isomer) trifluoroacetate 7-[2-(z-tritylaminothiazol-4-yl)-)'-(H-": Lysinioluponylmethoxy imino)acetamido)-3-(5-methyl-1,3,4-
Thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester (syn isomer) 2001? Dissolve in 0.3ml of r'e anisole,
Trifluoric acid e B mt is added under water cooling. After stirring at the same temperature for 1 hour, the mixture was poured into 100% isopropyl ether to remove the precipitated salt 'kF, washed with ether, and dried to obtain the target compound 53p2.

NMR (80MHz, δ value, ppm, DMSO-
d6)l=5(6H,bs+)2-6(3ii,a)
3,2~3.4 (4Tr, bs) 3.6 (2H
,s) 4,4 (2H,ABq)A-9(2H,a
)5-0 (IH, d, J=4,8Hz)5=g5
(lt(, d, d, J=4-8 Hz, 9.6
Hr, ) 6,7(l T(, Fl) Example 87-[2-(2-tritylminothiazol-4-yl)-2-(biberidinioluponyl〆togishiimi/) diocetamide]-3-chloromethyl- 3-cephem-4-carboxylic acid diphenylmethyl ester (syn isomer) 2-(2-)ditylaminothiazol-4-yl')-2-(piperidiniocarbonylmethoxyimino)acetic acid ( syn isomer) and 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid diphenylmethylnister Tokara synthesized 〇[VJM n (80huIz, δ value, ppm, CD
Cl3) 1.6 (6H, bs) 3-2 to 3.5
(4H,b) 3',5 (2H,bs) 4.
45 (2H,s) 4.95 (2H,s)5,
OO(l)1. d, J = 4-8 t(z)
5.85 (l H, d, d.

J=4.8Hz, 9Hz)642(IH,s)6.
92 (lH, 8) 7.3 (26H, bs) Implementation example 9 7-[2-(2-)guthylami/thiazole-4
-yl)=2-(piperidiniocarbonylmethoxyimino)acetamide)-3-(+-methylpyridinium-4-ylthiomethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester chloride (syn isomer) carried out 1 ] 4 to obtain N-methyl-4-pyridothione and 7-[2-(2-)IJ thylaminothiazole- obtained in Example 8.
O NM B C80MHz, δ value, ppm, cocz
)1.55 (6H,ba) 3.2~3.5 (4
H, bs ) 3.5 (2) 1. bB') 4.3
5 (5H,ba) 4.95 (2H,g)5・
O(I!(, d, J = 4.8 Hz) 5.
75 (lt(,d,d.

J=4. gH2,9Hz)6.76 (l Fl,
8) 6.85 (IN*a) 7.25 (26
'H, bs) 7°70.8.75 (4H.

AB(1,J=g)tz) Example 10 7-[2-(2-aminothiazole-4-
yl)-2-(piperidiniocarbonylmethoxyimino)acetamide]-3-(1-methylpyridinium-4-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) trifluoroacetate obtained in Example 9 7-[2-(2-)IJ thylaminothiazol-4-yl)-2-(piperidiniocarbonylmethoxyimino)acetamide]-3(1-methylpyridinium-4-ylthiomethyl)-3-cephem- 4-Carbonylated diphenylmethyl ester chloride (
syn isomer) using anisole and trifluoroacetic acid according to Example 5.

Claims (1)

[Claims] l. The following formula 01 [wherein, R is an amino group or a protected amino group, R is C
) (2, O, S or a group, N-R5 (wherein R is a lower alkyl group or a hydrogen atom that may have a substituent)
;R3 is a hydrogen atom, a halogen atom, a lower alkylthio group, or a lower alkoxy group. vinyl group or group -CH2Y (wherein, Y is a hydrogen atom; a halogen atom, a carboxyl group, a protected carboxyl group, an acyloxy group, a heterocyclic thio group which may have an R substituent, or a substituent) R' is a carboxyl group or a protected carboxyl group; 2. The compound according to claim 1, which is a syn isomer ◎ (1) The following formula (I[) R'' [wherein R3 is a hydrogen atom, -rogen atom, lower alkyl, ruthio group, or lower alkoxy group] 5 vinyl group or group -CH2Y
(In the formula, Y is a hydrogen atom, a -rogen atom, a carboxyl group, a protected carboxyl group, an acyloxy group, an optionally substituted heterocyclic thio group, or an optionally substituted pyridinio group) base 6)
; R' represents a carboxyl group or a protected carboxyl group, respectively] or a reactive derivative thereof at an amino group or a salt thereof; Protected amino group; R2 is CH2+ 0+ 8 or group N-R6 (
(wherein as is a lower alkyl group which may have a substituent or a hydrogen atom); or (2) represented by the following formula QV) [wherein R', R2, R' and X have the same meanings as above, and 2 is a substitutable residue of the nuclear compound] or (3) the following formula (■) [wherein, R', R3 and R4 has the same meaning as age chart, and B
represents a carboxyl group or a reactive derivative thereof] with a compound represented by the general formula (wherein R and X have the same meanings as above) to form the following formula (I) [in the formula ,R,
R, R, R and and/or an amino group into a nontoxic salt, or a carboxyl group into a metabolically unstable nontoxic ester.
) or a pharmaceutically acceptable salt thereof