CA1253486A - Cephalosporins, processes for producing the same, antibacterial agent containing the same, intermediates thereof and process for producing the intermediates - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Intermediates in the product of cephalosporine in which a substituted or unsubstituted 2,3-dioxo-1,2,3,4-tetrahydropyrazinyl, 2-oxo-1,2-dihydropyrazinyl, 3,6-dioxo-1,2,3,6-tetrahydropyridazinyl or 6-oxo-1,6-dihydropyridazinyl group is attached to the exomethylene group at the 3-position of the cephem ring through a carbon-nitrogen bond and which have the following group attached to the amino group at the 7-position:

wherein -A- represents a group of the formula, -CH2- or a group of the formula, in which R18 represents a hydrogen atom or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, heterocyclic group or a hydroxyl-protecting group or a group of the formula:

Description

~L2534~6 1 This invention relates to novel cephalosporins, processes for producing said cephalosporins, an anti-bacterial agent containing said cephalosporins, inter-mediates Eor the production of said cephalosporins and a process for producing said intermediates.
The present inventors have conduct:ed studies with the aim of discovering compounds having a broad antibacterial spectrum, exhibiting an excellent anti-bacterial activity against gram-positive and gram-negative bacteria, being stable to ~-lactamase produced by bacte-ria, having a low toxicity, being at the same time well absorbable upon oral or parenteral administration and having an excellent therapeutic effect on the diseases of human beings and animals. As a result, it has been found that novel cephalosporins characterized in that a substituted or unsubstitued 2,3-dioxo-1,2,3,4-tetrahydro-pyrazinyl, 2-oxo-1,2-dihydropyrazinyl, 3,6-dioxo-1,2,3,6-tetrahydropyridazinyl or 6-oxo-1,6-dihydropyridazinyl group is attached to the exomethylene group at the

2~ 3-position of the cephem ring through a carbon-nitrogen bond and the following group is attached to the amino group at the 7-posi~ion, have tAe above-mentioned excellent properties:

~1~53~B6 ~ N ~ A-CO-l wherein A, R4 and R5 are as defined below.
It is an object of this invention to provide novel cephalosporins having the above-mentioned chemical structural characteristic features~ having a broad antibacterial spectrum, being stable against ~-lactamase produced by bacteria, having a low toxicity, being well absorbed upon oraL or parenteral administration, and having an excellent therapeutic effect on the diseases of human beings and animals.
It is another object of this invention to provide a process for producing said novel cephalosporins.
It is a further object of this invention to provide an antibacterial agent containing said cephalos-porins.
It is a still further object of this invention to provide intermediates for the production of said novel cephalosporins and to provide a process for producing said intermediates.
Other objects and advantages of this invention will become apparent from the following descriptlon.
According to this invention, there is provided a novel cephalosporin, particularly a cephalosporin re-presented by the following formula, or a salt thereof:

~53~6 N A-CONH 1~ S ~
R5--~ ~N~CH2R2 [I]
COOR
1 wherein R represents a hydrogen atom or a carboxyl-protecting group; R2 represents a group of the formula, ~N R N i I ~ in which R6 represents a hydrogen atom, -N ~ R15 5 a hydroxyl group, a nitro group, a carbamoyl group, a thiocarbamoyl group, a sulfamoyl group or a sub-stituted or unsubstituted alkyl, alkenyl, alkynyl, alkadienyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, ar~l, aralkyl, acyl, alkoxy, alkylthio, acyloxy, cyclo-alkyloxy, aryloxy, alkoxycarbonyl, cycloalkyloxycarbonyl,acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclic sulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, acylcarbamoyl, acylthiocarbamoyl, 15 alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyl-sulfonylthiocarbamoyl, arylsulfonylthiocarbamoyl, alkylsulfamoyl, dialkylsulfamoyl, alkoxythiocarbonyl,

3~6 1 alkylideneamino, cycloalkylmethyleneamino, arylmethylene-amino, heterocyclic methyleneamino, or heterocyclic group, or a group of the formula, -N \ 17 (each of R16 and R17, which may be the same or different, re-presents a hydroyen atom or an alkyl group or R16 and R17 together with their adjacent nitrogen atom may form a ring); each of R, R8 R9 R10 Rll R12 14 and R15, which may be the same or different, represents a hydrogen atom, a halogen atom or a substituted or unsubstituted alkyl, aralkyl or aryl group; R represents a hydrogen atom, a halogen atom, a carboxyl, sulfo, carbamoyl or t~iocarbamoyl group, or a substituted or unsubstituted alkyl, aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxy-carbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkyl-sulfonyl, arylsulfonyl, heterocyclic sulfonyl, alkyl-carbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkyl-thiocarbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkyl-sulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonyl-0 thiocarbamoyl or arylsulfonylthiocarbamoyl group; R3h~ dro ~e~ 4 h dro5e,~ 5 represents a h~,rogen atom or a halogen atom; R
represents a hydrogen atom or a protected or unprotected amino group; and A represents a group of the formula, --C---CH2- or a group of the formula, ~ in which R18 oR18 3~18~, 1 represents a hydrogen atom, a substi-tuted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, heterocyclic group or a hydroxyl-protecting group;

or a group of the formula, ~P\ 20 (each of R and R , which may be the same or different, represents a hydroxyl, alkyl, aralkyl, aryl, alkoxy, aralkyloxy, or arylo~y group), and the bond ~vvmeans that the compound may be a syn-isomer or an anti-isomer or a mixture thereof.
This invention also provides a process for producing said cephalosporins and salts thereof, an anti-bacterial agent containing said cephalosporins, inter-mediates for the production of said cephalosphorins and a process for producing said intermediates.
This invention will be further illustrated in detail below.
Herein, unless otherwise specified, the term "alkyl" means a straight or branched chain Cl 14alkyl and includes, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, hexyl, heptyl, octyl, dodecyl, lauryl and the like; the term "alkoxy" means -O-alkyl in which the alkyl is as defined above; the term "lower alkyl" means a straight or branched chain Cl 5alkyl and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl and the like; the term "lower alkoxy" means -O-lower alkyl in which the lower ~3~

1 alkyl is as defined above, the lerm "acyl" means a formyl group; a C2 5alkanoyl ~roup whlch includes, for example, acetyl, propionyl, isovaleryl, pivaloyl, pentanecarbonyl and the like; a C5 8cycloalkanecarbonyl group which lncludes, for example, cyclopentylcarbonyl, cyclohexylcarbonyl and the like; an aroyl group which includes, for example, benzoyl, toluoyl, 2-naphthoyl and the like; and a heterocyclic carbonyl group which includes, for example, thenoyl, 3-furoyl, nicotinoyl and the like, the term "acyloxy" means -O-acyl in which the acyl is as defined above; the term "alkylthio"
means -S-alkyl in which the alkyl is as defined above;
the term "alkenyl" means C2 1Oalkenyl and includes, for example, vinyl, allyl, isopropenyl, 2-pentenyl, butenyl and the like; the term "alkynyl" means C2 lOalkynyl and includes, for example, ethynyl, 2-propynyl and the like; the term "cycloalkyl" means C3 7cycloalkyl and includes, for example, cyclopropyl, cyclobutyl, cyclo-pentyl, cyclohexyl, cycloheptyl and the like; the term alkadienyl" means C4_10alk~dienyl and includes, for example, 1,3-butadienyl, 1,4-hexadienyl and the like; the term "cycloalkenyl" means C5_7cycloalkenyl and includes, for example, cyclopentenyl, cyclohexenyl and the like;
the term "cycloalkadienyl" means C5 7cycloalkadienyl and includes, for example, cyclopentadienyl, cyclohexadienyl and the like; the term "aryl" includes, for example, phenyl, naphthyl, indanyl and the like; the term "aralkyl"
includes, for example, ben~yl, phenethyl, 4-methylbenzyl, ~ 6 1 naphthylmethyl and the like; the term "heterocyclic group"
means a heterocyclic group containing at least one hetero atom selected from oxygen, nitrogen and sulfur and in-cludes, for example, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiatriazolyl, oxatriazolyl, triazolyl, tetrazolyl, pyridyl, 4-~5-metyl-2-pyrrolinyl),

4-(2-pyrrolinyl), N-methylpiperidinyl, quinolyl, phenazinyl, b~ J -oc~ o x o~4"~
1,3- ~ , benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, phthalidyl, coumarinyl and the like; the term "heterocyclic alkyl" means a group consisting of the above-defined heterocyclic group and the above-defined alkyl group; and the term "halogen atom" includes, for example, fluorine, chlorine, bromine and iodlne.
The symbol Rl in the formulas in this specification represents a hydrogen atom or a carboxyl-protecting group, and the carboxyl-protecting group includes those which are conventionally used in the fields of penicillins and cephalosporins, for example, an ester-forming group which can be removed by a catalytic hydrogenation, a chemical reduction, or a treatment under other mild conditions an ester-forming group which can be easily removed in a living body; or an organic silyl-containing group, an organic phosphorus-containing group, or an organic tin-containing group or the like, which can easily be removed upon treating with water or an alcohol; and other various well-known ester-forming groups.

~53~6 1 Among these protecting groups, preferable groups are as fol].ows:
(a) al.kyl groups, for example, Cl_4alkyl, (b) substituted lower alkyl groups wherein at least one of the substituents is selected ~rom a halogen atom, or a nitro, acyl, alkoxy, oxo, cyano, hydroxyl, cyclo-alkyl, aryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, 5-alkyl~2-oxo-1,3-dioxol-4-yl, l-indanyl, 2-lndanyl, ~uryl, pyridyl, 4-imidazolyl, phthalimido, , a~, d,,7 v succinimido, ~ id no, aziridino, pyrrolidino, piperidino, morpholino, thiomorpholino, N-lower-alkylpiperazino, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazol~rl, thiadiazolyl, oxadiazolyl, thiatriazolyl, oxatriazolyl, triazolyl, tetrazolyl, quinolyl, phenazinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, coumarinyl, 2,5-dimethylpyrrolidino, 1,4,5~6-tetrahydro-pyrimidinyl, 4-methylpiperidino, 2,6-dimethylpiperidino, 4-t5-methyl-2-pyrrolinyl), 4-~2-pyrrolinyl), N-methyl-piperidinyl, 1,3-benzodioxolanyl, alkylamino, dialkyl-amino, acyloxy, acylthio, acylamino, dialkylaminocarbonyl,alkoxycarbonylamino, alkenyloxy, aryloxy, aralkyloxy, cycloalkyloxy, cycloalkenyloxy, heterocyclic oxy, alkoxy-carbonyloxy, alkenyloxycarbonyloxy, aryloxycarbonyloxy, aralkyloxycarbonyloxy, heterocyclic oxycarbonyloxy, alkenyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, hetero-cyclic oxycarbonyl or alkylanilino group or an alkylanilino group substituted by a halogen atom, a lower al]cyl or lower alkoxy group, 3~3Çi 1 (c) cycloalkyl group; lower alkyl-substituted cyclo-alkyl group; or (2,2-di-lower-alkyl-1,3-dioxol-4-yl)methyl groups, (d~ alkenyl groups, (e) alkynyl groups, (f) phenyl group; substituted phenyl groups wherein at least one of the substituents are selected from the substituents specifically mentioned in above ~b); or ~ryl groups such as groups represented by the formula:
~1 wherein -Y - is -CH=CH-O-, -CH=CH-S-, -CH2CH2S-, -CH=N-CH=N-, -CH=CH-CH=CH-, -CO-CH=CH-CO-, or -CO-CO-CH=CH-, or a substituted derivative thereof wherein the substituents are selected from those specifically mentioned in above (b), or groups represented by the formula:

~ y2 wherein -Y - is a lower alkylene group such as -(CH2)3-or -(CH2)4-, or a substituted derivative thereof wherein the substituents are selected from those specifically mentioned in above (b), (g1 aralkyl groups such as benzyl or substituted benzyl groups wherein at least one of the substituents are selected from those specifically mentioned in above (b), (h) heterocyclic group or substituted heterocvclic groups wherein at least one of the substituents are selected from those specifically mentioned in above (b),

5~
1 (i) indanyl or phthalidyl groups or substituted derivatives thereof wherein the substitueIlts are methyls or halogens; tetrahydronaphthyl groups or substituted derivatives thereof wherein the substituents are methyls or halogens, trityl, cholesteryl, bicyclo[4,4,0]decyl;
or the like, (j) phthalidylidene-lower-alkyl groups or substituted de~ivatives thereo wherein the substituents are halogens or lower alkyl groups.
The above-mentioned carboxyl-protecting groups are typical examples, and the carboxyl-protecting group may also be selected from the other protecting groups described in the following literaturei. U.S. Patent Nos.
3,499,909, 3,573,296 and 3,641,018; DT-OS Nos. 2,301,014, 2,253,287 and 2,337,105.
. Among these carboxyl-protecting groups, pre-ferable are diphenylmethyl, 5-lower alkyl-2-oxo-1,3-dioxol-4-yl-lower alkyl groups, acyloxyalkyl groups, acylthioalkyl groups, phthalidyl group, indanyl group, phenyl group, substitùted or unsubstituted phthalidylidene lower alkyl groups or those groups which can easily be removed in a living body such as groups represented by the following formulas: -CH(CH2)~0R21, -CHOCOOR 1, and ~q ,~ ~
H(CH2)mCOOR~wherein R21 represents a known substituted ' R 3 or unsubstituted alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic qroup; R22 represents a hydrogen atom or a ~ ~3~

1 known substi-tuted or unsubstituted alkyl, alkenyl, aryl, aralkyl, alicyclic or heteroc~clic group; R23 represents a hydrogen atom, a halogen atom or a known substituted or unsubstituted alkyl, cycloalkyl, aryl or heterocyclic 5 group, or -(CH2~nCOOR (R has the same meaning as defined above, and n represents 0, 1 or 2); and m repre-sen~s 0, 1 or 2~
Moxe specifically, there may be used S-lower alkyl-2-oxo-1,3-dioxol-4-yl-methvl groups such as 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, 5-ethyl-2-oxo-1,3-dioxol-4-yl-methyl, 5-propyl-2-oxo-1,3~dioxol-4-y]-methyl and the like; acyloxyalkyl groups such as acetoxy-methyl, pivaloyloxymethyl, propionyloxymethyl, butyrvl-oxymethyl, isobutyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, l-acetoxy-n-propyl, l-pivaloyloxyethyl, 1-pivaloyloxy-n-propyl and the like; acylthioalkyl groups such as acetylthiomethyl, pivaloylthiomethyl, benzoyl-thiomethyl, p-chlorobenzoylthiomethvl, l-acetylthioethyl, l-pivaloylthioethyl, l-benzoylthioethyl, l-(p-chloro-benzoylthio)ethyl and the like; alkoxymethyl groups suchas methoxymethyl, ethoxymethyl, propoxymethyl, isopro-poxymethyl, n-butyloxymethyl and the like; alkoxycarbonyl-oxyalkyl groups such as methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxvcarbonyloxymethyl, iso-propox~carbonyloxymethyl, n-butoxycarbonyloxymethyl, tert.-butoxvcarbonyloxymethyl, l-methoxycarbonyloxyethyl, / - ef~ o ~ ~j c ~ O r~ xy e f h.~ ~
, l-propoxycarbonyloxyethyl, l-isopropoxycarbonyloxyethyl, l-tert.-butoxycarbonyl-~ 3~

1 oxyethyl, l-n-butoxycarbonyloxyethyl and the like;
alkoxycarbonylmethyl groups such as methoxycarbonyl-methyl, ethoxycarbonylmethyl and the like~ phthalidyl group; indanyl group; phenyl group; phthalidilidene-alkyl groups such as 2-(phthalidylidene)ethyl, 2-(5-fluorophthalidylidene)ethyl, 2-(6-chlorophthalidylidene)-ethyl, 2-(6-methoxyphthalidylidene~ethyl and the like; etc.
R represents a group of the formula:

-N N-R ~ ~ N R ~ Rll ~ R14 ` -N ~ ~ R12 ~ R
O o O

in which R6 represents a hydrogen atom, a hydroxyl group, a nitro group, a carbamoyl group, a thiocarbamoyl group, a sulfamoyl group, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, alkadienyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl, aralkyl, acyl, alkoxy, alkylthio, acyloxy, cycloalkyloxy, aryloxy, alkoxycarbonyl, cyclo-alkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl,alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, hetero-cyclic sulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkylsulfonylcarbamoyl, arylsulfonyl-carbamoyl, alkylsulfonylthiocarbamoyl, arylsulfonylthio-carbamoyl, alkylsulfamoyl, dialkylsulfamoyl, alkoxythio-carbonyl, alkylideneamino, cycloalkylmethyleneamino, arylmethyleneamino, heterocyclic methyleneamino or i3 ~8~

1 heterocyclic group; a group of the formula, -N \ R17 (each of R16 and R 7, which may :be the same or different, represents a hydrogen atom or an alkyl group, or R16 and R17 together wi.th their adjacent nitrogen atom may form a ring), each of R7, R8, R9, Rl R11 R12 R14 d 15 which may be the same or different, represents a hydrogen atom, a halogen atom, or a substituted or unsubstituted alkyl, aralkyl or aryl group; R13 represents a hydrogen atom, a halo~en atom, a carboxyl group, a sulfo group, a carbamoyl group, a thiocarbamoyl group, or a substituted or unsubstituted alkyl, aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxy-carbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkyl-sulfonyl, arylsulfon~71, heterocyclic sulfonyl, alkvl-carbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkyl-thiocarbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkyl-sulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonyl-thiocarbamoyl or arylsulfonylthiocarbamoyl group. In each of the groups for R6 and R13 mentioned above, the term "cycloalkyloxy" means -O-cycloalkyl, the term "aryloxy"
means -O-aryl, the term "alkoxycarbonyl" means -C-O-alkyl, the term "cycloalkyloxycarbonyl" means -C-O-cycloalkyl, the term "acyloxycarbonyl" means -C-O-acyl, the term "aralkyloxycarbonyl" means -C-O-aralkyl, the term "alkylsulfonyl" means -SO2-alkyl, the term "cycloalkyl-sulfonyl" means -SO2-cycloalkyl, the term "arylsulfonyl"

~ 3~6 1 means -S02-aryl, the term "heterocyclic sulfonyl" means -S02-heterocyclic ring, the term 'lalkylcarbamovl" means alkyl -C-NH-alkyl, the term "dialkyl carbamoyl" means -C-N
~ alkyl O O
the term "alkylthiocarbamoyl" means -C-NH-alkyl, the term GJ~l Ik~/~h ;4' C~rho~ Oy/ alkyl '~ L'cy~'hie~b~ ~ means -C-N/ , the term "acyl-¦¦ \ alkyl carbamoyl" means -C-NH-acyl, the term "acylthiocarbamoyl"

means -C-NH-acyl, the term "alkylsulfonylcarbamoyl" means -C-NH-S02-alkyl, the term "arylsulfonylcarbamoyl" means -C-NH-S02-aryl, the term "alkylsulfonylthiocarbamoyl"

means -C-NH-S02-alkyl, the term "arylsulfonylthiocarbamoyl"

means -C-NH-S02-aryl, the term "alkylsulfamoyl" means -S02-NH-alkyl, the term "dialkylsulfamoyl" means /alkyl S2 N\ lk 1' the term alkoxythiocarbonyl" means -C-O-alkyl, the term "alkylideneamino" means -N=CH-alkyl, the term "cycloalkylmethyleneamino" means -N=CH-cycloalkyl, the term "arylmethyleneamino" means ~N=CH-aryl, 1 and the term "heterocyclic methyleneamino" means -N=CH-heterocyclic ring.

The groups of the formula, -N ~ 17 wherein R16 and R17 have the same meanings as defined above include amino group, alkylamino groups represented by alkyl -NH-alkyl, dialkylamino groups represented by -N\
alkyl and groups represented by the formulas -N ~ , -N ~ , /~ / \ /~ A A
-N 0, -N NH, -N N-alkyl, -N , -N ) , \ / \ \~ \~
A ~ A ~ N~l ~N=N
-N 0, -N ~ O, -N S, -N SO~, -N ~ , -N ~ or /N=N
-N ¦ .
~== N

The substituents for the various groups men-tioned above include halogen atoms, alkyl groups, aralkyl groups, aryl groups, alkenyl groups, hydroxyl group, oxo group, alkoxy groups, alkylthio groups, nitro group, cyano group, amino group, acyl groups, acyloxy groups, carboxyl group, carbamoyl group, sulfo group, sulfamoyl group, alkylamino groups represented by -NH-alkyl, dialkyl-/alkylamino groups represented by -N , acylamino groups \ alkyl ~ 6 1 represented by -NH-acyl, alkoxycarbonyl groups re-presented by -C-O-alkyl, acylalkyl groups such as acetyl-methyl, propionylmethyl. and the like, aminoalkyl groupssuch as aminomethyl, aminoethyl and the like, N-alkyl-aminoal]cyl groups such as N-methylaminomethyl, N-methyl-aminoethyl and the like, N,N-dialkylaminoalkyl groups such as N,N-dimeth~laminomethyl, N,N-dimeth~laminoethyl and the like, hydroxyalkyl groups such as hydroxymethyl, hydroxyethyl and the like, hydroxyiminoalkyl groups.such as hydroxyiminomethyl, hydroxyiminoethyl and the like, alkoxyalkyl groups such as methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl and the like, carboxyalkyl groups such as carboxymethyl, carboxyethyl and the like, alkoxycarbonylalkyl groups such as methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylmethyl, ethoxycarbo-nylethyl and the like, aralkyloxycarbonylalkyl groups such as benzyloxycarbonylmethyl, benzyloxycarbonylethyl and the like, sulfoalkyl groups such as sulfomethyl, sulfo-ethyl and the like, sulfamoylalkyl groups such as sulfa-moylmethyl, sulfamoylethyl and the like, carbamoylalkylgroups such as carbamoylmethyl, carbamoylethyl and the like, carbamoylalkenyl groups such as carbamoylallyl and the like, N-hydroxycarbamoylalkyl groups such as N-hydroxy-carbamoylmethyl, N-hydroxycarbamoylethyl and the like, a group of the formula -C =C-R in which R represents 0~0 3~-~86 l a lower alkyl group, etc. The above-mentioned various groups as to R6, R7, R8, R9 Rl Rll R12 Rl3 Rl4 d Rl5 may be substituted by at least one of the above-mentioned substituents. Among the ahove substituents, 5 the hydroxyl group, the amino group and the carboxyl group may be protected by a suitable protecting group usually available in the art. The hvdroxyl-protecting groups include all hydroxyl-protecting groups which can be usually used, such as easily removable acyl groups, for example, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo1benzyloxy-carbonyl, 4-(4-methoxyphenylazo)benzyloxycarbonyl, tert.-butoxycarbonyl, l,l-dimethylpropoxycarbonyl, isopropoxy-carbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxy-carbonyl, 2,2,2-tribromoethoxycarbonyl, 2-furfuryloxy-carbonyl, l-adamantyloxycarbonyl, l-cyclopropylethoxy-carbonyl, 8-quinolyloxycarbonyl, formyl, acetyl, chloro-acetyl, benzoyl, trifluoroacetyl and the like; alkyl-sulfonyl groups, for example, methanesulfonyl, ethane-sulfonyl and the like; arylsulfonyl groups, for example, phenylsulfonyl, toluenesulfonyl and the like; benzyl group; diphenylmethyl group; trityl group; methoxymethyl group tetrahydropyranyl group; tetrahydrofuranyl group;
2 nitrophenylthio group; 2,4-dinitrophenylthio group; and the like.
In addition, the amino-protecting groups include all usually usable amino-protecting groups such ;;3~8~;

l as easily removable acyl groups, for example, 2,2,2-trichloroethoxycarbonyl, 2,2,2~tribromoethoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, 4-nitrobenzyloxy-carbonyl, 2-bromobenzyloxycarbonyl, acetyl, (mono-, di-, tri-)chloroacetyl, trifluoroacetyl, formyl, tert.-amyloxy-carbonyl, tert.-butoxycarbonyl, 4-methoxybenzyloxycarbo-nyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo) benzyloxycarbonyl, 4-(4-methoxyphenylazo)benzyloxycarbo-nyl, pyridine-l-oxide-2-yl-methoxycarbonyl, 2-~uryloxy-carbonyl, diphenylmethoxycarbonyl, l,l-dimethylpropoxy-carbonyl, isopropoxycarbonyl, l-cyclopropylethoxycarbonyl, phthaloyl, succinyl, l-adamantyloxycarbonyl, 8-quino-lyloxycarbonyl and the like; further easily removable groups, for example, trityl, o-nitrophenylsulfonyl, 2,4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-l-naphthylmethylene, 3-h~droxy-4-pyridylmethylene, 1-methoxycarbonyl-2-propyli-dene, l-ethoxycarbonyl-2-propylidene, 3-ethoxycarbonyl-2-butylidene, 1-acetyl-2-propylidene, 1-benzoyl-2-pro-pylidene, l-[N-(2-methoxyphenyl)carbamoyl]-2-propylidene, l-[N-(4-methoxyphenyl)carbamoyl]-2-propylidene, 2-ethoxy-carbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, ~ 2-acetylcyclohexylidene, 3,3-dimethyl-5-oxocyclohexylidene, A ~ fro~r~ `aér~
~ and the like; di- or tri-alkylsilyl group; and the like. Then, the carboxyl-protecting groups include all usually usable carboxyl-protecting groups, and there are cases where the carboxyl group is protected by such a group as methyl, ethyl, n-propyl, iso-propyl, tert.-butyl, n-butyl, benzyl, diphenylmethyl, ~Z~;3~8~i;

1 trilyl, 4-nitrobenzyl, 4-methoxybenzyl, benzoylmethyl, acetylmethyl, 4-nitrobenzoylmethyl, p-bromobenzoyl-methyl, 4-methanesulfonylbenzoylmethyl, phthalimido-methyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2-propenyl, l,l-dimethylpropyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, 3-methyl-3-butynyl, succinimido-methyl, l-cyclopropylethyl, methylthiomethyl, phenylthio-methyl, dime~ylaminomethyl, ~uinoline-l-oxide~2-ylmethyl, pyridine-l-oxide-2-ylmethyl, bis~p-methoxyphenyl)methyl and the like, where the carboxyl group is protected by a non-metal compound such as titanium tetrachloride, and where the carboxyl group is protected by a silyl compound such as dimethylchlorosilan~ as described in Japanese Patent Application Kokai (laid-Open) No. 7073/71 and Dutch lS Patent Application No. 7105259 (Laid-Open).
R5 represents a hydrogen atom or a protected or unprotected amino group, and such amino-protecting groups include many gxoups usually employed in the fields of penicillins and cephalosporins, specifically all the amino-protecting groups mentioned above as to R2.
A represents a group of the formula, -CH2- or a group of the formula, ~ in which R18 represents a oR18 hydrogen atom; a substituted or unsubstituted alkyl, alke-nyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, hete-rocyclic group or a hydroxyl-protecting group, or a group il_if~ ~;3''~

1 of the formula, ~P / 20 (each of Rl9 and R20, which may be the same or different, represents a hydroxyl, alkyl, aralkyl, aryl, alkoxy, aralkyloxy or aryloxy group) and the bond means that the compound may be a syn-isomer or an anti-isomer or a mixture thereo. The said hydroxyl-protecting group includes the hydroxyl-protecting groups mentioned as to R . In addition, the above-mentioned various groups for R18 may be substituted by at least one substituent selected from halogen atoms, oxo group, cyano group, hydroxyl group, alkoxy groups, amino group, alkyl-amino groups, dialkylamino groups, heterocyclic groups and groups of the formulas: -COOR , -CON< 26 ~ -N-/R26 , -NHCOR and ~P< OR26 wherein Rl has the same meaning as defined above, and each of R25, R26 and R27, which may be the same or different, represents a hydrogen atom, an alkyl group, an aralkyl group or an aryl group. Among these substituents, the hydroxyl group, the amino group, and the carboxyl group may be protected respectively by the hydroxyl-protecting group and the amino-protecting group mentioned as to R and the carboxyl-protecting group mentioned as to Rl.

--C--The oximes of the formula, N include syn-~R18 and anti-isomers and mixtures thereof.

3'~8~

1 In the R ~ ~ group of each formula in R

this invention, there are tautomers as shown by the following equilibrium formulas where R5 is a protected or unprotected amino group, and such tautomers are included in this invention: H

R _ ~ ~ ~ R ~ ~

wherein R4 and R5 have the same meanings as defined above, and R a represents a protected or unprotected imino group.
In the above formulas, the imino-protecting group for R5a includes those groups used in the fields of penicillins and cephalosporins, and specifically, same groups as the monovalent groups among the amino-protecting groups mentioned above as to R2.
When the -CH2R group in the formula [I] is a group of the formula:

15 -CH N~ R6 or R IN ~ wherein R6, R10, Rll and R12 have the same meanings as defined above, there are tautomers as shown in the following equilibrium formulas when each of R6 and R10 is a hydrogen atom, and the tautomers are also included in this invention:

O OH
-CH2-N~=~NH -C~ CH -N N

~ CH2 N S R12 ~ he salts of the compounds of formula (I) include salts at the basic group and the acidic group which are well-known in the fields of penicillins and cephalosporins. The salts at the basic group include salts with mineral acids such as hydrochloric acid, nitric acid, sulfuric acid and the like; salts with organic carboxylic acids such as oxalic acid, succinic acid, formic ~cid, trichloroacetic acid, trifluoroacetic acid and the like; and salts with sulfonic acids such as methanesulfonic acid, ethanesul~onic acid, benzenesulfonic acid, toluene-2-sulfonic acid, toluene-4-sulfonic acid, mesitylenesulfonic acid (2,4,6-trimethylbenzenesulfonic acid), naphthalene-l-sulfonic acid, naphthalene -2-sulfonic acid, phenylmethanesulfonic acid, benzene-1,3-disulfonic acid, toluene-3,5-disulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6 disulfonic acid, naphthalene-2,7-disulfonic acid, benzene-1,3,5-trisulfonic acid, benzene-1,2,4-trisulfpnic acid, naphthalene-1,3,5-trisulfonic acid and the like. The salts at the acidic group include salts with alkali metals such as sodium, potassium, and the like; salts with alkaline earth metals such as calcium, magnesium and the like; ammonium salts; and salts with nitrogen-containing organic bases such as procaine, dibenzylamine, N-benzyl-~ -phenethylamine, l-ephenamine, N,N-dibenzylethylenediamine, 8i6 1 triethylamine, trimethylamine, tributylamine, pyridine, 7efh ~J~
N,~ .e'~ ~e, N-methylpiperidine, N-methylmorpho-line, diethylamine, dicyclohexylamine and the like.
This invention includes all optical isomers and the racemic compounds of cephalosphorins of the formula [I] and their salts, and also all crystal forms and hydrates of the said compounds. More specifically, pre-ferable examples of the compounds represented by the formula --C--[I] are oximes in which A is a group of the formula, N
o~R18 particularly syn-isomers thereof, in which R 8 is preferably an alky] group, especially methyl, ethyl; or a substituted alkyl group, especially -CH2COORl or -C-COORl (Rl has the same meaning as defined above).
Preferable examples of R2 are groups of the O O
formula, -N N-R6 in which R is a hydrogen atom, a sub-~ ~LVer stituted or unsubstituted/alkyl group or a group of the formula, -N/ l7 (R16 and R17 have the same meanings as defined above); groups of the formula, R ~

O R

in which each of R7, R8 and R9, which may be the same ~ 8~

l o.r different, represents a hydrogen atom or an alkyl RlO o group; groups of the formula, \ l~ Rll o each of R10, Rll and Rl2, which may be the same or dif-h~dr~
~~~ ferent, represents a-h~d~eVgr. atom, a halogen atom or R~/3 an alkyl group; and groups of the formula, I ~
~\ R

in which each of R13, R14 and R15, which may be the same or different, represents a hydrogen atom or an alkyl group.
Next, pharmacological effects are shown on some typical compounds represented by the formula [I].

l) Antibacterial activity ~Table 1) Accordlng to the standard method of Japan Society of Chemotherapy ~"CHEMOTHERAPY", Vol . 23, pp. 1-2 (1975)], a bacterial solution obtained by culturing in Heart Infusion broth (manufactured by Eiken Kagaku) at 37C for 20 hours was inoculated onto a Heart Infusion agar containing a drug and cultured at 37C for 20 hours, after which the growth of the bacteria was observed, to determine the minimum concentration at which the growth of the bacteria was inhibited as MIC ~g/ml). The amount ~. 5 3 ~ 6 1 of the inoculated bacteria was 104 cells/plate (10 cells/ml). The MIC values of the following test compounds are as shown ln Table 1:
(~) trifluoroacetic acid salt of 7 [2-(2-amino-thiazol-4-yl)-2-(syn) methoxyiminoacetamido]-3-{[1-(2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl~-~3-eephem-4-earboxylic acid, (B) triCluoroacetic acid salt of 7- [2- (~-amino-thiazol-4-yl)-2-(syn)-methoxyiminoaeetamido]-3-{[1-l4-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}--cephem-4-earboxylic acid, (C) trifluoroacetic aeid salt of 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoaeetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl~]methyl}-~3-eephem-4-carboxylie aeid, (D) trifluoroaeetie aeid salt of 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(4-isopropyl-2,3-dioxo-1,2,3,4-tetrahydropyrazin~l)]methyl}-~3-eephem-4-carboxylie aeid, (E) trifluoroaeetie aeid salt of 7-[2-(2-amlno-thiazol-4-yl)-2-(syn)-methoxyiminoaeetamido]-3-{[1-(4-dimethylamino-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]~
methyl}-~3--eephem-4-earboxylie aeid, (F) 7-[2-(2-aminothiazol-4-yl)-2-(syn)-earboxy-methoxyiminoaeetamido] 3-{[1-(2,3-dioxo-1,2,3,4-tetra-hydropyrazinyl)]methyl}-~3-eephem-4-earboxylie acid, (G) trifluoroaeetie aeid salt of 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-carboxymethoxyiminoacetamido]-3-1 {[1-(4-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-methyl}-Q3-cephem-4-carboxylic acid, (H) trifluoroacetic acid salt of 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-carboxymethoxyiminoacetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-methyl}-a3-cephem-4-carboxylic acid, (I) trifluoroacetic acid salt of 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-carboxymethoxyiminoacetamido~-3-{[1-(4-dimethylamino-2,3-dioxo-1,2,3,4-tetrahydro-pyrazinyl)]methyl}-Q3-cephem-4-carboxylic acid, (J) trifluoroacetic acid salt of 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(2-oxo-1,2-dihydropyrazinyl)]methyl}-~3-cephem-4-carboxylic acid, (K) trifluoroacetic acid salt of 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(3,6-dioxo-1,2,3,6-t.etrahydropyridazinyl)]methyl}-Q3-cephem-4~carboxylic acid, (L) formic acid salt of 7-[2-(2-aminothiazol-4-yl)-2-Isyn)-carboxymethoxyiminoaceta~ido]-3-{[1-(3,6-dioxo-1,2,3,6-tetrahydropyridazinyl)]methyl}-Q3-cephem-4-carboxylic acid, (M) ` trifluoroacetic acid salt of 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(3-methyl-6-oxo-l~6-dihydropyridazinyl)]methyl}-Q3-cephem 4-carboxylic acid, and (N) formic acid salt of 7-[2-(2-aminothiazol-4-yl)-2-~syn)-carboxymethoxyiminoacetamido]-3 3~

1 {[1-(3-methyl-6-oxo-1,6-dihydropyridazinyl)]methyl}-Q3-cephem-4-carboxylic acid.

53.~8~i _ __ _ __ _ ~ 1~ ~1 ~ ~ l l ~ ~ ~ ~i 00 [`
~) 0l 0 VOll O VOll VOll -_ __ _ _ _ _ H H~1 ~1 ~ ~`i r~l ~1 r-l ~1 ~ r-l 1S~ U~ O
~ VOII VOII VOII VOII VOII \/11 VOII ~ (~
.~ _ ~ ~ ~1 ~i ~ ~i ~ ~ ~1 ~ ~ ~D ~i l VOll VOll VOll VOll VOll l VOll r-~ ~D
_ _ _ __ V ~ ~i ~ ~ ~ ~ ~ ~ ~ ~ ~ l VD O O Vll O Vll VOll VOll VOll VO ~1 _ _ _ _ ~ ~1 ~ ~ ~ ~i ~ ~ ~ ~ ~ ~ i Vll VOll l VOll l VOll VOll VOll ___ ~1 ~ i ~ ~ ~O CO
01~ 011 011 011 Vll 011 011 Vll 011 ~_i 0 _~ ~ Li ~ ~ ~ ~ ~ ~ _I ~ t~i ~ In l ~U r-l VDVD VOD VD VOD VD Vll O O ~1 ~1 ~li . .
S ' U ~ ~ ~ ~ ~ ~ ~ r-i ~ ~i 00 ~i ~) VD VOD VD Vll VO VD vi voi vn ~i o ~D
R . . _ _ .~ ai ~ i ~ ~ ~i ~ ~ ~ _, ~i u~
vll v v~ vn v~ o . -~ ~ ~1 ~i . i ~ ~ ~ ~ ~i ~ ~ In Vil v~ vll vn vn vn vn VOl vn v o ~i __ __ _ ~c ~c ~i~o _~ ~ co ~ I O ~i ~ ~ ~D ~ ~1 ~D
o ¦ ~ 3 a l ~ v z z ol u~ ui ~E H 1.~ E E E O U 1~ )~ ~1 O
I u O O ~ ~ E E ~ . ~ 5 I ~ . . . ~ h O O O ~
L~ ~ _ ~ ~; ~c ai __ __ ~' _ ~ 5i3~

s~
.,, ~
Ul U~
.,~
~ ~, .,, ~
t, o s~
o s~
P~ ~
Q~ C
U~ ,, s~
o U~
,, o .,, '~
a ~ C~
*
#

..

z Z _ _ ~ _ _ ____ _~ _.
o o o o o o o o o V~ Vll Vll VllVll Vll ~ _ ___ _ _ CO
~ ~ ~ I~ ~ ~ ~ ~ I~
. . . l ~ . . .. . .
0~ VOll O O O O O O O O
_ __ 00 ~ ~D
U~ ~ ~1 . .. l l .. . . . .
O O O Or-l O O O 1~
(D Vll V11V!l Vll Vil 5~ _ ___ _ __ CO
~ ~ ~ ~ ~ ~ ~ ~1 t`
E~ X . . . l l . . . . . .
O O O O O O O O O
\'ll Vll Vll Vll Vll Vll Vll ;3q~

1 2) Urinary recovery A tes-t compound was orally administered to mice (ICR, male, 4 weeks old) in an amount of 1 mg/mouse, and a urinary recovery was determined. The results ohtained are shown in Table 2.
In the test compounds (No. l and No. 2), the ester group is easily removed in a living body, whereby the com-pounds are converted into the corresponding free carboxylic acids. Therefore, the urinary recovery was determined by quantitatively measuring the free carboxylic acids excreted into urine.
Administration method: A test compound sus-pended in 0.5~ CMC (Carboxy Methyl Cellulose) was orally administered.
Quantitative measurement method: The amount of free carboxylic acid was measured by bioassay (a paper-disc methodj using the test organism mentioned in Table 2.

~f~ 8~, . ~D .

~ ~o\O +l +l +l ,~ O a~ ~r ~ a) Lr o o ~;

______ U~ +~ ~ ~ ~
,1 ~ ~ o a)~ Q ~
tn ~ E~
~; ~ ~
~ ~, C~ ~; .
U~CO~ U~
l~o g~o o~o ~ ~o E~ J 1~ O 1 Z-- _ N ~ ~ _ _ O
~ O
N N ~O
~ __ _ O

~ 5: UZ
_ ~ . ~ _ .. Z . .__ _ __.
.~ .
~.

~ 3~8 l 3) ~cute toxicity LD50 values of the following test compounds were 3 g/kg or more when the compounds were intravenously administered to mice (ICR, male, body weight 20-24 g).

Test compounds:
o Sodium 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido~-3-{rl-(2,3-dioxo-1,2,3,4-t~tra-hydropyrazinyl~]methyl}-Q3-cephem-4-carboxylate, o so~ium 7-[2-(2-aminothiazol-4-yl)~2-(syn)-10 methoxyiminoacetamido]-3-{[1-(4-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-Q3-cephem-4-carboxylate, o sodium 7-[2-(2-aminothiazol-4-yl)-2-(syn)-`
methoxyiminoacetamido~-3-{[1-t3,6-dioxo-1,2,3,6-tetra hydropyridazinyl)]methyl}-~3-cephem-4-carboxylate, and 15 o sodium 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(3-methyl-6-oxo-1,6-dihydro-pyridazinyl)]methyl}-~3-cephem-4-carboxylate.
Next, an explanation is made below of production processes.
The compound of this invention can be prepared by the following processes:

._ a) ~

s~ s~,, o o ~ ` o z,,~

x~ ~

~ e~ c , `~ ~ s o c.) ~ ~ ~
~ rl ~ C tO O
~~ ~ o o ~ a) S ~ ~ _ O S
O ~
~ ~ o~ VV~

H H~0 0 'a ~ \\
\\ ` O
X O ' ` ~ ~0 ~ ~ O

H H ~ ~ ~ U ~ ~ ~ ~ ~ V
V ~ ~ -- -- O V-- ~ V ~

4~
~; ~ o g H ,_ S~
~ ~ z X rC
H 1~ ' X ~ O .,~

æ u~ a) E ZN ~
~ o ~
~, x A~ ~
X I ~ ,~
o v~
o ~ Z;
N N N
N `~ ~1 ~
~1 ~ O N N
N O~) S ~:: X ~
~ ' O
~ o S S~ ~ ~ g ~
Z ~~ s~ ,1 \~ Z H 0 ~ ; X
I ~a~ o ~ ~ I xa~ IY'----I \\ -- ,C
=~ K- ~ O ~ ~O ~ ~ Z O
O ~ . Z
= Z~O O ~)=Z~,O
N ~ H O ~ ~1 H C) X
X O H X ~ ~ S
~ ~ H O 8 ~ a) o ~
~ a~ o~
C) s ~ ~ O
8 ~ - z'~
C)=Z~O ~ ~ ~ ~ o ~o ~ s ~
t ~ ~n H ~ N 1~ rl ~ // :~
U // ~3 ~g~ o~o~ ~ D
s o o O UcZ~O
,1-- o u~ o ~ ~ Q' ~
o ~ a) ' o H ~ ~ .
U - N ~ --C ) -- ~ ~ rl rl O
h ~1 C~ S~ U2 O O 11~ ~rl O
~ ~ x ~ ~ 3~ ~
~:~,-- co O 0,~ ~ h O a N ~1 C 1~ I S
~ O ~ Il~ ~ ~IS tJ~

~ ~;3~

~ U~
Z ~ o ~ ~ ~
o~ o ~; o u~
.,, .,, .~ .,, H H H H

'I ~ ~;
O O O O

,_ .. ~r z ~ 53~b Production Route 2 ,R3 R30-CoNH r~ ~ [XVI]
0 1' COOR
or a salt thereof Q ~ o (conver- HN NR ~III-a]
sion at ~=~
,R3 3-position) or a salt thereof R -CONH ~ ~S~ o O
N ~ CH2N NR6 COOR

+ ~ [XVII]
,R3 R30-coNHt~s~ o O
N ~ CH2N NR6 COOR J
or salts thereof ¦ (conversion into Q3-cephem) ,R3 ~

R30-CoNH ~ S~ ~ O
O ~ C 2 ~=JNR [XVIII]
COORl or a salt thereof ; (deacylation) / (Cont'd) i3~'b Production Route 2 (Cont'd~
`I
R,3 H N ' ' ~ ~ 6 N ~H2N NR [XIX]
COOR

or a salt thereof ~f~3~

1 In the above formulas, R , R , R , R , R , R , 7 8 9 10 Rll R12 R13 R14, R15, R , A and the bond ,v-~ have the same meanings as defined above; R 8a represents the groups for R18 except a hydrogen atom; R 8 represents an amino group, or a group of the formula, 32\ C=C-NH- in which each of R , R and R 3, which may l33 be the same or different, represents a hydrogen atom or an organic residue not participating in the reaction, or a group of the formula, 35> C-N- in which each of R34 and R35, which may be the same or differentl represents a hydrogen atom or an organic residue not participating in the reaction; R29 represents a substituted or unsubstituted acyloxy or carbamoyloxy group; R30 represents benzyl, phenoxymethyl or a group of the formula, R5 ~ ~ in which R4, R and A have the same R

meanings as defined above; X represents a halogen atom;
>Z represents >S or >S-~O; and the dotted line in the rins represents a double bond between the 2- and 3-positions or the 3- and 4-positions.
A further detailed explanation is made below.
R 8 represen~s an amino group, a group of the formula, ~ ~3~b R31\ R34\
1 32/ C=C-NH- or a group of the formula, 35/ C-N-, and the group of the formula, 32> C=C-NH- includes the group R3 \ R33 of the formula, R32/ CH-C=N- which is its isomer. The l33 organic residues not participating in the reaction for 5 R31, R32, R33, R3 and R 5 include those well-known in the art, specifically substituted or unsubstituted aliphatic residues, alicyclic residues, aromatic residues, aromatic-aliphatic residues, heterocyclic residues, acyl groups and the like. More specifically, the ~ollowing groups are included:
(1) aliphatic residues: alkyl groups; alkenyl groups, (2) alicyclic residues: cycloalkyl groups;
cycloalkenyl groups, (3) aromatic residues: aryl groups, (4) aromatic-aliphatic residues: aralkyl groups, (5) heterocyclic residues: heterocyclic groups,

(6) acyl groups: acyl groups which can be derived from organic carboxylic acids which include aliphatic carboxylic acids, alicyclic carboxylic acids and alicyclo-aliphatic carboxylic acids; and also include aromatic aliphatic carboxylic acids, aromatic-oxyaliphatic carboxylic acids, aromatic-thioaliphatic carboxylic acids, heterocyclic aliphatic carboxylic acids, heterocyclic-oxyaliphatic carboxylic acids, and heterocyclic-3(~8~

a~ ~, c J 1 thioaliphatic carboxylic acids, in which an ~re_mti~rresidue or a heterocyclic group is bonded, directly or through an oxygen or sulfur atom, to an aliphatic carboxylic acid;
organic carboxylic acids wherein an aromatic residue, an aliphatic group or an alicyclic group is bonded to the carbonyl group through an oxygen, nitrogen or sulfur atom; aromatlc carboxylic acids; heterocyclic carboxylic acids; and the like.
The above aliphatic carboxylic acids include formic acid, acetic acid, propionic acid, butanoic acid, isobutanoic acid, pentanoic acid, methoxyacetic acid, methylthioacetic acid, acrylic acid, crotonic acid and the like, the above alicyclic carboxylic acids include cyclohexanoic acid and the like and the above alicyclo-aliphatic carboxylic acids include cyclopentaneaceticacid, cyclohexaneacetic acid, cyclohexanepropionic acid, cyclohexadieneacetic acid and the like.
Also, the aromatic residues in the above-mentioned organic carboxylic acids include phenyl, naphthyl and the like.
Each of the groups constituting these organic carboxylic acids may be further substituted by a sub-stituent such as a halogen atom, a hydroxyl group, a pro-tected hydroxyl group, an alkyl group, an alkoxy group, an acyl group, a nitro group, an amino group, a protected amino group, a carboxyl group, or a protected carboxyl group.
Also, the substituted or unsubstituted acyloxy and carbamoyloxy groups for R29 include alkanoyloxy ~ ~3 ~

1 groups such as acetoxy, propionyloxy, butyryloxy and the like; alkenoyloxy groups such as acryloyloxy and the llke; aroyloxy groups such as benzoyloxy, naphthoyloxy and the like; and carbamoyloxy group. These groups may be substituted by one or more substituents such as halogen atoms, nitro group, amino group, alkyl groups, alkoxy groups, alkylthio groups, acyloxy groups, acylamino groups, hydroxyl group, carboxyl group, sulfamoyl group, carbamoyl group, alkoxycarbonylcarbamoyl groups, aroyl-carbamoyl groups, alkoxycarbonylsulfamoyl groups, arylgroups, carbamoyloxy group and the like.
In the above-mentioned substituents for R29, hydroxyl group, amino group, carboxyl group and the like may be protected with protecting groups which are usually employed, and the protecting groups include, specifically the hydroxyl-protecting groups, amino-protecting groups and carboxyl-protecting groups which have been mentioned above as to R .

(a) Conversion reaction at 3-position

7-Substituted or unsubstituted amino-3-substi-tuted methyl cephem carhoxylic acid of the formula [IV] or a salt thereof can be produced in a high yield with a hiyh purity using an industrially easy procedure by reacting a 2,3-dioxo-1,2,3,4-tetrahydropyrazine of the formula [III-a], a 2-oxo-1,2-dihydropyrazine of the formula [III-b], a 3,6-dioxo-1,2,3,6-tetrahydropyridazine of the formula [III-c], or a 6-oxo-1,6-dihydropyridazine of the ~ 6 1 formula [III-d], or a salt thereof with a cephalosporanic acid represented by the formula [II] or a salt thereof in the pr~sence of an acid or a complex compound of an acid, then if desired, removing the protecting group, protecting the carboxyl group or converting the obtained compound to a salt thereof. Further, the above-mentioned 2,3-dioxo-1,2,3,4-tetrahydropyrazine can be prepared by the method described in the Journal of Chemical Society, Perkin I, pp. 1888-1890 ~1975).
Furthermore, if necessary, the substituent on the amino group at the 7-positiQn can be removed in a conventional manner to form a 7-unsubstituted amino compound. According to this procedure, not only ~3-cephem compounds but also ~2-cephem compounds can be used as the starting compounds, and where the ~2_ cephem compounds are used as the starting compounds, the reaction product ~2-cephem compounds are further converted to ~3-cephem compounds.
Also, not only compounds where >Z is >S but also compounds where >Z is >S~O can be used as the starting materials, and in the latter case >S~O can be converted to >S during the reaction or in an after-treatment step.
If the 2,3-dioxo-1,2,3,4-tetrahydropyrazine of the formula [III-a], the 2-oxo-1,2-dihydropyrazine of the formula ~III-b], the 3,6-dioxo-1,2,3,6-tetrahydro-pyridazine of the formula tIII-C] ~ff~ the 6-oxo-1,6-dihydro-pyridazine of the formula [III-d] which ~ used as ~f~ ~3~

a reactant in the reac-tion, has a basic or acidic group as the substituent, these compounds may, i~ necessary, be applied in the form of the corresponding salt to the reaction. In this case, the salts at the basic groups and the salts at the acidic groups include those mentioned as to the salts of the compounds of the formula ( I).

Also, the salts of the compounds of the formulas (II) and (IV) include salts at the basic groups and at the acidic groups, and these salts include those mentioned about the salts of the compounds of the formula ( I). The salts of the compounds of the formula ( II 3 may be previously isolated and then used, or may be prepared in situ.

As the acids or the complex compounds of acids used in the reaction, there are mentioned, for example, protonic acids, Lewis acids or complex compounds of Lewis acids. The protonic acids include sulfuric acids, sulfonic acids and super acids (super acids means acids stronger than 100% sulfuric acid and includes some of the above-mentioned sulfuric acids and sulfonic acids). More specifically, the protonic acids include sulfuric acids such as sulfuric acid, chlorosulfuric acid, flurorsulfuric acid and the like, sulfonic acids, for example, alkyl (mono- or di-) sulfonic acids such as methanesulfonic acid, trifuloromethanesulfonic acid and the like, aryl(mono-~ di- or tri-) sulfonic acids such as p-toluenesulfonic acid and the like, super acids, such as perchloric acid, magic acid (FS03H-SbF5), FSO3H-ASFs~ CF3S03H-SbFs, HF-BF3, H2S04-S03 and the like.

The Lewis acids include, for example, boron trifluoride, and the complex compounds of Lewis acids include complex compounds of boron trifluoride with dialkyl ethers such as diethyl ether, di n-propyl ether, di-n-butyl ether and the like; with amines such as ethylamine, n-propylamine, n-butylamine, triethanolamine and the like; with esters such as ~ ~3l~
ethyl formate, ethyl acetate and the like; with aliphatic acids such as acetic acid, propionic acid and the like; and with nitriles such as acetonitrile, propionitrile and the like.

The reaction is preferably conducted in the presence of an organic solvent. The organic solvents used include all organic solvents inert to the reaction, for example, nitroalkanes such as nitromethane, nitroethane, nitropropane and the like;
organic carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, dichloroacetic acid, propionic aci~ and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, ethyleneglycol dimethyl ether, anisole, 1,2 dimethoxy ethane and the like;
esters such as ethyl formate, diethyl carbonate, methyl acetate, ethyl acetate, ethyl chloroacetate, butyl acetate and the liks;
nitriles such as acetonitrile, butyronitrile and the like; and sulfolanes such as sulfolane and the like. These solvents may be used in admixture of two or more. In addition, complex compounds formed from these or~anic solvents and Lewis acids can be used as the solvent. It ~ ~3~6 1 is sufficient that the amount of the acid or the complex compound of the acid used is at :Least equimolar to the amount of the compound represented by the formula [II] or a salt thereof, and the amount may be varied depending on the respective cases. In particular, the use in a proportion of 2-10 moles per mole of the compound of the formula [II] or a salt thereof ls preferred. Where the complex compound of the acid is used, it can be use~ per se as a solvent, and two or more of the complex compounds may be used in admixture.
It is sufficient that the amount of the 2,3-dioxo-1,2,3,4-tetrahydropyrazine of the formula [III-a], the 2-oxo-1,2-dihydropyrazine of the formula [III-b], the 3,6-dioxo-1,2,3,6-tetrahydropyridazine of the formula [III-c] or the 6-oxo-1,6-dihydropyridaæine of the formula [III-d] or a salt thereof is at least equimolar to the amount of the compound represented by the formula [II] or a salt thereof, and particularly, ab~
the use in an amount~of~l.0-5.0 moles per mole is preferred.
This reaction is usually carried out at 0-80C, and completes in ten minutes to thirty hours. The pxe-sence of water in the reaction system may cause undesirable side reactions such as lactonization of the starting l~cta~
material or products and clea~age of ~-1QC ~m ring, so that it is desirable to keep the system under the anhydrous conditions. In order to fulfill this require-ment, it is sufficient to add, to the reaction system, 1 a suitable dehydrating agent, for example, a phosphorus compound such as phosphorus pentoxide, polyphosphoric acid, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride or the like; an organic silylat-ing agent such as N,O-bis(trimethylsilyl)acetamide, trimethylsilylacetamide, trimethylchlorosilane, dimethyl-dichlorosilane or the like; an organic acid chloride such as acetyl chloride, p toluenesulfonyl chloride or -the like;
an acid anhydride such as acetic anhydride, trifluoroacetic anhydride or the like; an inorganic dehydrating agent such <~nh~drous as anhydrous magnesium sulfate, ~hydrous calcium chloride, a molecular sieve, calcium carbide or the like.
If a compound represented by the formula [II]
wherein Rl represents a carboxyl-protecting group is used as the starting material, a compound represented by the formula [IV] wherein Rl represents a hydrogen atom can, in some cases, be directly obtained by the reaction, or can be obtained by removing the protecting group in a conventional manner.
Next, conversion reaction at 3-position, which is described in Production Route 2, is explained.
The halogenated compound represented by the formula [XVI~ can be prepared according to the method described in Tetrahedron L~tters, No. 46, pp. 3991-3994 25 ~1974) and Tetrahedron Letters No. 40, pp. 3915-3918 ~1981).
The compound represented by the formula [XVII]
or a salt thereof can be prepared by the reaction of a - 4~ -

8~

1 halogenated compound represented by the formula [XVI] or a salt thereof with a 2,3-dioxo-1,2,3,4-tetrahydro-pyrazine of the formula [III-a] or a salt thereof in the presence of a base. The base includes alkali metal pOf ~55~ tr~
~ 5 carbona~es (for example, sodium carbonate,/or the like); ' alkali metal hydrogencarbonates (for example/ sodium hydrogencarbonate, potassium hydrogencarbonate and the like); alkali metal hydroxides (for example, so~ium hydroxide, potassium hydroxide, and the like); nitrogen-containing organic bases, for example, triethylamine,pyridine, N,N-dimethylaniline and the like.
The conversion at 3-position is generally carried out in a suitable solvent. The solvent lncludes halogenated hydrocarbons such as chloroform, methylene chloride and the like; ethers such as tetrahydrofuran, dioxane and the like; N,N-dimethylformamide; N,N-dimethyl-acetamide; acetone; water; and mixtures thereof.
In this case, the compound represented by the formula [III-a] or a salt thereof is preferably used in an amount of about 1.0-2.0 moles per mole of the compound represented by the formula ~XVI] or a salt thereof. The reaction is generally carried out at a temperature of 0-50C for 30 minutes to 10 hours.
The mixture of a Q2_ and Q3-cephem compound thus obtained, that is, a compound represented by the formula [XVII] or a salt thereof, can be easily converted into the ~3-cephem compound, to prepare the compound of the formula [XVIII] or a salt thereof, which is then ~if~.~3 ~8~

1 converted into the compound of the Eormula [XIX] or a salt thereof by the deacylation. Said conversion reaction and deacylation are kno~m in the ~ields of penicillins and cephalosporins and are specifically described in the Journal of Organic Chemistry, Vol. 35, No. 7, pp. 2430-2433 (1970) and "Cephalosporins and Penicillins" ~by Flynn, Academic Press), pp. 56-64.
If the substituents of the 2~3-dioxo-1,2,3,4-tetrahydropyrazi.ne of the formula ~III-a], the 2-oxo-1,2-dihydropyrazine of the formula [III-b], the 3,6-dioxo-1,2,3,6-tetrahydropyridazine of the formula [III-c], or the 6~oxo-1,6-dihydropyridazine of the formula ~III-d] or the salt thereof, which are used as the reactants in the reaction, are substituted by a hydroxyl group, an amino group, a carboxyl group or the like, these groups may be protected by the above-mentioned protecting groups prior to the reaction and subjected to a con-ventional removal reaction after the completion of the reaction to obtain a desired compound.
Also, the compound represented by the formula [IV] or [XIX] can, if necessary, be protected at the carboxyl group or converted into the salt according to a conventional method, to obtain the objective compound.
Also, the compound represented by the formula ~IV~ wherein R28 represents an amino group can be converted into a reactive derivative at the amino group or the compound represented by the formula [XIX] as mentioned hereinafter by a conventional method.

~;3~

1 (b~ Acylation When the compound represented by the formula [V~, [VI], ~VII], [VIII] or [XIII], or a salt thereof, or a reactive derivative thereof is reacted with a compound represented by the formula [IV] or a salt thereof or a reactive derivative at the amino group, a compound represented by the formula [I], [IX], [X], [XI] or [XIV], or a salt thereof is obtained.
The salts of the compound represented by the formula [V], [VI], [VII], [VIII3 or [XIII] include salts at the basic group or the acidic group, which specifically include those mentioned as to the salts of the compound represented by the formula [I].
The reactive derivatives at the amino group of the compound represented by the formula [IV] include all derivatives which are often used in acylation, for e~ample, an isocyanate; a Schiff base produced by the reaction of the compound represented by the formula [IV]
or a salt thereof with a carbonyl compound such as an aldehyde, a ketone, or the like lketimine type or its isomer, namely, enamine type); a silyl derivative, a phosphorus derivative or a tin derivative, produced by the reaction of a compound represented by the formula [I~] or a salt thereof with a silyl compound such as bisltrimethylsilyl)acetamide, trimethylsilylacetamide, trimethylsilyl chloride, or the like, a phosphorus com-ro, ro, pound such as phosporus trichloride, L /PC1, 1 /PCl, \
~ O~ 3 2 )2PCl, (CH3CH2)2PCl or the like, or a tin compound such as ~C4Hg)3SnCl or the like.
The reactive derivatives of the compounds repre-sented by the formulas [V], [VI], [VII], [VIII] and [XIII]
include specifically acid halides, acid anhydrides, mixed acid anhydrides, active acid amides, active esters, reactive derivatives obtained by reaction of the compounds represent-ed by the formulas [V], [VI], [VII], [VIII] and [XIII] with a Vilsmeier reagent. The mixed acid anhydride includes c~c~fk~7q~e, a mixed acid anhydxide with a monoalkyl aarb~nt~ such as monoethyl carbonate, monoisobutyl carbonate and the like, a mixed acid anhydride with a lower alkanoic acid which may be substituted by a halogen, such as pivalic acid, tri-chloroacetic acid or the like. The active acid amide includes N-acylsaccharin, N-acylimidazole, N-acylbenzoyl-amide, N,N'-dicyclohexyl-N-acylurea, N-acylsulfonamide and the like. The active ester includes cyanomethyl ester r substituted phenyl esters, substituted benzyl esters, substituted thienyl esters and the like.
The reactive derivatives obtained by reaction with a Vilsmeier reagent include those obtained by re-action with a Vilsmeier reagent obtained by reacting an acid amide such as N,N-dimethylformamide, N,N-dimethyl-acetamide or the like with a halogenating agent such as phosgene, thionyl chloride, phosphorus trichloridel phosphorus tribromide, phosphorus oxychloride, phosphorus pentachloride, trichloromethyl chloroformate, oxalyl chloride or the like.

~ 6 1 If each of the compounds represented by the formulas [V], [VI], [VII], [VI.II] and [XIII] is used in the form of a free acid or a salt, a suitable condens-ing agent is used. The condensing agent includes N,N'-disubstituted carbodiimides such as N,N'-dicyclo-hexylcarbodiimide; a~olide compounds such as N,N'-thionyldiimidazole; dehydrating agents such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, alkoxyacetylenes and the l.ike; 2-halo-genopyridinium salts such as 2-chloropyridiniummethyl iodide and 2-i.luoropyridiniummethyl iodide; and the like.
This acylation reaction is usually carried out in a suitable solvent in the presence or absence of a base. As the solvent, there may be used a solvent inert to the reaction, for example, a halogenated hydro-carbon such as chloroform, methylene chloride or the like; an ether such as tetrahydrofuran, dioxane or the like; N,N-dimethylformamide; N,N-dimethylacetamide;
acetone; water; or a mixture thereof. As the base, there may be used an inorganic base such as an alkali metal hydroxide, an alkali metal hydrogencarbonate, an alkali metal carbonate, an alkali metal acetate or the like; a tertiary amine such as trimethylamine, triethyl-amine, tributylamine, pyridine, N-methylpiperidine, N-methylmorpholine, lutidine, collidine or the like; or a secondary amine such as dicyclohexylamine, diethy-lamine or the like.

3~86 The compound representPd by the formula (IX) or a salt thereof which can be converted into the compound represented by the formula (Ia) or (Ib) or a salt thereof can be produced by the following procedure:

In order to obtain the compound represented by the formula ( IX ) or a salt thereof using the compound represented by the formula (IV) or a salt thereof, a 4-halogeno-3-oxo-butyryl halide which is obtained by the reaction of diketene with a halogen such as chlorlne or ~romine [Journal of the Chemical Society, 97, 1987 (1910)] may be reacted with the compound represented by the formula (IV) or a salt thereof according to a usual method. Reaction conditions and procedures which are known in the art can be applied to this reaction. And the salt of the compound represented by the formula (IX) can easily be prepared according to a usual method, and the salt includes the same salts as mentioned above as to the salts of the compound represented by the formula (I). Although the compound represented by the formula (IX) or a salt thereof may be isolated and purified, it can be used for the subsequent reaction without isolation.

In addition, the compound represented by the formula ~v)~ (VI), (VII), (VIII) or (XIII) or a salt thereof or a reactive derivative thereof is preferably used in an amount of about one mole to several moles per mole of the compound represented by the formula (IV) or a salt thereof or its reactive derivative at the amino group. The reaction is usually carried out at a temperature ranging from ~f~

l -50 to 40C. The reaction time is usually lO minutes to 48 houxs.
Furthermore, the compounds represented by the formulas [IJ, [IX], [X], [XI] and [XIV] wherein Rl is a carboxyl-protecting group can be converted to the compounds represented by the formulas [I], [IX], [X], [XI] and [XIV]
wherein Rl is a hydrogen atom, or their salts according to the usual method; and similarly the compounds represented by the general ormulas [I], ~IX], [X], [XI] and [XIV]
wherein Rl is a hydrogen atom can be converted to the com-pounds represented by the formulas [I], [IX], [X], [XI] and [XIV] wherein R is a carboxyl-protecting ~ ~or salts thereof; and the salts of the compounds represented by the formulas [I], [IX], [X], [XI] and [XIV] can be converted to the corresponding free acid forms, respectively.
Also, in this acylation reaction, if R , R and R contain groups active to the reaction, these groups can suitably be protected witn conventional protecting groups prior to the reaction, and the protecting groups can also be removed by a usual method after the reaction.
The compound represented by the formula [I] ~a salt thereof of this invention obtained by the above-mentioned method can be isolated by a conventional method.

(c) Nitrosation Subsequently, in order to obtain the compound represented by the formula [X~ or a salt thereof from the compound represented by the formula [IX] or a salt thereof, a nitrosating agent is reacted with the compound 3~8~i l represented by the formula [IX] or a salt thereof. The reaction is usually carried out in a solvent, and as the solvent, there may be used a solvent inert to the re-action such as water, acetic acid, benzene~ methanol, ethanol, tetrahydrofuran or the like. Preferable examples of the nitrosating agent include nitric acid and deriva-tives thereof, for example, nitrosyl halides such as nitro-syl chloride, nitrosyl bromide and the like, alkali metal nitrites such as sodium nitrite, potassium nitrite and the like, alkyl nitrites such as butyl nitrite, pentyl nitrite and the like. If a nitrous acid salt is used as the nitro-sating agent, it is preferable to carry out the reaction in the presence of an inorganic or organic acid such as hydrochloric acid, sulfuric acid, formic acid, acetic acid or the like. If an alkyl nitrite is used as the nitrosatin~ agent, it is preferable to carry out the reaction in the presence of a strong base such as an alkali metal alkoxide or the like. The reaction is usually carried out at a temperature ranging from -15 to 30C, and the reaction time is usually 10 minutes to 10 hours.
The salt of the compound represented by the formula [X] can easily be prepared according to a usual method, and the salt includes the same salts as mentioned above as to the salts of the compound represented by the formula [I]. Although the compound represented by the formula [X] or a salt thereof thus obtained can be isolated and purified by a well-known method, it can be used for the subsequent reaction without isolation.

- 54 ~

~ 3~,~6 1 (d) Etherification and phosphorylation In order to obtain the compound represented by the formula [XI] or a salt thereof from the compound represented by the formula [X] or a salt thereof, the compound represented by the formula [X] or a salt thereof is subjected to etherification reaction or phosphoryla-tion reaction.
The etherification reaction and the phosphoryla-tion reaction can be carried out by a usual method such as described in Japanese Patent Application Kokai (Laid-Open~ Nos. 137,988/78~ 105,689/80, 149,295/80 and the like.
For example, alkylation can be carried out according to a usual method. The reaction is generally carried out at a temperature of -20~ to 60C and completes in 5 minutes to 10 hours.
As the solvent, there may be used a solvent inert to the reaction, ~or example, tetrahydro-furan, dioxane, methanol, ethanol, chloroform, methylene chloride, ethyl acetate, butyl acetate, NrN-dimethyl-formamide, N,N-dimethylacetamide, water, or a mixture thereof.
As the alkylating agent, there may be used, for example, a lower alkyl halide such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide or the like, dimethyl sulfate, diethyl sulfate, diazomethane, diazo-ethane, methyl p-toluenesulfonate or the like. If an alkylating agent other than diazomethane and diazoethane 33 ~86 1 is ~sed, the reaction is carriecL out in the presence of an alkali metal carbonate such as sodium carbonate, potassium carbonate or the like; an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or the like;
or an organic base such as triethylamine, pyridine, N,N-di-methylaniline or the like.
Also, the salt of the compound represented by the formula [XI] can easily be obtained according to a usual method, and the salt includes the same salts as mentioned above as to the salts of the compound represented by the formula [I].
In addition, a protecting group can be introduced and removed according to a usual method, whereby a compound can be changed into a corresponding objective compound.
Although the compound represented by the formula [XI] or a salt thereof thus obtained may be isolated and purified by a usual method, they can be used for the sub-sequent reaction without isolation.

(e) Ring closure reaction The compound represented by the formula [Ia] or [Ib] or a salt thereof of this invention can be obtained by the reaction of the compound represented by the formula ~IX], ~X] or [XI] or a salt thereof with the thioformamide or thiourea represented by the formula [XII]. This reaction is usually carried out in a solvent. As the solvent, there may be used a solvent inert to the reaction, for example, water, methanol, ethanol, acetone, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetaminde, N-methylpyridone, alone or in admixture of two or more. Although it is not essential to add an acid-removing agent, the reaction sometimes proceeds smoothly by add:Lng an acid-removing agent in such an amount that the cephalosporin skeleton will not be influenced. the acid-removing agent used for the reaction includes inorganic and organic bases such as alkali metal hydroxides, alkali metal hydrogen-carbonates, triethylamine,pyridine, N,N-dimethylaniline and the like. The reaction is usually carried out at a temperature of 0-100C.
Thioformamide of thiourea is usually used in an amount of about one mole to several moles per mole of the compound represented by the formula (IX), (x) or (XI) or a salt thereof. The reaction time is 1-48 hours, preferably 1-10 hours. Furthermore, in the compound represented by the formula (Ia~ or (Ib), the protection of the carbonyl group and removal of the carboxyl-protecting group or conversion of the product to a salt can be carried out according to a usual method to convert the compound to the corresponding ob~ective compound. If Rl, R2, and R5 ln the formula (Ia) or (Ib) contain groups active to the reaction, these groups can be suitably protected by a conventional protecting group prior to the reaction and the protecting group can be removed by a usual method after the reaction. The ob~ective compound represented by the formula (Ia) or (Ib) or its salt thus obtained can be isolated by usual method.

~3~

1 (f) Oximination The compound represented by the formula [Ib]
or a salt thereof is obtained by reacting the compound represented by the formula [XIV] or a salt thereof with the compound represented by the formula [XV] or a salt thereof. The salt of the compound represented by the formula [XV~ includes hydrochlorides, hydrobromides, sulfates and the like. This reaction is usually carried out not only in a solvent such as water, an alcohol, N,N-dimethylacetamide or the like but also in other solvents inert to the reaction or a mixed solvent there-of. The reaction is carried out at a temperature of 0 to 100C, preferably in a range of 10 to 50C. The reaction time is usually 10 minutes to 48 hours. The compound represented by the formula [XV] or a salt thereof is used in an amount of about one mole to several moles per mole of the compound represented by the formula [XIV] or a salt thereof. Although the salt of the compound represented by the formula ~XV]
can be used per se for the reaction, it can also be reacted in the presence of a base, for example, an inorganic base such as an alkali metal hydroxide (for example, sodium hydroxide, potassium hydroxide or the like), an alkaline earth metal hydroxide (for example, magnesium hydroxide, calcium hydroxide or the like), an alkali metal carbonate (for example, sodium carbo-nate, potassium carbonate or the like), an alkaline earth metal carbonate (for example, magnesium carbonate, calcium carbonate or the like), an alkali metal ~ ~3~

hydrogencarbonate (for example, sodium hydrogencarbonate, potassium hydrogencarbonate or the like), an alkaline earth metal phosphate (for example, magnesium phosphate calcium phosphate or the like)~ an alkali metal hdyrogenphosphate (for example, disodium hydrogenphosphate, dipotassium hydrogenphosphate) or an alkali metal acetate (for example, sodium acetate, potassium acetate), an organic base such as a trialkylamine (for example, trimethylamine, triethylamine, or the like), plcoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo-t4,3,0]-5-nonene, 1,4-diazabicyclo[2,2,2]octane, 1,5-diazabicyclo[5,4,0]-7-undecene or the like. The compound represented by the formula (Ib) or a salt thereof of this invention thus obtained can undergo conversion of Rl in a conventional manner, and can also be isolated by a usual method. (g) Alkoxylation: The compound represented by the formula (IV) wherein R3 is an alkoxy group can be synthesized from the compound represented by the formula (IV) wherein R3 is a hydrogen atom by a method known per se, for example, the method described in the Journal of Synthetic Organic Chemistry, Japan, 35, (7), 563-574 (1977).
Furthermore, the compound represented by the formula (I), (Ia), (Ib), (IX), (X), (XI) or (XIV) wherein R3 is an alkoxy group can be synthesized from the respective compound represented by the formula (I), (Ia), (Ib)~ (IX), (X), (XI) or (XIV) wherein ~ ~3~

1 is a hydrogen atom in a manner known per se, for example, the method described in Japanese Patent Application Kokai (Laid-Open) Nos. 24,888~79 and 103,889/79.
The compound represented by the formula ~I] or S a salt thereof thus obtained can be administered to human beings and animals in the form of a free acid or in the form of a pharmaceutically acceptable salt or ester for the purpose of the treatment of and protection against bacterial infections. It is preferable to parenterally administer the compound in the form of a free acid or a pharmaceutically acceptable salt or orally administer the compound in the form of a pharmaceutically acceptable ester.
In that case, it is sufficient that the compound is formed into a dosage form usually used in cephalosporin medi-cines, for example, tablet, càpsule r powder, fine granule,granule, syrup, injection lincluding drip), suppository or the like. When the above-mentioned medicine is formed into a dosage form, there may be used diluents and/or additives, for example, vehicles such as starch, lactose, sugar, calcium phosphate, calcium carbonate or the like; bonding agents such as gum arabic, starch, micro-crystalline cellulose, carboxymèthyl cellulose, hydroxy-propyl cellulose or the like; lubricants such as talc, magnesium stearate or the like; disintegrating agents such as carboxymethyl calcium, tàlc or the like.

3l`~816 1 When the compound represented by the formula [I] or a salt thereof ls administered, the dosage~
the administration time and the administration method can be varied depending on the symptoms of patient, and generally it is sufficient to administer orally or parenterally to an adult in a dose of about 50-5000 mg in 1 to 4 portions a day.
This invention is explained below with reference to Referential Examples and Examples which are merely by way of illustration and not by way of limitation.

Referen~ial Example 1 (1) To a solution of 20.0 g of ethyl N-(2,2-di-ethoxyethyl)oxamate in 60 ml of ethanol was added 6.1 ml of 70% by weight aqueous ethylamine solution~ and the mixture was subjected to reaction at room temperature for 1 hour. After the completion of the reaction, the precipitated crystals were collected by filtration and recrystallized from ethanol to obtain 17.0 g (yield: 85.1%) of N-ethyl-N'-(2,2-diethoxyethyl)oxamide having a melting point of 131-132C.
IR (KBr) cm : vC=O 1650 In a similar manner, the compounds shown in Table 3 were obtained.

3~36 Table 3 (CH3CH20)2CHCH2NE~CoCONHR6 Compound Solvent for m.p. ¦ IR ~KBr) cm 1 recrystal- (C) ~C-O
R6 lization -H Ethyl 141-142 1650, 1635 acetate -CH3 Ethanol 135-136 1645 (CH2)2CH3 Acetone 84-85 1645 \ CH n-Hexane145-146 1650, 1635 (2)3 3 n-Hexane111-112 1645 (2)4 3 n-Hexane 92-93 1650 -(CH2)5CH3 n-Hexane 87-88 1650 ~C 2)7C 3 n-Hexane110-111 1645 -(CH2)11CH3 n-Hexane 83-84 1645 Ethanol154-155 1640 -CH2~ ~ n-Hexane113-114 1655 _ .
-CH2CH2OH Ethanol118-119 C~3 OCH ~ Ethanol 157-158 1645 ~ _ 128-129 1655 -CH2 ~ -OCH3 ~ i ~ 5~

1 (2) To a solution of the 17.0 g of N-ethyl-N'-(2,2-diethoxyethyl3oxamide obtained in above (1) in 85 ml of acetic acid was added 0.05 ml of con-centrated hydrochloric acid. The mixture was refluxed for 30 minutes. After com~letion of the reaction, the solvent was removed by distillation under reduced pressure, and 70 ml of acetone was added to the residue, and crystals were collected by filtration. The crystals were recrystal-lized from methanol to obtain 6.8 g (yield: 61.8~) of 4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine having a melting point of 173-174QC.
IR (KBr) cm 1 vc=O 1680-1620 In a similar manner, the compounds shown in Table 4 were obtained.

3`~
Table 4 o Compound ¦ recrystal- ¦ ~P~ IR (KBr) cm R6 lization l vc=o -H . > 280 1680-1640 -CH3 Ethanol220-231 1690-1635 -(CH2)2CH3 Acetone 182-183 1680-1640 CH ~ CH Acetone215-219 1680, 1625 - (CH2) 3CH3 Acetone149-150 1680, 1640 ~ 2) 4 3 Acetone171-172 1620 - (CH2) 5CH3 Acetone141-142 1520 .
- (CH2) 7CH3 Acetone145-146 1670, 1635 - (CH2) 11CH3 Ethanol145-146 1660, 1625 .
Acetone254-255 1670, 1635 -CH2 ~ Acetic acid 225 1665, 1635 .~
2 2 C C 3 Methanol178 - 180 1720, 1675, CH _ _ _ --CH3 ¦ Ethanol229-230 1700-1625 I
~--\ I 175-176 1740-1620 2~ 3 ~

~ ~ ~3~

1 (3) To a suspension of 5.2 g of the 4-(2,4-dimethoxybenzyl)-2,3-dioxo-1,2,3,4-tetrahydropyrazine obtained in above (2) in 26 ml of N,N-dimethylformamide was added 4.1 g of potassium carbonate, and the mixture was stirred at rocm temperature for 30 minutes. Subsequ-ently, 5.8 g of 4-bromomethyl-5-methyl-1,3-dioxol-2-one was added thereto, and the mixture was subjected to reaction at 50-60C for 3 hours. The reaction mixture was introduced into a mixed solvent of 200 ml of ethyl acetate and 200 ml of water, after which the organic layer was separated, washed with 100 ml of water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by a rq4~ar~4 column chromatography (Wako Silica Gel C-200/, eluen~;
chloroform) to obtain 4.9 g lyield, 66.0%, of 1-(2,4-dimethoxybenzyl)-4-(5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine having a melting point of 154-156C.
IR (KBr) cm : vC=O 1820, 1675, 1630 In a similar manner, the compounds shown in Table 5 were obtained.

Table 5 ~CH3 o~4o H30~ CH2-N N-~R6 Compound I m. p. ( c) IR (KBr) cm 1: vc O
_ _ O 1-8-190 1775, 1700, 1650 -CH2OCOC ~ CH 3) 3 100- 101 1750, 1690, 1660, .

-CH2COOC(CH3)3 105-106 1740, 1690, 1650 ~53~

1 (43 In a mixed solvent of 37 ml of trifluoroacetic acid and 10.8 g of anisole was dissolved 3.7 g of 1-(2,4-dimethoxybenzyl)-4-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-2,3-dioxo-1,2,3,4~tetrahydropyrazine ob-tained in above (3) and the mixture was reacted at 50Cto 60C for 2 hours. Subsequently, the solvent was removed by distillation under reduced pressure. To the residue was added 30 ml of diethyl ether and crys-tals were collected by filtration to obtain 2.0 g (yield, 90.9%) of 4-(5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine having a melting point of 225-226C.

IR (KBr) cm : VC O 1825, 1805, 1725, 1690, 1670 In a similar manner, the compounds shown in Table 6 were obtained.

Table 6 0,~_</o HN N_R6 Compound _ I __ __ m.p. (C) IR (KBr) cm 1 ~C O
o ~ >270 1790, 1775, 1730, _ . _ -CH2OCOC(CH3)3 166-167 1740, 1700, 1660 -CH2COOH (decomp.) ~ 1730, 1670-1630 1 (5) To a solution of 2.6 g of 1-carboxymethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine in 13 ml of N,N-dimethyl-acetamide was added 3.9 g of diphenyldiazomethane at room temperature, and the mixture was subjected to reaction for for 10 minutes. The reaction mixture was introduced into a mixed solvent of 25 ml of ethyl acetate and 25 ml of water, and the mixture was stirred for 15 minutes. Precipitated crystals were collected by filtration, and washed with 10 ml of ethyl acetate and 10 ml of diethyl ether ln this order to obtain 2.9 g ~ ~3`~6 1 (yield, 80.4~) of l-diphenylmel-hyloxycarbonylmethyl-2~3 dioxo-1,2,3,4-tetrahydropyrazine having a melting point of 97-98C.

IRIKBr)cm : vC=O 1750, 1675, 1645 Example 1 (1) To a solution Or 10 ml of ethyl acetate con-taining 2.71 g of boron trifluoride were added 2.72 g of7-aminocephalosporanic acid (hereinafter referred to as 7-ACA) and 1.54 g of 4-ethyl-2,3-dioxo-1,2,3,4-tetrahy-dropyrazine, and the mixture was subjected to reaction at room temperature for 16 hours. After completiGn of the reaction, the reaction mixture was introduced into 50 ml of methanol with cooling, and then 3.16 g of py-ridine was added dropwise thereto. Precipitated crys-tals were collected by filtration, washed sufficiently with 30 ml of methanol, and thereafter dried to obtain 3.10 g (yield, 88.1%) of 7-amino-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-A3-cephem-4-carboxylic acid having a metling point of 191-195C
(decomp.).
IR (KBr) cm : ~C O 1795, 1670, 1620 NMR ~CF3COOD) ~ values:
1.44 (3H, t, J=7Hz, `~NCH2CH3), 3.69 (2H, bs, C2-H), 4.08 (2H, q, J=7Hz, ~ NCH2CH3), 5.14, 5.51 (2H, ABq, J=15Hz, S ~, 5.48 (2H, s, C6-H, C7-H), ~ CH2-~33~6, l 6.74, 7.00 (2H, ABq, J-6Hz, ~ ) (2) The conversion reaction at 3-position mentioned in above (1) was carried out under the reaction condi-tions shown in Table 7 to obtain 7-amino-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-i3 cephem-4-carboxylic acid in the yields shown in Table 7.

~ 70 -~3-~8~

Table 7 _ _ Starting material Acid or Reaction Amount No. Solvent complex condi- (Yield) _ 7-ACA IN N <EI~CH, compo nd tions .

l 2 72l 54 Sulfo- Boron Room 2.6 g . g . g lane tri- tempera- (73.9%) lO ml fluoride ture 2.7l g 2 hours 54 Nitro- Boron Room 2.85 g 2 2.72 g l. g methane tri- tempera- (8l.0%) l4 ml fluoride- ture ether 16 hours 5co7mpgex l (3) In a similar manner to that in above (l~, the compounds shown in Table 8 were obtained.
(In this case, the objective compounds were obtained by pouring into ice-water the reaction mixture after completion of the conversion at 3-position and adjusting to pH 3.5 with 28% by weight aqueous ammonia solution with ice-cooling.) ~5~ 6 _ U ~ ~ ~ ~ .
U~ ~ . ~ X
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1 (4) The conversion reaction at 3-position mentioned in above ~1) was carried out under the reaction conditions shown in Table 9 to obtain 7-amino-3-{[1-(3,6-dioxo-1,2,3,6-tetrahydropyridazinyl)]methyl}-~3-cephem-4-carboxylic acid in the yields shown in Table 9.

Table 9 Starting Acid or Reaction Amount No. mate: ial Sol- complex condi- (Yield~

7 -ACA hydr a - vent of acid ~

Tri- Boron tri- Room 1.72 g fluoro- fluoride- temper- (72 3%) 1 2.0 g 0.91 g acetic diethyl ature 10 ml complex 16 hour-Sul- Boron tri- Room 2.75 g 22.72 g 1.23 g folane fluoride temper-(84-9%) _3 hours .

(5) In a ~imilar manner to that in above (1), the crude crystals shown in Table 10 were obtained.

~3~

Table 10 2 Tl~ S l CH R2 COOH
_ __ No . Compound _ R2 l -N N-CH2CH2CH3 4 3~N /C~3 -N N ( CH2 ) 3CH3 6 --N N~3 7 -N N ( CH2 ) 1 1CH 3 - 50nt ' d ~3~

Table 10 (Cont 'd) 8 -N ~-CH2CH20COCH3 -N N-CH2--~>

-N N-N

r -N~

12 --N~CH3 _ l *2 HN~ _Cl - Cont ' d ~2~;;3~L8~

Table 10 (Cont'd) 14 HN~ C~3 ~ ~3 .

--N ~J

r~ 1 1 Note: The compounds in Nos. 10, 11, 12, 13, 14 and 15 were obtained by the reaction using sulfolane as a solvent.
*1: This compound was obtained by the procedure of introduction into methanol, filtration of insolubles and addition of pyridine into the filtrate.
*~: The representation was taken because it was not confirmed whether the chlorine atom was placed at 4- or 5-position, and whether the product was composed of a single compound or a mixture. (Such representations in Tables ~ ~3 ~b~

l appearing hereinafter have the same meaning.) *3: The representation means that the product was a mixture of a 4-substituted compound and a 5-substituted compouncl. (Such representations in Tables appearing hereinafter have the same meaning.) Example 2 To a suspension of 3.0 g of the 7-amino-3-{[l-(4-e~hyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylic acid obtained in Example l-(l) in 30 ml of methanol was added 1.62 g of p-toluene-sulfonic acid monohydrate to form a solution, and then 5.0 g of diphenyldiazomethane was slowly added to the solution, after which the resulting mixture was subjected to reaction at room temperature for 15 minutes. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was dissolved in a mixed solvent of 20 ml ethyl acetate and 20 ml of water. The solution was adjusted to pH 7.0 with sodium hydrogencarbonate. Sub-sequently, the organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (Wako Silica Gel C-200, eluent; benzene:ethyl acetate = 1:4 by volume) to obtain 3.1 g (yield, 70.3~) of diphenylmethyl 7~amino-3-{[l-;3~

1 (4-ethyl~2,3~dioxo~ ,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxyla-te having a melting point of 183-186C (decomp.).
IR (Ksr) cm : vC_O 1765, 1730, 1680, 1630 In a similar manner, the compounds sh~wn in Table 11 were obtained.

-- ~0 --3`~

Table 11 H2N~
0~ ~\CH2R
COOCHI ~ )2 . . _ . .
Compound m.p. (C~ IR (KBr) c~ : VC O

o~o _ 129-130 1765, 1725, -N NH (decomp.) 1690, 1630 0~,0 ' .
; -N N-CH 127-128 1770, 1725, ~ ~==) 3 (decomp.) 1690, 1640 O O -169-171 1765, 1730, -N N(CH2)2CH3 (decomp.) 1685, 1635 O O
C~3 179-180.5 1760, 1720, -N~ NCH~ ( decomp.) 1685, 1635 O O
180-189 1760, 1725, -N N(CH2) 3CH3 (decomp.) 1680, 1630 O O _.
~ 185-194 1765, 1730, -N N(CH2) 4CH3 (decomp.) 1685, 1630 - Cont'd -~.r~3~6 Table 11 (Cont'd) Compound m-p. (C~ IR (KBr) cm : VC o O ~ O 170-174 ~ 1765, 1730, -N~ N(CH2)5CH3 (decomp.) ~ 1685, 1635 ~ 1186-188 1 176~i, 1730, -N N(CH2)7CH3 ¦(decomp.) ¦ 1685, 1635 ~ 164-172 1 1765, 1730, -N N(CH2)11CH3 (decomp.) I 1685, 1635 O ~ O 165-168 1765, 1725, -N N ~ (decomp.) 1680, 1625 O O _ 155-160 1770, 1725, -N N-CH2 ~ (decomp.) 1680, 1630 O ~ O 146-148 1770, 1725, -N~==JNCH2CH2ccH3 (decomp.) 1678, 1623 O O ~
~ ~ CH3 172-175 1760, 1720, -N N-N ~ 1680, 1630 N 82-85 1775, 1720, ___ (decomp.) 1650 - Cont'd -Table 11 (Contld) ~ _ Compound m.p. (~C) IR (KBr) cm 1 vc O

. . , N 108-114 1765, 1725, (decomp.) 1650 . ___ _ _ O 132-135 1780, 1730, H~N ~ ~ 1665 H~ ~ 178-181 1780, 1730, ~ Cl (decomp.) 1660 O O
~ ~ 3 +N~ (decomp.) 1780, 1730, O O .

~ 90-93 1770, 1720, N ~ ~ (decomp.) 1660 - . _ .

~ 2 3 . 138-143 1770, 1720, N ~ (~-c ~ ~ 1660 Example 3 In a mixed solvent of 25 ml of trifluoroacetic acid and 10 ml of anisole was dissolved 4.9 g of diphenylmethyl 7-amino-3-[1- (2,3-dioxo-1,2,3,4-tetra-5 hydropyrazinyl)methyl]-~3-cephem-4-carboxylate and the solution was su}:jected to reaction at room temperature for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and 50 ml o~ diethyl ether 10 was added to the residue, after which erystals were eolleeted by filtration. The crystals were sufficiently washed with 40 ml of diethyl ether and then dried to obtain 4.25 g (yield, 97.0g6) of trifluoroacetic acid salt of 7-amino-3-{~1-(2,3-dioxo-1,2,3,4~tetrahydropyrazinyl)]-15 methyl}-Q3-eephem-4-earboxylic aeid having a melting point of 105-106C (deeomp.) IR (KBr) em : vC=O 1780, 1700-1630 NMR (CF3COOD) ~ values:

3.72 (2H, bs, C2-H), S
5.14, 5.52 (2H, ABq, J=15Hz, ~LCH
5.44 (2H, s, C6-H, C7-H), 6.78, 6.98 (2H, ABq, J=6Hz, H H

In a similar manner, the eompounds shown in Table 12 were obtained.

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-- 93 ~

~ 3~ ~6 1 Example 4 To a suspension of 5.0 g of 7-amino-3-{[1-(3-methyl-6-oxo-1,6-dihydropyridazinyl)]methyl}-~3-cephem-4-carboxylic acid in 15 ml of acetone were added 2.36 g 5 of 1,8~diazabicycloL5,4,01-7-undecene and 4~51 g of pivaloyloxymethyl iodide at 10-15C, and the mixture was subjected to reaction for 30 minutes. After completion of the reaction, the reaction mixture was introduced into a mixed solvent of 50 ml of water and 50 ml of ethyl 10 acetate, and the organic layer was separated, washed with water and then dried over anhydrous magnesi~m sulfate.
Subsequently, 10 ml of an ethyl acetate solution containing 1.~0 g of oxalic acid was added thereto, and the precipit-ated crystals were collected by filtration and washed with 15 ethyl acetate to obtain 4.59 g (yield, 56.2%) of oxalic acid salt of pivaloyloxymethyl 7-amino-3-{[1-(3-methyl-6-oxo~l,6-dihydropyridazinyl)]methyl}-~3-cephem-4-carboxylate having a melting point of 145-147C (decomp.).
IR (KBr) cm : vc=O 1790, 1750, 1660 NMR (d6-DMSO) ~ values:
1.21 (9H, s, -CH3x3).
2.29 (3H, s, ~ CH3), 3.52 (2H, bs, C2-H), 4.94, 5.33 (2H, ABq, J=15Hz, ~ ~, -5.14 (lH, d, J=5Hz, C6-H), 5.76-6.23 (3H, m, C7-H, -OCH2O-), ~ 94 -3fl8~

- H
1 7.01, 7.53 (2H, ABq, J=lOHz, ~ ), 7.44 (3H, bs, -NH ~) ~xample 5 (1) To a solution of 2.69 g of 1-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine in 27 ml of N,N-dimethylformamide was added 1.52 g of potas-sium carbonate, and the resulting mixture was stirred at room temperature for 20 minutes. Subsequently, 4.67 g of tert.-butyl 7-phenylacetamido-3-bromomethyl-~2-cephem-4-carboxylate was added thereto with ice-cooling, and the mix-ture was subjected to reaction at room temperature for 2 hours. The reaction mixture was introduced into a mixed solvent of 200 ml of ethyl acetate and 150 ml of water, and the organic layer was separated, washed with 150 ml of water, and then dried over anhydrous magnesium sulfate.
Subsequently, the solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in 100 ml of chloroform. To the solution was added 2.45 g (purity, 70~) of m-chloroperbenzoic acid, and the mixture was subjected to reaction at room temperature for 1 hour.
The solvent was removed by distillation under reduced pre-ssure, and to the residue were added 100 ml o ethyl ace-tate and 100 ml of water. The organic layer was separated, washed with 100 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was puri-fied by a column chromatography ~Wako Silica Gel C-200, ~ ~3 ~

1 eluent; chloroform~ to obtain 2.70 g (yield, 43.2~ of tert.-butyl 7-phenylacetamido-3-{[1-[4-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-2,3-dioxo-1,2,3,4-tetrahydro-pyrazinyl]]methyl}-~3-cephem-4-carboxylate-1-oxide having a melting point of 135-136C (decomp.).
IR (KBr) cm 1 ~C O 1820, 1790, 1720, 1685, 1650 (2) In a mixed solvent of 12 ml of N,N-dimethyl-formamide and 6 ml of acetonitrile was dissolved 3.0 g ~f tert.-butyl 7-phenylacetamido-3-{[1-t4-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-2,3-dioxo-1,2,3,4-tetrahydro-pyrazinyl]]methyl}-~3-cephem-4-carboxylate-1-oxide. To the solution were added 1.0 g of stannous chloride and 1.58 g of acetyl chloride in this order with ice-cooling, and the mixture was subjected to reaction at room temper-ature for 30 minutes. The solvent was removed by distil-lation under reduced pressure, and to the residue were added 50 ml of ethyl acetate and 50 ml of water, after which the resulting mixture was adjusted to pH 6.0 with sodium hydrogencarbonate. Subsequently, the organic layer was separated, washed with 50 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by a column chromatography (Wako Silica Gel C-200, eluent; toluene:ethyl acetate = 3:2 by volume) to obtain 2.12 g (yield, 72.4%) of tert.-butyl 7-phenyl-acetamido-3~{[1-[4-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-2,3-dioxo-1,2,3,4-tertrahydropyrazinyl]]methyl}-~3-cephem-4-carboxylate having a melting point of 120-122C

(decomp~).

1 IR (KBr) cm : vC=O 1820, 1775, 1715, 1685, 1645 NMR (CDC13) ~ values.
1.58 (9H, s, -C(CH3)3), 2.28 (3H, s, -CH3) 3.17, 3.61 (2H, ABq, J-18Hz, C2-H), 3.77 (2H, s, ~ CH2-), 4.53, 5.13 (2H, ABq, J=15Hz, S~ ), ~ CH2-4.71 (2H, s, ~NCH2-), 5.03 (lH, d, J=SHz, C6-H), 5.93 (lH, dd, J=5Hz, J=8Hz, C7-H), 6.53, 6.89 (2H, ABq, J=6Hz, ~ / ), H H
7.32-7.51 (5H, m, ~ ), 7.57 (lH, d, J=8Hz, -CONH-) In a similar manner to that in above (1) and (2), the compounds shown in Table 13 were obtained.

~3~

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1 (3) In 30 ml of anhydrous methylene chloride was dissolved 2.0 g of tert.-butyl 7-phenylacetamido-3-{[1-[4-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl]]met:hyl}-~3-cephem-4-carbo-xylate. To this solution were added 1.59 g of N,N-dimethylaniline and 0.57 g of trimethylsilyl chloride in this order, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to -90C, and 0.89 g of phosphorus pentachloride was added thereto, and the mixture was subjected to reaction at -30 to -20C for 2.5 hours. Subsequently, the reaction mixture was cooled to -40C, and 5.2 g of anhydrous meth-anol was added thereto, after which the reaction was con-tinued with ice-cooling for 1 hour. To the reaction mixture was added 20 ml of water and stirring was continued for a further 30 minutes. Subsequently, the reaction mixture was adjusted to pH 0.5 with 6 N
hydrochloric acid, and then the aqueous layer was sepa-rated. To this aqueous layer was added 50 ml of ethyl acetate, and the mixture was adjusted to pH 6.5 with sodium hydrogencarbonate. The organic layer was separated, washed with 50 ml of water, and then dried over anhydrous magne-sium sulfate. The solvent was removed by distillation under reduced pressure, and to the residue was added 50 ml of diethyl ether. The crystals were collected by filtra-tion to obtain 1.05 g (yield, 64.8~) of tert.-butyl 7-amino-3-{[1-[4-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl~
2,3-dioxo-1,2,3,4-tetrahydropyrazinyl]]methyl}-~3-cephem-~ ~3'~6 1 4-carboxylate having a melting point o~ 185-188C (decomp.).
IR (KBr ) cm : \~C=O 1820, 1765, 1705, 1690, 1635 NMR (CDC13+d6-DMSO) ~ values:
1-52 (9H, s, -C(CH3)3~, 2.24 (3H, s, -CH3), 3.46 (2H, bs, C2-H), 4.35, 5.08 (2H, ABq, J=15Hz, S~ ), ~CH 2 ~
4.76-5.09 (4H, m, ~NCH2~, C6-H, C7-H), 6.74 (2H, s, H - - ~H
In a similar manner, the compounds shown in Table 14 were obtained.

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~ 6 1 Example 6 ~1) In 2.29 ml of N,N-dimethylacetamide and 4.58 ml of acetonitrlle was dissolved 2.29 g of 2-~2-formamido-thiazol-4-yl)-2-(syn)-methoxyiminoacetic acid, and to the resulting solution was added dropwise 1.62 g of phospho-rus oxychloride, after which the mixture was subjected to reaction at -5 to 0C for 1 hour. Subsequently, 5.18 g of diphenylmethyl 7-amino-3-{[1-(4-ethyl-2,3~dioxo-1,2,3,4-tetrahydropyrazinyl~3methyl}-~3-cephem-4~carboxylate was added to the reaction mixture, and the mixture was subjected to reaction at -5 to 0C for 1 hour. After completion of the reaction, the reaction mixture was poured into a mixed solvent of 80 ml of water and 80 ml of ethyl acetate, and the resulting solution was ad-justed to pH 6.5 with sodium hydrosencarbonate. Subse-quently, the organic layer was separated, and dried over anhydrous magnesium sulfate. The solvent was re-moved by distillation under reduced pressure, and to the residue was added 60 ml of diethyl ether. Then, the crystals were collected by filtration to obtain 6.05 g (yield, 83.0%) of diphenylmethyl 7-[2-(2-formamido-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylate having a metling point of 165-168C.
IR (KBr) cm : VC O 1780, 1720, 1680, 1640 NMR (d6-DMSO) ~ values:
1.18 (3H, t, J-7Hz, ~N-CH2CH3), 3.59 (2H, bs~ C2-H), 3.72 (2H, q, Js7Hz, ~N-CH2CH3), 33`~

3.97 (3H , s , -OCH3), 4.42, 5.04 (2H, A13q, J=15Hz, S ), ~L CH 2 ~
5.30 (lH, d, J=5E~z, C~;-H), 6.02 ( lH , dd , J=5Hz , J=8Hz , C7-E~), 6.50, 6.62 (2H, ABq, J=6Hz, \ / ), A

H H
7.04 ( lH , s , -CH~ ), N

7.17~7.82 (llH~ m, ~ x2, ~ ), S H

8.63 (lH, s, HCO-),

9.89 (lH, d, J=8Hz, ~CONH-), 12.68 (lH, bs, HCONH-) In a simila.r manner, the compounds shown in Tables 15, 16 and 17 were obtained.

3~

Table 15 ~N - C -CONH ~ 1 C 2 ~S ~ R4 N ~ H2R
\OCH3 COOCH( ~ )2 (syn-isomer) Compound R2 R4m.p. (C) vc=o _ _ O~ O H 1~0-125 1780, 1720, -N ~-CH3 (decomp. ) 16~0-1640 _ O O H -154-156 1785, 1720, ~ (decomp.) 1685, 1645 -N~=~N-(CH~)4CH3 O O H 131-136 1783, 1725, ~ ` (decomp.) 1680, 1645 -N~==N(CH2)5CH3 .

_ O H 180-182 1780, 1720, O~ (decomp.) 1680-1640 -N~=~N(CH2)7CH3 _ _ 158-166 1780, 1725, O ~O H (decomp.) 1675, 1640 -N N-(C~12)11CH3 ~ H126-138 1785, 1725, -N N-CH2 ~
._ _ . ~

- Cont'd --3`~6 Table 15 (Cont' d) O~O Br ( de c omp . ) 1675, 1640 _ O H 171-173 1780, 1720, N ~ Idec omp . ) ~ I ~ 9 1~

H 148-151 1780, 1730, (decomp. ) 1690 1660 _ . H 191-195 1775, 1720, ~ decomp.~ L~

~3~

Table 16 CH3 N C-CONH ~S~
CH3cH2 Cl oCNH~ s~rN ~ N ~ CH2R2 \oRl3 COOCH~ ~ )2 (syn-isomer) Compound m.p. (C) ~ IR ~XBr) c~m 1 O ~ 176-179 1780, 1720, -N~=~NH -CH3 (decomp.) 1680, 1640 CH 152-155 1780, 1720, o ~o - 3(decomp.) 1680, 1640 -N N-(CH2)2CH3 , . _ _ 158-160 1780, 1720, ~ / 3 -CH3(decomp.) 1680, 1640 -N NCH \
~=~ CH3 166-167 1780, 1720, o ~ o -CH3(decomp.) 1685, 1645 -N~=~W-(CH2)3CH3 O O -CH162-165 1780, 1720, ~ 3(decomp.) 1680, 1640 -N~=~N ~

145-147 1780, 1720, O ~O -CH3(decomp.) 1682, 1640 ~ _ .
- Cont'd -~ ~3 ~6 Table 16 (Cont'd) O O` -CH 138-144 1780, 1715, ~ 3 (decomp.) 1690, 1620 -N~=~N-(CH2)7CH3 ~J \ CH 3 ~ ~ ~ 16 9 0 16 2 0 ~ _ O ~ O -CH2C 3 (decomp.) 1786, 1723, C -CH 118-120 1780, 1720, U2CH3 3 (deco~p.) 1660 ... _ ...
-N~ -CH3 190-193 ~

- Cont'd -Ta~le 16 (Cont'd) . -CH 183-185 1780, 1720, O 3 (decomp.) 1670 O
.. _ .. _ .. .
-CH 128-131 1780, 1720, 3 (decomp.) 1680, 1 ,_ .

~ ~3'~

Table 17 fH3 N C CONH S
CH CH2C-OCONH 4 ~- 11 F ~r~lCH2R
3OCH3 COOC(CH3)3 (syn-isomer) Compound -1 _ R m.p. (C) IR (KBr~ cm ~-4 141-143 1815, 1775, -N N - CH2 ~ CH3 (decomp.) 1640 154-156 1775, 1710, 0 0 (decomp.) 1700 1680 -N N ~ 1650 O 85-88 1785, 1730, 0~ (decomp.) 1715, 1 660 -N N-CH20COC(CH3)3 144-146 1775, 1745, 0 ~0 (decomp.) 1650 -N N-CH2COOCH( ~ )2 - 1~12 -1 (2) To a solution of 6.05 g of diphenylmethyl 7-[2-(2-formamidothiazol-4-yl)-2-(syn)-methoxyiminoace-tamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydro-pyrazinyl)]methyl}-~3-cephem-4 carboxylate in 31 ml of methanol was added 0.5 ml of concentrated hydrochloric acid, and the mixture was subjected to reaction at 35C
for 2 hours. After completion of the reaction, the sol-vent was removed by distillation under reduced pressure.
To the residue were added 100 ml of ethyl acetate and 100 ml of water, and the resultlng solution was adjusted to pH 6.0 with sodium hydrogencarbonate. Subsequently, the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distilla-tion under reduced pressure, and to the residue was added 50 ml of diethyl ether. The crystals were collected by filtration to obtain 5.1 g (yield, 87.7%) of diphenylmethyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)~methyl}-~3-cephem-4-carboxylate 20 having a melting point of 165-167C.
IR (KBr) cm 1 vc=O 1780, 1720, 1680, 1640 NMR (d6-DMSO) ~ values:
1.18 (3H, t, J=7Hz, >N-CH2CH3), 3.55 (2H, bs, C2-H), 3.75 (2H, q, J=7HZ, ~N-CH2CH3), 3 90 (3H, s, -OCH3), 4.41, 5.02 (2H, ABq, J=15Hz, S ~ ), ~LCH2 -5.26 (lH, d, J=5Hz, C6-H~, ~2~

1 6.01 (lH, dd, J-5Hz, J=8Hz, C7-H), 6.52, 6.65 (2H, ABq, J=6Hz, ~ ), H H
N
Ç~C9 (lH, s, ~ H)~

7.07 (lH, s, -CH ~), 7.15-7.84 (lOH, m, ~ x2), 9.81 (lH, d, J=8Hz, -CONH-) In a similar manner, the compounds shown in Table 18 were obtained.

'r~ble 18 N ~ -C-CONU ~ ~ ~

\OCH3COOCH( ~ )2 (syn-isomer) . Compound m.p. (C~IR (KBr) cm 1 O~ O H 158-166 1780, 1720, -N N-CH 3 tdecomp. )1680, 1640 ~ _ _ ~_ _ _ O O 151-1561780, 1720, ~ H (decomp.) 1680, 164Q

-N~=J -(CH2)4CH3 .

150-156 1780, 1720, O~ O H (decomp.) 1680, 1640 -N~=) -(CH2)5CH3 . .=..... .. v____.... _ _ 168-175 1775, 1723, O~ O H (decomp.) 1685, 1640 -N N-(CH2)11CH3 . O~ O H161-166 1680, 1640 -N NCH2 ~

O~ O Br 146 1680, 1640 _ _ __ _ ~

Cont'd -Table 18 (Corlt'd) O H 175--178 1780, 1720, Hn~ ~decomp.) 1 3~ 560 CH H 146-148 1780, 1720, _ ~decomp.) 1660 1 (3) In a mixed solvent of 25.5 ml of trifluoroacetic acid and 7.86 g of anisole was dissolved 5.1 g of diphenyl-methyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyimino-acetamido]-3-{[1-(4-ethyl-2,3~dioxo-1,2,3,4-tetrahydro-pyrazinyl)]methyl}-~3-cephem-4-carboxylate, and the solu-tion was subjected to reaction at room temperature for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. To the residue was added-40 ml of diethyl ether and the crystals were collected by filtration to obtain 4.3 g (yield, 91.1%) of trifluoroacetic acid salt of 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylic acid having a melting point of 155-157C (decomp.).
IR (KBr) cm : vC=O 1775, 1710-1630 NMR (d6-DMSO) ~ values:
1.21 (3H, t, J=7Hz, ~N-CH2CH3), 3.52 (2H, bs, C2-H), 3.73 (2H, q, J=7Hz, >N-CH2CH3), 3.96 (3H, s, -OCH3), 4.44, 5.12 (2H, ABq, J=15Hz, S ~ ), ~ 2 5.21 (lH, d, J=5Hz, C6-H), 5.83 (lH, dd, J=5Hz, J=8Hz, C7-H), 5.86 (3H, bs, -NH3~
6.71 (2H, bs, ~ ), H H

~ ~33^~i.B~

1 6.95 (lH, s, ~ ), S H
9.90 (lH, d, J=8Hz, -CONH-) In a similar manner, the compounds shown in Tahles 19 and 20 were obtained.

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1 (4) In 30 ml of water was dissolved 6.35 g of trifluoroacetic acid salt of 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3~{[1-(2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-Q3-cephem-4-earboxylic acid, and the resulting solution wasadjusted to pH 7.4 with sodium hydrogencarbonate. Subse-quently, this solution was purified by passing through an rac~e(Y~f ~) Amberlite XAD-2/column to obtain 4 . 7 g (yield, 86.6~) of sodium 7-[2-(2 aminothiazol-4-yl)-2-(syn)-methoxyimino-aeetamido]-3-{[1-(2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-methyl~-~3-cephem-4-earboxylate having a melting point of 200C or more.
IR (KBr~ cm : VC o 1763, 1670, 1650-1620 In a similar manner, the following compounds were obtained:
o Sodium 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoaeetamido]-3-{[1-(4-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-eephem-4-earboxylate.
m.p.: 190-195C (deeomp.) IR (KBr) cm 1 vc=O 1760, 1670, 1650, 1630 o Sodium 7-[2-(2-aminothiazol-4-yl) 2-(syn)-methoxyiminoaeetamido]-3-{[1-(3,6-dioxo-1,2,3,6-tetra-hydropyridazinyl)]methyl}-~3-eephem-4-earboxylate O Sodium 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{~ 3-methyl-6-oxo-1~6-dihydro-pyridazinyl)]mathyl}-~3-cephem-4-earboxylate.

1 Example 7 (1) To a solution of 3 g of 2-(2-tritylaminothiazol-4-yl)-2-(syn~-tert.-butoxycarbonylmethoxyiminoacetic acid in 15 ml of N,N-dimethylacetamide was added dropwise 0.93 g of phosphorus oxychloride at -10C, and the mixture was subjected to reaction at -5 to 0C for 1 hour. This solution was added dropwise to a solution of 19.4 ml of anhydrous methylene chloride containing 1.94 g of 7-amino-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-methyl}-~3-cephem-4-carboxylic acid and 2.25 g of bis(tri-methylsilyl)acetamide at -5 to 0C. After completion of th dropwise addition, the mixture was subjected to reaction at the same temperature for 30 minutes and then at 0 to 10C for ~0 minutes. After completion of the reaction, methylene chloride was removed by distillation under reduced pressure, and to the residue was added a mixed solvent of 100 ml of saturated aqueous sodium chloride solution and 100 ml of acetonitrile. Su~sequently, the organic layer was separated and washed twice with 50~ml portions of saturated aqueous sodium chloride solution, and then the solvent was removed by distillation under reduced pressure. The resulting residue was dissolved in 50 ml of methanol, after which 1 g of diphenyl-diazomethane was added to the solution at 5 to 10C, and the mixture was subjected to reaction at the same temperature for 30 minutes. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was purified by a column ~f~3~

1 chromatography (Wako Silica Gel C-200, eluent; benzene:
ethyl acetate=3:1~ to obtain 1.6 g ~yield, 27.8~) of diphenylmethyL 7~[2-(2-tritylaminothiazol-4-yl~-2-~syn~-tert.-butoxycarbonylmethoxyiminoacetamido]-3-{[1-(4-ethyl-2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylate having a melting point of 98-100C (decomp.~.
IR (KBr) cm : VC O 1780, 1720, 1680, 1630 NMR (d6-DMSO) ~ values:
G~
7~` 1.17 (3H, t, J=7Hz, ~2CH3), 1.44 (9H, s, -C(CH3)3), 3.62 (2H, bs, C2-H), 3.74 ~2H, q, J=7Hz, >N~CH2CH3), 4.55 (2H, s, -OCH2C-), 4.51, 5.16 (2~, ABq, J=15Hz, S~ ), -5.27 (lH, d, J=5Hz, C6-H), 5.87 (lH, dd, J=5Hz, J=8Hz, C7-H), 6.55 (2H, bs, ~ ), H H
6.80 ~lH, s, -CH~), 6.97 (lH, s, ~ ), S H

7.05-7.67 (25H, m, ~ x 5), 8.86 (lH, bs, ( ~ )3C-NH-) t 9.54 (lH, d, J=8Hz, -CONH-) In a similar manner, the compounds shown in Tables 21 and 22 were obtained.

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-- 1~5 --1 (2) In a mixed solvent of 8 ml of trifluoroacetic acid and 3 ml of anisole was dissolved 1.6 g of diphenyl-methyl 7-[2-(2-tritylaminothiazo:L-4-yl)-2-(syn)-tert.-butoxycarbonylmethoxyiminoacetam:ido]-3-{~1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylate, and the solution was subjected to reaction at room temperature for 1 hour. After completion of the reaction, the solvent was removed by distillation under resuced pressure. To the residue was added 10 ml of di-ethyl ether and the crystals were collected by filtration.Then, the crystals obtained were dissolved in 20 ml of 50% by weight aqueous formic acid solution, and the solution was subjected to reaction at 45 to 55C for 1 hour. After completion of the reaction, the precipitated crystals were separated by filtration, and the solvent was removed by distillation under reduced pressure. To the residue was added 10 ml of ethyl acetate and the crystals were col-lected by filtration. Subsequently, the crystals were sufficiently washed with 10 ml of ethyl acetate 20 and dried to obtain 0.7 g (yield, 80.7%) of 7-[2-(2-aminothiazol-4-yl)-2-(syn)-carboxymethoxyiminoaceta-mido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyra-zinyl)]methyl}-~3-cephem-4-carboxylic acid having a melt-ing point of 139-140C (decomp.).
IR (KBr) cm : VC O 1775, 1695, 1680, 1635 NMR (d6-DMSO) ~ values:
1.22 (3H, t, J=7Hz, >NCH2CH3), 3.53 (2H, bs, C2 H), 1 3.74 ~2H, q, J=7Hz, ~NCH2CH3), 4.70 (2H, s, -OCH2CO-), 4.45, 5.10 (2H, ABq, J=15Hz, S ), ~L CH2-5.23 (lH, d, J=SHz, C6-H), 5.90 (lH, dd, J=5Hz, J=8Hz, C7-H), 6.69 (2H, bs, ~ ), H H

6.94 (lH, s, N ~ ~, S H
9.70 (lH/ d, J=8Hz, -CONH-) In a similar manner, the compounds shown in Table 23 were obtained.

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1 Example 8 (1) To a solution of 1.68 g of diketene in 8.40 ml of anhydrous methylene chloride was added dropwise a solution of 2.08 g of bromine in 6.25 ml of anhydrous methylene chloride with stirring at -30C, and the mix-ture was subj~cted to reaction at -30 to -20C for 30 minutes. The thus obtained reaction mixture was added dropwise at -30C or less to a solution of 50 ml of anhydrous methylene chloride containing 5.20 g of di-phenylmethyl 7-amino-3-{[1-(4-ethyl-2,3~dioxo-1,2~3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylate and 4.08 g of bis(trimethylsilyl)acetamide.
After completion of the dropwise addition, the mixture was subjected to reaction at -3G to -20C for 30 minutes and then at 0 to 10C for 1 hour. After comple-tion of the reaction, the solvent was removed by distil-lation under reduced pressure, and the residue thus ob-tained was dissolved in 50 ml of ethyl acetate and 40 ml of water. Then the organic layer was separated, washed with 40 ml of water and 40 ml of a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. To the residue was added 50 ml of diisopropyl ether, and the thus obtained crystals were collected by filtration to obtain 5.85 g (yield, 85.6%t of diphenylmethyl o ~bu~ur~ /a 7-(4-bromo-3-o~but~ ido~-3-{[1-(4-ethyl-2,3-28 dioxo-l~2~3l4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylate having a melting point of - 156 ~

1 138-lY2C (decomp.).
IR (KBr) cm : VC O 1778, 1720, 1680, 1640 NMR (d6~DMSO) ~ values:
1.22 (3H, t, J=7Hz, -NCH2CH3), 3.40 (2H, bs, C2-H), 3.85 (2H, q, J=7Hz, ~NCH2CH3), 3.87 (2H, bs, BrCH2COCH2-), 4.18 (2H, bs, BrCH2CO-), 4.47, 4.96 (2H, ABq, J=15Hz, S ~ ), ~ CH2-5.04 (lH, d, J=5Hz, C6~H), 5.90 (lH, dd, Js5Hz, J=8Hz, C7-H), 6015, 6.50 (2H, ABq, J=6Hz, ~ ), H H

6.98 (lH, s, -CH< ), 7.40 (lOH, bs, ~ x 2), 8.55 (lH, d, J=8Hz, -CONH-) In a similar manner, the following compound was obtained:
.....
r ~ 4.09 g (yield, 62.6%) of diphenylmethyl 7-(4-~ b~ r~
bromo-3-oxo-but~ am}de~-3-{[1-(3,6-dioxo-1,2,3,6-tetra-hydropyridazinyl) ]methyl}-~3-cephem-4-carboxylate having a melting point of 124-126C (decomp.).
IR (KBr) cm 1 vc=O 1780, 1725, 1660 NMR (d6-DMSO) ~ values:
O O
Il 11 3.49 (4H, bs, C2-H, -CCH2C-), 3~

1 4.52 (2H, s, BrCH2C-), 5.06 ~lH, bs, S~ ), ~ CH~-5.26 (lH, d, J=5Hz, C6--H), 5.90 ~lH, dd, J=5Hz, J=8Hz, C7-H), 7.01, 7.25 (2H, ABq, J=lOHz, ~ ), 7.09 (lH, s, -CH~ ), 7.24-7.91 (lOH, m, ~ x 2), 9.34 (lH, d, J=lOHz, -CONH-) (2) To a solution of 5.50 g of diphenylmethyl 7-~4-c7~(0~f~

10 bromo-3-o~obut7~lmldo)-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4_ tetrahydropyrazinyl)]methyl}-Q3-cephem-4-carboxylate in 30 ml of acetic acid was added dropwise a solution of 5 ml of water containing 0.74 g of sodium nitrite with ice-cooling over a period of 1 hour, and the resulting mixture was subjected to reaction at room temperature for 2 hours.
After completion of the reaction, the reaction mixture was poured into 500 ml of water to precipitate crystals. The crystals were collected by filtration, washed sufficiently with water, and dried. Then, the crystals were dissolved in 10 ml of chloroform and then purified by a column chromatography (Wako Silica Gel C-200, eluent; benzene :
ethyl acetate=2:1 by volume), to obtain 3 15 g (yield, 54.9~) of diphenylmethyl 7-(4-bromo-2-hydroxyimino-3-o~ob~ ~y,~ o oxobutyla~ide)-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetra-1 hydropyrazinyl)]methyl}-~3-cephem-4-carboxylate ha~ing a melting point of 127-132C (decomp.) IR ~KBr) cm : Vc 0 1778, 1720, 1680, 1635 NMR (CDC13) ~ values:
1126 (3H, t, J=7Hz, >NCH2CH3), 3A47 (2H, bs, C2-H), 3081 (2H, q, J-7Hz, ~NCH2CH3), 4.52 ~2H, s, BrCH2CO-), 4.53, 4.78 (2H, ABq, J=15Hz, Sl ), 5.11 (lH, d, J=5Hz, C6-H), 5.80-6.15 (lH, m, C7-H), 6.13, 6.52 (2H, ABq, J=6Hz, ~ ), 7.02 (lH, s, -CH< ), 7.41 (lOH, bs, ~ x ~), 9.2Q (lH, d, J=8Hz, -CONH-~
In a similar manner, the following compound was obtained:
., 4.71 g (yield, 75.1~) of diphenylmethyl 7-(4-~ t ~ ,~ob~4r~
bromo-2-hydroxyimino-3-e*e}~ )-3-{[1-(3,6-dioxo-1,2,3,6-tetrahydropyridazinyl)]methyl}-~3-cephem-4-carboxylate having a melting point of 138-141C (decomp.) IR (KBr) cm 1 vc 0 1780, 1720, 1660 NMR (d6-DMSO) ~ values:
3.46 (2H, bs, C2-H), 4.62 (2H, s, BrCH2CO-) ~ 3 1 4.96 (2H, bs, S~ ), 5.18 (lH, d, J=5Hz, C6-H~, 5.93 (lH, dd, J=SHz, J=8Hz, C7-H), ~,H
6.89, 7.13 (2H, ABq, J=lOHz, ~ ), 6.96 (lH, s, -CH< ), 7.13-7.72 ~lOH, m, ~ x 2), 9.45 (lH, d, J=8Hz, -CONH-), 13.36 (lH, s, =N-OH) (3) In 12 ml of N,N-dimethylacetamide were dissolved 0 3.00 g of the diphenylmethyl 7-(4-bromo-2-hydroxyimino-3-b,,lt~1 fo,m i~
oxob~t~L~mid~ -3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetra-hydropyrazinyl~methyl}-~3-cephem-4-carboxylate obtained in above (2) and 0.42 g of thiourea, and the resulting solution was subjected to reaction at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into a mixed solvent of 120 ml of water and 240 ml of ethyl acetate. Subsequently, the mixture was adjusted to pH 7.0 with sodium hydrogen-carbonate, after which the organic layer was separated, and washed with 50 ml of water and 50 ml of a saturated aqueoussodium chloride solution in this order. After the organic layer was dried over anhydrous magnesi-um sulfate r the solvent was removed by distillation under reduced pres-sure. To the residue was added 20 ml of diethyl ether and the crystals were collected by filtration to obtain 2.10 g 1 (yield, 72.3%) of diphenylmethyl 7-[2-(2-aminothiazo]-4~
yl)-2-(syn)~hydroxyiminoacetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)~methyl}-~3-cephem-4-carboxylate having a melting point of 137-140C (decomp.).
IR ~KBr) cm 1 vc 0 1778, 1720, 1680, 1640 NMR ~d6-DMSO) ~ values:
1.19 (3H, t, J=7Hz, >NCH2CH3), 3.4~ (2H, bs, C2-H), 3.68 (2H, q, J=7Hz, >NCH2CH3), 4.46, 5.04 (2H, ABq, J=15Hz, S~ l, ~CH2 -5.28 (lH, d, J=5Hz, C6-H), 5.97 (lH, dd, J=5Hz, J=8Hz, C7-H), 6.57, 6.75 (2H, ABq, J=6Hz, ~ ), H H

6.79 (lH, s, ~ ), S H

7.07 ~lH, s, -CH< ), 7.53 (lOH, bs, ~ x 2), 9.70 (lH, d, J=8Hz, -CONH-) (4) In a mixed solvent of 10.0 ml of triflusroacetic acid and 2.0 ml of anisole was dissolved 2.00 g of the 20 diphenylmethyl 7-[2-(2-aminothiazol-4-yl)-2-(syn~-hydro-xyiminoacetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetra-hydropyrazinyl)]methyl}-~3-cephem-4-carboxylate obtained in above (3), and the resulting solution was subjected to reaction at room temperature for 2 hours. After comple-tion of the reaction, the solvent was removed by 9~

1 distillatlon under reduced pressure, and to the residue was added 15 ml of diethyl ether, after which the crystals were collected by filtration. Subsequently, the crystals were sufficiently washed with 10 ml of diethyl ether and then dried to obtain 1.62 g IYield, 87.6~) of trifluoro-acetic acid salt of 7-[2-(2-aminothiazol-4-yl)-2-(syn)-hydroxyiminoacetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylic acid having a melting point of 112-118C (decomp.).
IR (KBr) cm : ~C O 1780, 1680, 1620 NMR (d6-DMSO) ~ values:
1.19 (3H, t, J=7Hz, ~N-CH2CH3), 3.47 (2H, bs, C2-H), 3.72 (2H, q, J=7Hz, >NCH2CH3), 4.45-6.70 (4H, m, S~ , C6-H, C7-H~, 6.59-6.83 (3H, m, ~ ~ N
H H

- Example 9 ~1) To a solution of 7.1 g of diphenylmethyl ~, Dxo Jz futc~ /o 7-(4-bromo-2-hydroxyimino-3-o~obut~lamido)-3-1[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-methyl}-~3-cephem-4-carboxylate in 70 ml of anhydrous methylene chloride was slowly added a solution of diazomethane in diethyl ether at -5 to 0C, and the resulting solution was subjected to reaction at th~
same temperature for 30 minutes. After confirming the - ~62 -33~

1 disappearance of diazomethane, the solvent was removed by distillation under reduced pressure. Then, the obtained residue was purified by a column chromatography (Wako Silica Gel C-200, eluent; benzene : ethyl acetate=3:1 by volume) to obtain 2.32 g (yield, 32.0%) of diphenylmethyl O ~ Yfo~, '~
A 7-[4-bromo-2-(syn)-methoxyimino-3-o~e-bu~ Q~o]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylate having a melting point of 135-140C ~decomp.).
IR (KBr) cm : Vc 0 1778, 1720, 1682, 1638 NMR (CDC13) ~ values:
1.25 (3H, t, J=7Hz, >~CH2CH3), 3.48 (2H, bs, C2-H), 3.84 (2H, q, J=7Hz, ~NCH2CH3), 4.00 (3H, s, -OCH3), 4.10 (2H, s, BrCH2CO-), 4.48, 4.67 (2H, ABq, J=15Hz, S~ ), ~CH2-5.10 (lH, d, J=5Hz, C6-H), 6.05 (lH, dd, J=5Hz, J=8Hz, C7-H), 6.38, 6.73 (2H, ABq, J-6Hz, ~ ), H H
6.98 (lH, s, -CH <), 7.32 (lOH, bs, ~ x 2), 9.18 (lH, d, J=8Hz, -CONH-) In a similar manner, the following compound was obtained:
1.70 g (yield, 24.5~) of diphenylmethyl ~j ~xo bu ~ /o 1 7-[4-bromo-2-(syn)-methoxyimino-3~ ~ ]-3-{[l-(3,6-dioxo-1,2,3,6-tetrahydropyridazinyl)]methyl}-~3-cephem-4-carboxylate having a melting point of 145-148C

(dec.).

5IR (KBr) cm l vc 0 1780, 1730, 1660 NMR (d6-DMSO) ~ values:

3.49 (2H, bs, C2-H), 4.03 (3H, s, -OCH3), 4.60 (2H, s, BrCH2CO-), 105.02 (2H, bs, S~ ), ~CH2 -5.30 (lH, d, J=5Hz, C6-H), 6.02 (lH, dd, J=5Hz, J=8Hz, C7-H), 6.92, 7.16 (2H, ABq, J=lOHz, ~ ), 6.99 (lH, s, -CH~), i 7.17-7.78 (lOH, m, ~ x 2), 10.16 (lH, d, J=8Hz, -CONH-) (2) In 14 ml of N,N-dimethylacetamide were dissolved 2.3 g of diphenylmethyl 7-[4-bromo-2-(syn)-methoxy-0%0~ y~ ~o imino-3-ol~obutylam~e]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylate and 0.32 g of thiourea, and the resulting solution was sub-jected to reaction at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into a mixed solvent of ~0 ml of water and 150 ml of ethyl /~f ~rc~qe~7cc~6 0~
acetate. Then, sodium ~bY~ ~r~n~t was added there-33~6 1 to adjust the mixture to pH 6.7, and then the organic layer was separated. The aqueous layer was further extracted twice with 100-ml portions of ethyl acetate.
The combined organic layer was washed with water and dried over anhydrous magnesium sulfate, and the sol-vent was removed by distillation under reduced pres-sure. To the residue was added 20 ml of diethyl ether, and the crystals were collected by filtration to obtain 1.92 g (yield, 86.3%) of diphenylmethyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{~1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-methyl}-~3-cephem-4-carboxylate having a melting point of 165-167C.
IR(KBr)cm : VC O 1780, 1720, 1680, 1640 In a similar manner, the following compound was obtained:
o Diphenylmethyl 7-[2-(2-aminothiazol-4-yl-2-(syn)-methoxyiminoacetamido]-3-{[1-(3,6-dioxo-1,2,3,6-tetrahydropyridazinyl)]methyl}-~3-cephem-4-carboxylate, m.p., 175-178C (decomp.) IR (KBr) cm : ~C=O 1780, 1720, 1685-1660 The same ring-closure reaction as above was conducted and then the reaction mentioned in Example 6-(3) or Example 7-(2) was conducted, to obtain the ¢ompounds shown in Tables 24, ?5 and 26.

~ ~33`~36 ~ ! ~ 5 ~o ~ o ~/ ~ ~ Z
~.~ I ~ ~-~ =o ~- ~o _ _ c~ r _ 33,~86 _ oXz~ oXz~ _ 3 ~

~ ~, ~,~X~) UN

oXz~l ~Z~ ~

o Q ~ O 0 E-1 ~Z~D ~Z~I ~

_ .

_ N
~X 3 Y 3 oX~

- - ; .

o~o ~D o~o :~ l l :c l er Q

h ~7 O
\ / ~ ~

z z _~ r Table 25 5~N~ C - CONH~

`OR 18 COOH
syn-isomer ) ~ ~ 2 -CE2C :~:

. _.. __ _.v~_ -- - . ~

--N NCH CH3CF3COOH~NH2-- ~ -C-C OH

~ 0~0 --N NH NH 2 ~ -CH 2CH

0~0 --N~N--N 3 CF3COOH~NH2- ~ ~

- Cont ' d - 170 ~

3 ~

Table 25 (Cont ' d) CH ~ _ \ ~ HC~OH NH2- -CH COOH

--N NCH~ C~ CH 7 NH2- -CH2COOH

__ _ --N N ~) N 2 -CH2COOH

. 0~ .
--N CH20COC (CH3) 3 NH2- --CH2COOH
. - I
- Cont'd -3~36 Table 25 (Cont ' d) --N NCH2 OOH NH2- ~ --CH2 OOH

--N--/NCH2CH3 HCOOH- NH2- -CH2COO~
;

8~i Table 26 ~N ~ C- CONH ~ S ~

OCH3 O l 1 COOR
(syn-isomer) _ . .

-fHOCOC(CH3)3 -N NCH2CH3 . -0~0 -fHOCOC(CH3)3 -N NCH3 - . _ . -- , _ 0~,0 -7HOCOC(CH3)3 - N N-(CH2)4CH3 _ 0~0 -fHococ(cH3)3 -N N-(CH2)5CH3 ____ . ~ ....... ... ...

- Cont'd -~ ~33~

Table 26 (Cont id) 0~ 0 -CHOCOC (CH3) 3 --N N (C~2) 7CH3 0;~,0 -ICHOCOC ICH3) 3 ~ --N N (CH2~11CH3 _ ' 0~0 -CH20COC (CH3) 3 --N~CH2CH3 -CHOCOOC (CH3 ) 3 --N~NCH2cH 3 ~ --N NCH 2CH 3 , ~ ~CH2) 3CH3 --N NCH2CH3 - Cont'd -~z~

Table 26 (Cont'd) -CH2C=C-CH3 ~ 4 --CH20COC (CH3) 3 N~D
_ _ C~d~H 3 -CH 20COC ( CH3 ) 3 --N~
- o -CH20COC (CH3) 3 --N~D
. _ -C~120COC (C33) 3 ~ --Nf~

- Cont'd -Table 26 ~Cont'd) -FHOCOC~CH3 3 -Nl ~ 3 . _ . ~ ., -CH20COCICH3)3 ~ ~ O

Note: * Hydrochloride l Physical properties (m.p., IR and NMR spectra) of the above compounds were the same as those obtained in Examples 6, 7, 11 and 12.

1 Example 10 (1) To a suspension of 2.2 g of 2-(2-formamido-thiazol-4-yl)glyoxylic acid in 11 ml of N,~-dimethyl-acetamide was added dropwise 1.8 g of phosphorus oxychloride at -20C, and the resulting mixture was subjected to reaction at the same temperature for 2 h~urs. Then, to this reaction mixture was ad~ed a solution of 26 ml of methylene chloride containing 5.2 g of diphenylmethyl 7-amino-3-{[1-(4-ethvl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)~methyl}-~3-cephem-4-carboxylate at -30 to -20C. After completion of the dropwise addition, the mixture was subjected to reaction at same temperature for one hour. After completion of the reaction, 70 ml of water and 50 ml f methylene chloride were added to the reaction mixture. Then, sodium hydrogencarbonate was added thereto to adjust the mixture to pH 6.5, and the insolubles were removed by filtration. The organic layer was thereafter separated, washed with 100 ml of water and 10 ml of a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (Wako Silica Gel 3~

1 C-200, eluent; chloroform:methanol=20:1 by volume) to obtain 1.4 g (yield, 20.0~) of diphenylmethyl 7-[2-12-formamidothiazol-4-yl)glyoxylamido]-3-{[1-~4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylate having a melting point of 140-145C (decomp.).
IR (KBr~ cm : VC O 1780, 1720, 1680, 1670, 1640 NMR (d6-DMSO) ~ values:
1.20 (3H, t, J=7Hz, ~NCH2CH3), 3.50 (2H, bs~ C2-H~, 3.69 (2H, q, J=7Hz, ~NCH2CH3), 4.40, 5.00 (2H, ABq, J=15Hz, S~ ~, ~L CH2-5.30 (lH, d, J=5Hz, C6-H), 6.00 (lH, dd, J=5Hz, J=9Hz, C7-H), 6.50, 6.62 (2H, ABq, J=5Hz, ~ ), H H

7.04 (lH, s, -CH~ ), 7.30 (lOH, bs, ~ x 2), 8.64 (lH, s, N ~ ), S H
8.81 (lH, s, HCONH-), 10.20 (lH, d, J=9Hz, -CONH-), 12.90 (lH, bs, HCONH-) In a similar manner, the following compound was obtained: 0.09 g (yield, 19.2~) of diphenylmethyl 7-[2-(2-formamidothiazol-4-yl)glyoxylamido]-3-l[l-(3,6-dioxo-1,2,3,6-tetrahydropyridazinyl)]methyl}-~3-cephem-4-carboxylate, ;33~

1 m.p.: 153-154C (decomp.).
IR (Ksr~ cm : VC O 1780, 1725, 1690, 1665 NMR (CDC13+d6-DMSO) ~ values:
3.42 (2H, bs, C2-H), 4.96-5.40 (3H, m~ S~ , C6-H), ~LCH2-5.95 (lH, dd, J=5Hz, J=8Hz, C7-H), 6.72-7.78 (13H, m, -CH~ , ~ , ~ x 2), 8.66 (lH, s, ~ ), S H
8.73 tlH, s, HCO-), 9.86 (lH, d, J=8Hz, -CONH-) ~2) To a solution of 7.0 g of diphenylmethyl 7-[2-(2-formamidothiazol-4-yl)glyoxylamido]-3-{[1-~4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-methyl}-~3-cephem-4-carboxylate in 35 ml of N,N-dimethylacetamide was added l.~ g of methoxy-amine hydrochloride with ice-cooling, and the resulting mixture was subjected to reaction at 15-20C for 3 hours.
After completion of the reaction, the reaction mixture was poured into a mixed solvent of 250 ml of water and 250 ml of ethyl acetate, and the organic layer was separated, washed with 250 ml of water and 250 ml of a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate.

Then, the solvent was removed by distillation under ~3i~

1 reduced pressure. To the resi.due was added 50 ml of diethyl ether, and the resulting crystals were collected by filtration to obtain 6.1 g (yield, 83.7%) of diphenyl-methyl 7-[2-(2-formamidothiazol-4~yl)-2-(syn)-m~thoxy-iminoacetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetra-hydropyrazinyl)]methyl}-~3-cephem-4-carboxylate having a melting point of 165-168C.
IR(KBr) cm 1 VC O 1780, 1720, 1680, 1640 In a similar manner, the following compound was obtained: / ~
o Dl~phc~cth~ 7-[2-(2-formamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(3,6-dioxo-1,2,3,6-tetra~ydropyridazinyl)]methyl}-~ -cephem-4-carboxylate, m.p. 171-173C (decomp.).
Th~ same oximination reaction as above was conducted, and then, the reaction mentioned in Example 6-(2), (3) and/or Example 7-(2) was conducted, to obtain the following compound and the compounds shown in Tables 27, 28 and 29:
O Trifluoroacetic acid salt of 7-[2-(2-amino-5-bromothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-methyl}-~l-cephem-4-carboxylic acid, m.p.: 147C (decomp.) IR(KBr) c~ 1 vc O 1775, 1680, 1640 ~3~8~

. _ _~a /~ O N U U
u~ ~, O~Z~ o~z~D
~0- l l _ t` l3Z~ _' Q Z~ ~rl ~ æ

8 ~

~; ~Z~l O"[Z~

. ~ _ ~ ~33 ~B6 U

_ r7 X ~
\ / ~ ~J
~ C~ I
o~z~ o~z~l o~, ~I

e ~J N--O0~ U
oXz~D ~Z~I oX~

~ N N
O 0~

~3~

._ _ .

C~
r~ $
- ~z_z~ ~Z~D o~o R _ ~ ' . O
~ ~ S

0~
_l I . _ ~;

~3~8Ç~

Table 28 5 ~ N ~ -C - CONH - ~ ~

oR18COOH
(syn-isomer~

~ ~ 1 0~0 _ ,, I

_ _ - Cont'd -;3~36 Table 28 (Cont ' d) r 3COOH IIH2- -CH2C OH

N ~ 3C~OH . ~H2_ -CH2C OH

~4;

O O ' . . I

N ~ICL~ ICOC (CH 3) 3 21H2 ~ CH2C O

- Cont'd -Table 28 (Cont ' d) ~<U:~

--N~ NCH2CH3 HCOOH. NH2~ -CH2COO~

0~0 _ . , .
--N ~CH 2CH 3 HCOOH NH 2 - --CH 2COO~

.. 0~0 _ ~3~

Table 29 C--CONH

OCH 3 O l 1 COOR
(syn-isomer ) . . _ . . . .

.. .. _ 0~,0 .
-CHOCOC (CH3) 3 --N NCH2CH3 0~0 -CHOCOC (CH3) 3 --N NCH3 . _,, 0~,0 -fHococ (CH3~ 3 --N N--(CH2~ 4CH3 C~I3 0~
CU(~CCC l~ H3~ 3 --N N- (CH2) 5C~;~

- Cont'd --- 1~8 --: Table 29 (Cont'd) 0~0 -fHOCOC(C~3)3 -N N(C~2)7CH3 ~-4 -fHococ(cH3)3 ~=~ ( 2)11 H3 0,~<0 -CH20COC(CH3)3 -N~==JNCH2CH3 -CHOCOOC(CH3)3 - N~ NCH2CH3 o ~O * .. .. .

~ -N NCH2CH3 . --(C~2)3CH3 - N NCH2CH3 -- Coni'd -3~6 Tab le 2 9 (Cont ' d ~

-CH2C=C-CH3 ~4 O ~ O --N NCH 2C~ 3 --CEI2OCOC SC~3) 3 --N ~D

--CH2OCOC (CH33 3 .
.

-CH2OCOC (CH3) 3 --N~
_ _ _ -C32Ococ IC33) 3 - Cont'd -;i3~6 Table 29 (Cont'd) -CHOCOC(C33 3 O

' _ . . ~ . .

COC~C:I ) Note: * Hydrochloride 1 Physical properties (m.p., IR and NMR spectra) of the above compounds were the same as those obtained in Examples 6, 7, 11 and 1~.

1 Example 11 ~ ~3~86 (1) In a mixed solvent of 37 ml of trifluoroacetic acid and 10.8 g of anisole was dissolved 7.29 g of di-phenylmethyl 7 [2-(2-formamidothiazol-4-yl~-2-(syn)-methoxyiminoacetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylate, and the resulting solution was subjected to reaction at room temperature for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. To the resulting residue was added 50 ml of diethyl ether, and the crystals were collected by filtration, washed sufficiently with 50 ml of diethyl ether and dried to obtain 5.2 g (yield, 92.4%) of 7-[2-(2-formamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-methyl}-~3-cephem-4-carboxylic acid having a melting point of 155-158C (decomp.~.
IR (KBr) cm : Vc O 1775, 1710, 1675, 1640 NMR ~d6-DMSO) ~ values:
1.20 (3H, t, J=7Hz, ~NCH2CH3), 3.49 (2H, bs, C2-H), 3.73 (2H, q, J=7Hz, ~NCH2CH3), 3.91 (3H, s, -OCH3), 4.42, 4.95 (2H, ABq, J=15Hz, S~ ), ~5 5.21 (lH, d, J=5Hz, C6-H), 5.89 (lH, dd, J=5Hz, J=8Hz, C7-H), 6.65 (2H, bs, Hk=~H )' 1 7.46 (lH, s, ~ ), S H

8.59 (lH, s, HCONH-), 9.77 (lH, d, J=8Hz, -CONH-), 12.58 (lH, bs, HCONH-) In a similar manner, the compounds shown in Table 30 were obtained.

3~86 Table 30 N C - CONH l~
HCONH ~ ~ N ~ CH2R
.:~ OCH3 COOH
(syn-isomer) _ _ . . .~
Compound O IR (KBr) .. R2 m.p. ( C) cm : VC=o . _ _ . Q "O 195-198 1775, 1720, (decomp.) 1680~1640 ` -N N-CH
. . _ ..
O O
: -N N-(CH ) CH 122-125 1775, 1680, 2 4 3 (decomp.) 1640 . _ _ .___ :~ ~0~0 ;~ -N N-(CH2)5CH3 165-170 1775~ 1680, ~=J (decomp.) 1640 .__ _, _. _.. , -N N ~ ~ O 195-198 1775, ~685, ~ ~decomp.) 1650 :~
"
._ 0~0 ,, : -N N~CH2) CH3 155-158 1780, 1720, . ~ 7 ~decomp.) 1680-164Q
_ . _ _ _ _ ~
( 2)11CH3 144-147 1778, 1685, J ~decomp.) 1660, 1645 ._ _ I

- Cont'd -Table 30 (Cont'd) ¦ ~ 186-188 ~ 1775, 1710, -N (dec omp . ) 1 6 9 0 , 1 6 5 0 .

\~ 218-221 1775, 1670, O (decomp. ) 1650 . _ ...

~33~36 1 (2) To a solution of 5.63 g of 7-[2-(2-formamidothiazol-4-yl?-2-(syn)-methoxyiminoacet~
amido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydro-pyrazinyl)~methyl}-~3-cephem-4-carboxylic acid in 25 ml of N,N-dimethylacetamide were added 1.52 g of 1,8-diazabicyclo[5,4,0]-7-undecene and 3.84 g of 1-pivaloyloxyethyl iodide with ice-cooling, and the resulting mixture was subjected to reaction for 30 minutes. After completion of the reaction, the reactio~
mixture was poured into a mixed solvent of 100 ml of water and 100 ml of ethyl acetate. Subsequently, the organic layer was separated, washed with wat~r, and then dried over anhydrous magnesium sulfate. The solvent was remo~ed by distillation under reduced pressure. To the residue was added 50 ml of diethyl ether, and the crystals were collected by filtration to obtain 5.5 g ~yieldt 79.6~) of 1 pivaloyloxyethyl 7-[2-~2-formamido-thiazol-4-yl~-2-(syn)-methoxyiminoacetamido]-3-{~1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carbo~ylate having a melting point of 140-142C.
IR (KBr) cm : ~C=O 1780, 1740, 1680, 1640 In a similar manner, the compounds shown in Table 31 were obtained. In this case, the compounds shown in Table 31 can also be obtained by the same method as in Example 6-(1), except that the correspond-ing esters were substituted for the diphPnylmethyl esters.

~ ~33 -~36 _~ _ -, _ o o ;~ o o o o .. o o` o` l ~ ~ ~ ~ OD
'~ S~ ~D W ~D ~D

~:: K o o o o U~O P; O ~ ~ O
`r c~ c~:) 00 co 0 _ , _ O ~ _ _ ~ u~ cO -~, ~ C~ o C~ ~ ~ ~ ~ ~D
O _ ~ ~ _~ ~ ~
I C~ I O l I O
Z . N O O ~ CO
~:4 co O ~ a) O ~D O

~ ~r~ ~ _ _ Z
C ~ . ~.~ ~
~ r r _ o o~z~ o~zD o~z~D o~z~
~J .

~ C~ ~ ~) ~
~ o o ~ o ~ o _ c ~ rc r~ _ ~ I C _ ~ 197 ~

-- - - ~

~r o ~r ~D ~ ~
n o ~ o co a~ oo O co ~9 ~7 l O ~ ~D
~1 ,_J ,_1 ,_1 ~1 O O O
~D CO t~l ~` ,_1 D
~ ~1 ~ ~ -1 ~ O O O O
l~ ~10 0~ C~ C~
--O ~ ~
~`J ~D In ~D
OD O O
a~ ~ ~ ~ ~o ~ ~

E~
. , _ U~
:~
~`3 ~ ~ ~ :q ~ ~ ~ ~ C~
C~ ~ ~ ~ ~
C~ ~ :1: :C
o~z~ o~Z3 o~z~ o~z~ o~z~
... .

~ ~C
o~ o~ U ~ o~ ~
~ ,u ~

~3~6 .

o o` o C) r~ o ~D Ln ~D
o U~ o ~ CO

U~ ~ o I~ ~r n o o U) o ~ ~ r~ c~
o~ ~ ,_ I_ ~: -_ _ ,,~ e a~ ~ u , o ~ ~ a Q ~ ~ ~1 ~ ~1 ~
E~
.
.' O
,l, __ .
_ ~
V 0~ X
~0/ 0~ C
C~ C~
. .

~3~36 ..
~r o -o -- ~ h ., ~ I t) CO

E~

~0 ~

C~ , , ca a a X ~

3:~ Z
. _ .

1 (3) To a solution of the 5.5 g of l-pivaloyloxy-ethyl 7-[2-(2-formamidothiazol-4-yl~-2-(syn~-methoxy-iminoacetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylate obtained in above (2) in 27.5 ml of methanol was added 1.13 ml of concentrated hydrochloric acid, and the resulting mixture was subjected to reaction at 35C for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. To the residue were added 50 ml of ethyl acetate and 50 ml of water, and the mixture was adjusted to pH 6.0 with sodium hydrogencarbonate. Subsequently, the organic layer was separated and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. To the residue was added 45 ml of diethyl ether, and the crystals were collected by filtration to obtain 4.65 g (yield, 88.1~) of l-pivaloyloxyethyl 7-[2-(2-aminot~iazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{~1-(4-ethyl-2,3-dioxo-1,2,3,4 tetrahydropyrazinyl)]methyl}-~ -cephem-4-carboxylate having a melting point of 148-150C.
IR (KBr~ cm : VC o 1780, 1740, 1680, 1640 NMR (d6-DMSO) ~ values:
0.90-1.39 (12H, m, -C(CH3)3,> NCH2CH3~, 1.52 (3H, d, J=5Hz, -OfHO-), 3.52 (2H, bs, C2-H), 3.76 (2Hr q, J=7Hz, ~NCH~CH3), ~2~ 36 l 3.88 (3H, s, -OCH3), 4.38, 5.04 (2H, ABq, J=15Hz, 1 ~, 5.Zl (lH, d, J=5Hz, C6-H), 5.87 (lH, dd, J=5Hz, J=8Hz, C7-H¦, 6.61 12H, bs, ~ ), H H

.
6. 78 ~lH, s, N~ ), S H
7.04 (lH, q, J=5Hz, -OCHO-), ; CH3 7.22 (2H, bs, -NH2~, 9.67 (lH, d, J=8Hz, -CONH-) In a similar manner, the compounds shown in Table 32 were obtained.

~;3~8~

. . . _ _ ~ `'~ ` N 5 ~
~ ~ m I . ' ~ ,, I O v a~ ~~ D O
e ~ ~ O
U~ ~ _ ` ` `
.,~ 4~ ~ ~ ~ :C ~ `
N
~i ~ C~
U~ O C~
U~ O ~ , 1` 5 :C ~ ~ ~. ~ In ~ ~O
; a~ ~ ~I u~ 1 11 -- ~ ~ N
P:; al ~ o o o ~ X
~ O ~
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~3~86 1 (4) To a solution of 1.05 g of the 7-[2-(2-formamido-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(2,3-dimethyl-6-oxo-1,6-dihydropyrazinyl)]methyl}-~3-cephem-4-carboxylic acid obtained in above (1) in 10 ml of methanol was added 0.38 ml of concentrated hydrochloric acid, and the resulting mixture was subjected to reaction at 35~C for 2 hours~ After completion of the reaction, the solvent was removed by distillation under reduced pressure. To the residue was added 10 ml of diethyl ether, and the crystals were collected by filtration to obtain 0.43 g (yield, 84.8~) of hydrochloride of 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(2,3-dimethyl-6-oxo-1,6-dihydropyrazinyl)]methyl}-~3-cephem-4-carboxylic acid having a melting point of 250C or more.
IR(KBr) cm 1 ~C=O 1765, 1660, 1620 NMR(d6-DMSO) ~ values:
2.20 (6H, bs, -CH3 x 2), 3.18 (2H, bs, C2-H), 3.90 (3H, s, -OCH3), 4.94, 5.24 (2Hf ABq, J=15Hz, ~ CH - )' A 5.10 (lH, d, ~5HZ, C6-H), 5.78 (lH, dd, J=5Hz, J=8Hz, C7-H), 6.89 (lH, s, S ~ H)' 7.82 (lH, s, ~ H), 9.79 (lH, dd, J=8Hz, -CONH-) 1 Example 12 (1) In a similar manner to that in Example 7-(1), the compounds shown in Table 33 were obtained from the starting materials shown below.

N C-COOH
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(starting material, syn-isomer) NH2 --- ~ -S~ O~ O
oO~N~f CH2N~ cH2cH3 COOCH( ~ )2 ~N~ C CONH ~ ~ ~ O ~ O

OCH2COORl COOCH( ~ )2 (objective compound, syn-isomer) Table 33 _ _ Objective Compound m.p. (C) IR (KBr) Rl cm : VC O
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127-130 1780, 1720, (decomp.) ~685, 1645 , . ~ ~ . . _ ._ 127-130 178~, 1720, (decomp.3 1685, 1635 _ 150-152 1780, 1720, -CH2CH3 (decomp.) 1680, 1645 1 12) The compounds shown in Table 34 were obtained by reacting the above-mentioned compounds in a similar manner as in Example 7-(23.

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1 Example 13 (1) To a solution of 2.72 g of 2-(2-tert.-amyloxy-carboxamidothiazol-4-yl)acetic acid in 40 ml of anhydrous methylene chloride was added 1.06 g of N-methylmorpholine, and the mixture was cooled to 35C. Subsequently, 1.12 g of ethyl chlorocarbonate was added thereto, and the mixture was subjected to reaction at -35 to -25C for 1.5 hours, after which 5.18 g of diphenylmethyl 7-amino-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4~tetrahydropyrazinyl)]-methyl}-~3-cephem-4-carboxylate was added thereto, and the mixture was subjected to reaction at -30 to -20C
for 1 hour and then at -10 to 10C for 1 hour. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was dissolved in 40 ml of ethyl acetate and 30 ml of waterO
The organic layer was separated, and 30 ml of water was added again thereto. The mixture was adjusted to pH 7.0 with sodium hydrogencarbonate with ice-cooling.
The organic layer was separated, washed with 30 ml of water and 30 ml of a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distil-lation under reduced pressure. To the residue was added 35 ml of diethyl ether, and the crystals were collected by filtration to obtain 3.62 g (yield, 90.5%) of di-phenylmethyl 7-[2-(2-tert.-amyloxycarboxamidothiazol-4-yl)acetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl]methyl}-~3-cephem-4-carboxylate 1 having a melting point of 152-154C (decomp.).
IR (RBr~ cm : VC O 1780, 1720, 1685, 1640 In a similar manner, the following compound was obtained: 6.15 g ~yield, 82.7%) of diphenylmethyl 7-[2-(2-tert.-amyloxycarboxamidothiazol-4-yl)acetamido]-3-{[1-(3,6-dioxo-1,2,3,6-tetrahydropyridazinyl)]methyl}-~3-cephem-4-carboxylate~
m.p.: 136-139C ~decomp.) IR lKsr) cm : VC O 1780, 1720, 1665 (2) The compounds shown in Table 35 were obtained by subjecting the compounds obtained in above (1) to reaction in the same manner'as in Example 6-~3).

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-3~6 1 Example 14 n 48 ml of N,N-dimethylacetamide were dissolved o>~ob~ o 6.82 g of diphenylmethyl 7-(4-bromo-3-~e~ tL#~h~)-3-[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-methyl} -a 3-cephem-4-carboxylate and 1 g of thiourea, and the mixture was subjected to reaction at room temperature for 2 hours. After completion of the reaction, the reac~ion mixture was poured into a mixed solvent of 500 ml of water and 500 ml of ethyl acetate, and the mixture was adjusted to pH 6.7 with sodium hydrogen-carbonate. The organic layer was separated and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. Subsequently, the residue was dissolved in 33 ml of trifluoroacetic acid and 8 ml of anisole, and the mixture was subjected to reaction at room temperature for 1 hour. After completion of the reaction, the solvent was removed by distillation under reduced pres-sure. To the residue was added 40 ml of diethyl ether, and the crystals were collected by filtration to obtain 4.50 g ~yield, 74.1%) of trifluoroacetic acid salt of 7-[2-(2-aminothiazol-4-yl)acetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylic acid having a melting point of 109 115C
(dec.).
In a similar manner, the following compound was obtained: Trifluoroacetic acid salt of 7-[2-(2-amino-thiazol-4-yl)acetamido]-3-{[1-(3,6-dioxo-1,2,3,6-tetra-l hydropyridazinyl)]methyl}-~3~cephem-4-carboxylic acid, 486 m.p.: 200C or more.
Physical properties ~IR, NMR values~ of this compound were identical with those in Example 13-(2).

l Preparation Example l An aqueous sodium salt solution of 7-~2-(2-aminothiazol-4-yl)-2~(syn)-methoxyiminoacetamido]-3-{[l-(2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylic acid was treated in a conventional mannex to obtain a freeze-dried and sterilized sodium salt. One gram (potency) of the sodium salt was dis-solved in 20 ml of physiological saline solution to obtain an injection.

Preparation Example 2 One gram (potency) of the freeze-dried ~"~ product obtained in Preparation Example l was dissolved in 4 ml of 0.5% (W/V) aqueous lidocaine hydrochloride solution to obtain a dilutable injection.

Preparation Example 3 One gram (potency) ol the freeze-dried product obtained in Preparation Example l was dissolved in 20 ml of 5% glucose solution to obtain an injection.
Moreover, the other compounds of the formula [I] can also be formed into the corresponding freeze-dried products (sodium salts) or injections by processing them in the same manner as in Preparation Examples l to 3.

Claims (72)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for producing a cephalosporin represented by the following formula or a pharmaceutically acceptable salt thereof, wherein R1 repre-sents a hydrogen atom or a carboxyl-protecting group; R2 repre-sents a group of the formula:

in which R6 represents a hydrogen atom, a hydroxyl group, a nitro group, a carbamoyl group, a thiocarbamoyl group or a sulfamoyl group, or an alkyl, alkenyl, alkynyl, alkadlenyl, cycloalkyl, cycloalkenyl, cycloalkadlenyl, aryl, aralkyl, acyl, alkoxy, alkylthlo, acyloxy, cycloalkyloxy, aryloxy, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocycllc sulfonyl, alkylcarbamoyl, dlalkylcarbamoyl, alkylthlocarbamoyl, dlalkylthiocarbamoyl, acylcarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonylthiocarbamoyl, arylsul-fonylthlocarbamoyl, alkylsulfamoyl, dlalkylsulfamoyl, alkoxy-thlocarbonyl, alkylldeneamlno, cycloalkylmethyleneamlno, aryl-methyleneamlno, heterocyclic methyleneamlno or heterocycllc group which may be substltuted by at least one substltuent selected from the group conslstlng of halogen atoms, alkyl groups, aralkyl groups, aryl groups, alkenyl groups, hydroxyl group, oxo group, alkoxy groups, alkylthlo groups, nltro group, cyano group, amlno group, acyl groups, acyloxy groups, carboxyl group, carbamoyl group, sulfo group, sulfamoyl group, alkylamlno groups, dlalkyl-amino groups, acylamino groups, alkoxycarbonyl groups, acylalkyl groups, aminoalkyl groups, N-alkylaminoalkyl groups, N,N-dlalkyl-amlnoalkyl groups, hydroxyalkyl groups, hydroxylmlnoalkyl groups, alkoxyalkyl groups, carboxyalkyl groups, alkoxycarbonylalkyl groups, aralkyloxycarbonylalkyl groups, sulfoalkyl groups, sul-famoylalkyl groups, carbamoylalkyl groups, carbamoylalkenyl groups, N-hydroxy-carbamoylalkyl groups and a group of the for-mula in which R24 represents a lower alkyl group or a group of the formula, (each of R16 and R17, which may be the same or dlfferent, represents a hydrogen atom or an alkyl group, or R16 and R17 together with their adjacent nitrogen atom may form a ring); each R7, R8, R9, R10, R11, R12, R14 and R15, whlch may be the same or different, represents a hydrogen atom or a halogen atom or an alkyl, aralkyl or aryl group which may be substituted by at least one substltuent selected from the group consisting of halogen atoms, alkyl groups, aralkyl groups, aryl groups, alkenyl groups, hydroxyl group, oxo group, alkoxy groups, alkylthlo groups, nitro group, cyano group, amlno group, acyl groups, acy-loxy groups, carboxyl group, carbamoyl group, sulfo group, sulfa-moyl group, alkylamlno groups, dlalkylamlno groups, acylamlno groups, alkoxycarbonyl groups, acylalkyl groups, amlnoalkyl groups, N-alkylamlnoalkyl groups, N,N-dl-a1kylamlnoalkyl groups, hydroxyalkyl groups, hydroxylmlnoalkyl groups, alkoxyalkyl groups, carboxyalkyl groups, alkoxycarbonylalkyl groups, aralky-loxycarbonylalkyl groups, sulfoalkyl groups, sulfamoylalkyl groups, carbamoylalkyl groups, carbamoylakenyl groups, N-hydroxy-carbamoylalkyl groups and a group of the formula in whlch R24 represents a lower alkyl group; R13 represents a hydrogen atom, a halogen atom, a carboxyl group, a sulfo group, a carbamoyl group or a thiocarbamoyl group or an alkyl, aralkyl, aryl, alkoxy. alkylthio, acyl, alkoxycarbonyl, cycloalkoxycar-bonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclic sulfonyl, alkyl-carbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthiocar-bamoyl, acylcarbamoyl, acylthiocarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonylthiocarbamoyl or arylsul-fonylthiocarbamoyl group which may be substituted by at leas tone substituent selected from the group consisting of halogen atoms, alkyl groups, aralkyl groups, aryl groups, alkenyl groups, hydroxyl group, oxo group, alkoxy groups, alkylthio groups, nitro group, cyano group, amino group, acyl groups, acyloxy groups, carboxyl group, carbamoyl group, sulfo group, sulfamoyl group, alkylamino groups, dialkylamino groups, acylamino groups, alkoxy-carbonyl groups, acylalkyl groups, aminoalkyl groups, N-alkyl-aminoalkyl groups, N,N-di-alkylaminoalkyl groups, hydroxyalkyl groups, hydroxyiminoalkyl groups, alkoxyalkyl groups, carboxy-alkyl groups, alkoxycarbonylalkyl groups, aralkyloxycarbonylalkyl groups, sulfoalkyl groups, sulfamoylalkyl groups, carbamoylalkyl groups, carbamoylalkenyl groups, N-hydroxycarbamoylalkyl groups and a group of the formula in which R24 represents a lower alkyl group; R3 represents a hydrogen atom or an alkoxy group; R4 represents a hydrogen atom or a halogen atom;
R5 represents a hydrogen atom or a protected or unprotected amino group; A represent a group of the formula, -CH2- or a group of the formula in which R18 represents a hydrogen atom or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl or heterocyclic group which may be substituted by at least one substituent selected from the group consisting of halogen atoms, oxo group, cyano group, hydroxyl group, alkoxy groups, amino groups, alkylamino groups, dialkylamino groups, heterocyclic groups and groups of the formulas: -COOR1.

-NHCOR25 and wherein R1 has the same meaning as defined above, and each of R25, R26 and R27, which may be the same or different, represents a hydrogen atom, an alkyl group, an aralkyl group or an aryl group, or a hydroxyl-protecting group of a group of the formula, (each of R19 and R20, which may be the same or different, repre-sents a hydroxyl, alkyl, aralkyl, aryl, alkoxy, aralkyloxy or aryloxy group) and the bond means that the compound may be a syn-isomer or an anti-isomer or a mixture thereof, which com-prises [A] reacting a compound of the following formula, or a salt thereof:

II
wherein R28 represents an amino group or a group of the formula, in which each R31, R32 and R33, which may be the same or differ-ent, represents a hydrogen atom or an organic residue not partic-ipating in the reaction or a group of the formula, in which each of R34 and R35, which may be the same or different, represents a hydrogen atom or an organic residue not participat-ing in the reaction, and R1, R2 and R3 have the same meanings as defined above, with a compound represented by the following for-mula, or a reactive derivative thereof in the carboxyl group thereof:

III

wherein R4, R5 and A have the same meanings as defined above, or [B] reacting a compound of the following formula or a salt thereof:
IV
wherein X represents a halogen atom and R1, R2, R3 and A have the same meanings as defined above, with a compound represented by the formula:
V

wherein R5 has the same meaning as defined above, or [C] reacting a compound of the following formula, or a salt thereof:

VI
wherein R1, R2, R3, R4 and R5 have the same meanings as defined above, with a compound represented by the following formula, or a salt thereof:

wherein R18 has the same meanings as defined above, and if desired, after the step of [A], [B] or [C], removing the protect-ing group, protecting the carboxyl group or converting the prod-uct to a pharmaceutically acceptable salt thereof.

2. A process according to claim 1, which comprises reacting a compound of the following formula or a salt thereof:

wherein R1, R2, R3 and R28 have the same meanings as defined in claim 1 with a compound represented by the following formula, or reactive derivative in the carboxyl group thereof:

wherein R4, R5 and A have the same meanings as defined in claim 1 and then, when required, removing the protecting group, protect-ing the carboxyl group or converting the product to a salt thereof.

3. A process according to claim 2, wherein the reac-tion is effected at a temperature of -50°C to 40°C.

4. A process according to claim 1, which comprises reacting a compound of the following formula or a salt thereof:

wherein R1, R2, R3, A and X have the same meanings as defined in claim 1, with a compound represented by the formula wherein R5 has the same meaning as defined in claim 1 and then, when required, removing the protecting group, protecting the car-boxyl group or converting the product to a salt thereof.

5. A process according to claim 4, wherein the reac-tion is effected at a temperature of 0° to 100°C.

6. A cephalosporin derivative represented by the for-mula I

or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5 and A are as in claim 1.

7. A process according to claim 2, wherein A repre-sents a group of the formula, which R18 and the bond have the same meanings as defined in claim 1.

8. A process according to claim 1, wherein A repre-sents a group of the formula, in which R18 and the bond have the same meanings as defined in claim 1.

9. A process according to claim 1, which comprises reacting a compound of the following formula, or a salt thereof:

wherein R1, R2, R3, R4 and R5 have the same meanings as defined in claim 1 with a compound represented by the following formula, or a salt thereof:

wherein R18 has the same meaning as defined in claim 1 and then, when required, removing the protecting group, protecting the car-boxyl group or converting the product to a pharmaceutically acceptable salt thereof.

10. A process according to claim 9, wherein the reac-tion is effected at a temperature of 0°C to 100°C.

11. A compound represented by the following formula, or a pharmaceutically acceptable salt thereof:

wherein R1, R2, R3, R4, R5, R13 and the bond have the same meanings as defined in claim 1.

12. A process according to claim 1, wherein R3 is a hydrogen atom.

13. A process according to claim 12, wherein R4 is a hydrogen atom.

14. A process according to claim 13, wherein R5 is an amino group.

15. A process according to claim 14, wherein A is a group of the formula, in which R18 represents a hydrogen atom or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl or heterocyclic group which may be substituted by at least one substituent selected from the group consisting of halogen atoms, oxo group, cyano group, hydroxyl group, alkoxy groups, amino groups, alkylamino groups, dialkylamino groups, hetero-cycllc groups and groups of the formulas: -COOR1, -NHCOR25 and wherein R1 has the same meaning as defined above, and each of R25, R26 and R27, which may be the same or different, represents a hydrogen atom, an alkyl group, an aralkyl group or an aryl group, or a hydroxyl-protecting group of a group of the formula, (each of R19 and R20, which may be the same or different, rep-resents a hydroxyl, alkyl, aralkyl, aryl, alkoxy, aralkyloxy or aryloxy group) and the bond means that the compound may be a syn-isomer or an anti-isomer or a mixture thereof.

16. A process according to claim 15, wherein R18 is a substituted or unsubstituted alkyl group.

17. A process according to claim 14. wherein A is a group of the formula (syn isomer).

18. A process according to claim 14, wherein A is a group of the formula (syn-isomer) in which R1 represents a hydrogen atom or a carboxyl-protecting group.

19. A process according to claim 14, wherein A is a group of the formula (syn-isomer) in whlch R1 represents a hydrogen atom or a carboxyl-protecting group.

20. A process according to claim 14. wherein R2 is a group of the formula, in which R6 represents a hydrogen atom, a hydroxyl group, a nitro group, a carbamoyl group, a thiocarbamoyl group or a sulfamoyl group, or an alkyl, alkenyl, alkynyl, alkadlenyl, cycloalkyl, cycloalkenyl, cyclo-alkadlenyl, aryl, aralkyl, acyl, alkoxy, alkylthio, acyloxy, cycloalkyloxy, aryloxy, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkyl-sulfonyl, arylsulfonyl, heterocyclic sulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, acyl-carbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyl-sulfonylthiocarbamoyl, arylsulfonylthiocarbamoyl, alkylsulfamoyl, dialkylsulfamoyl, alkoxythiocarbonyl, alkylldeneamino, cyclo-alkylmethyleneamino, arylmethyleneamino, heterocyclic methyl-eneamino or heterocyclic group which may be substituted by at least one substituent selected from the group consisting of halo-gen atoms, alkyl groups, aralkyl groups, aryl groups, alkenyl groups, hydroxy, group, oxo group, alkoxy groups, alkylthio groups, nitro group, cyano group, amino group, acyl groups, acy-loxy groups, carboxyl group, carbamoyl group, sulfo group, sulfa-moyl group, alkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonyl groups, acylalkyl groups, aminoalkyl groups, N-alkylaminoalkyl groups, N,N-dialkylaminoalkyl groups, hydroxyalkyl groups, hydroxylmlnoalkyl groups, alkoxyalkyl groups, carboxyalkyl groups, alkoxycarbonylalkyl groups, aralky-loxycarbonylalkyl groups, sulfoalkyl groups, sulfamoylalkyl groups, carbamoylalkyl groups, carbamoylalkenyl groups, N-hydroxy-carbamoylalkyl groups and a group of the formula in which R24 represents a lower alkyl group or a group of the formula, (each of R16 and R17, which may be the same or different, represents a hydrogen atom or an alkyl group, or R16 and R17 together with their adjacent nitrogen atom may form a ring).

21. A process according to claim 20, wherein R6 Is a hydrogen atom, a heterocyclic group, an alkyl, aralkyl or cyclo-alkyl group, or a group of the formula, in which each of R16 and R17, which may be the same or different, represents a hydrogen atom or an alkyl group, or R16 and R17 together with their adjacent nitrogen atom may form a ring.

22. A process according to claim 20, wherein R6 is a hydrogen atom, an alkyl, aralkyl or cycloalkyl group, or a group of the formula, in which each of R16 and R17, which may be the same or different, represents a hydrogen atom or an alkyl group, or R16 and R17 together with their adjacent nitrogen atom may form a ring.

23. A process according to claim 14, wherein R2 is a group of the formula, in which R7, R8 and R9 which may be the same or different, repre-sents a hydrogen atom or a halogen atom or an alkyl, aralkyl or aryl group which may be substituted by at least one substituent selected from the group consisting of halogen atoms, alkyl groups, aralkyl groups, aryl groups, alkenyl groups, hydroxyl group, oxo group, alkoxy groups, alkylthio groups, nitro group, cyano group, amino group, acyl groups, acyloxy groups, carboxyl group, carbamoyl group, sulfo group, sulfamoyl group, alkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonyl groups, acylalkyl groups, aminoalkyl groups, N-alkylaminoalkyl groups, N,N-di-alkylaminoalkyl groups, hydroxyalkyl groups, hydroxylmlnoalkyl groups, alkoxyalkyl groups, carboxyalkyl groups, alkoxycarbonylalkyl groups, aralkyloxycarbonylalkyl groups, sulfoalkyl groups, sulfamoylalkyl groups, carbamoylalkyl groups, carbamoylalkenyl groups, N-hydroxycarbamoylalkyl groups and a group of the formula in which R24 represents a lower alkyl group.

24. A process according to claim 23, wherein each of R7, R8 and R9, which may be the same or different, is a hydrogen atom or an alkyl group.

25. A process according to claim 14, wherein R2 is a group of the formula, in which R10, R11 and R12 which may be the same or different, represents a hydrogen atom or a halogen atom or an alkyl, aralkyl or aryl group which may be substituted by at least one sub-stituent selected from the group consisting of halogen atoms, alkyl groups, aralkyl groups, aryl groups, alkenyl groups, hydroxyl group, oxo group, alkoxy groups, alkylthio groups, nitro group, cyano group, amino group, acyl groups, acyloxy groups, carboxyl group, carbamoyl group, sulfo group, sulfamoyl group, alkylamino groups, dialkylamino groups, acylamino groups, alkoxy-carbonyl groups, acylalkyl groups, aminoalkyl groups, N-alkyl-aminoalkyl groups, N,N-di-alkylaminoalkyl groups, hydroxyalkyl groups, hydroxylmlnoalkyl groups, alkoxyalkyl groups, carboxy-alkyl groups, alkoxycarbonylalkyl groups aralkyloxycarbonylalkyl groups, sulfoalkyl groups, sulfamoylalkyl groups, carbamoylalkyl groups, carbamoylalkenyl groups, N-hydroxycarbamoylalkyl groups and a group of the formula in which R24 represents a lower alkyl group.

26. A process according to claim 25, wherein each of R10, R11 and R12, which may be the same or different, is a hydro-gen atom, a halogen atom or an alkyl group.

27. A process according to claim 14, wherein R2 is a group of the formula, in which R14 and R15 which may be the same or different, repre-sents a hydrogen atom or a halogen atom or an alkyl, aralkyl or aryl group which may be substituted by at least one substituent selected from the group consisting of halogen atoms, alkyl groups, aralkyl groups, aryl groups, alkenyl groups, hydroxyl group, oxo group, alkoxy groups, alkylthio groups, nitro group, cyano group, amino group, acyl groups, acyloxy groups, carboxyl group, carbamoyl group, sulfo group, sulfamoyl group, alkylamino groups, dialkylamino groups, acylamino groups, alkoxycarbonyl groups, acylalkyl groups, aminoalkyl groups, N-alkylaminoalkyl groups, N,N-di-alkylaminoalkyl groups, hydroxyalkyl groups, hydroxylmlnoalkyl groups, alkoxyalkyl groups, carboxyalkyl groups, alkoxycarbonylalkyl groups, aralkyloxycarbonylalkyl groups, sulfoalkyl groups, sulfamoylalkyl groups, carbamoylalkyl groups, carbamoylalkenyl groups, N-hydroxycarbamoylalkyl groups and a group of the formula in which R24 represents a lower alkyl group; and R13 represents a hydrogen atom, a halogen atom, a carboxyl group, a sulfo group, a carbamoyl group or a thiocarbamoyl group or an alkyl, aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxycarbonyl, cycloalkoxycarbonyl, acyloxycar-bonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclic sulfonyl, alkylcarbamoyl, dialkylcar-bamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonylthiocarbamoyl or arylsulfonylthiocarbamoyl group which may be substituted by at leas tone substituent selected from the group consisting of halogen atoms, alkyl groups, aralkyl groups, aryl groups, alkenyl groups, hydroxyl group, oxo group, alkoxy groups, alkylthio groups, nitro group, cyano group, amino group, acyl groups, acyloxy groups, carboxyl group, carbamoyl group, sulfo group, sulfamoyl group, alkylamino groups, dialkyl-amino groups, acylamino groups, alkoxycarbonyl groups, acylalkyl groups, aminoalkyl groups, N-alkylaminoalkyl groups, N,N-di-alkylaminoalkyl groups, hydroxyalkyl groups, hydroxylmlnoalkyl groups, alkoxyalkyl groups, carboxyalkyl groups, alkoxycarbonyl-alkyl groups, aralkyloxycarbonylalkyl groups, sulfoalkyl groups, sulfamoylalkyl groups, carbamoylalkyl groups, carbamoylalkenyl groups, N-hydroxycarbamoylalkyl groups and a group of the formula in which R24 represents a lower alkyl group.

28. A process according to claim 27, wherein each of R13, R14 and R15, which may be the same or different, is a hydro-gen atom or an alkyl group.

29. A cephalosporin derivative represented by the for-mula I given in claim 1 or a pharmaceutically acceptable salt thereof wherein R1, R2, R4, R5 and A are as in claim 1 and R3 is as in claim 12.

30. A cephalosporin derivative represented by the for-mula I given in claim 1 or a pharmaceutically acceptable salt thereof wherein R1, R2, R5 and A are as in claim 1, R3 is as in claim 12 and R4 is as in claim 13.

31. A cephalosporin derivative represented by the for-mula 1 given in claim 1 or a pharmaceutically acceptable salt thereof wherein R1, R2 and A are as in claim 1, R3 is hydrogen, R4 is hydrogen and R5 is as in claim 14.

32. A cephalosporin derivative represented by the for-mula I given in claim 1 or a pharmaceutically acceptable salt thereof wherein R1 and R2 are as in claim 1, R3 and R4 are hydro-gen, R5 is amino and A is as in claim 15.

33. A cephalosporin derivative represented by the for-mula I given in claim 1 or a pharmaceutically acceptable salt thereof wherein R1 and R2 are as in claim 1, R3 and R4 are hydro-gen, R5 is amino, A is as in claim 15 and R18 is as in claim 16.

34. A cephalosporin derivative represented by the for-mula I given in claim 1 or a pharmaceutically acceptable salt thereof wherein R1 and R2 are as in claim 1, R3 and R4 are hydro-gen, R5 is amino and A is as in claim 17.

35. A cephalosporin derivative represented by the for-mula I given in claim 1 or a pharmaceutically acceptable salt thereof wherein R1 and R2 are as in claim 1, R3 and R4 are hydro-gen, R5 is amino and A is as in claim 18.

36. A cephalosporin derivative represented by the for-mula I given in claim 1 or a pharmaceutically acceptable salt thereof wherein R1 and R2 are as in claim 1, R3 and R4 are hydro-gen, R5 is amino and A is as in claim 19.

37. A cephalosporin derivative represented by the for-mula I given in claim 1 or a pharmaceutically acceptable salt thereof wherein R1 and A are as in claim 1, R3 and R4 are hydro-gen, R5 is amino and R2 is as in claim 20.

38. A cephalosporin derivative represented by the for-mula I given in claim 1 or a pharmaceutically acceptable salt thereof wherein R1 and A are as in claim 1, R3 and R4 are hydro-gen, R5 is amino and R2 is as in claim 20 and R6 is as in claim 21.

39. A cephalosporin derivative represented by the for-mula I given in claim 1 or a pharmaceutically acceptable salt thereof wherein R1 and A are as in claim 1, R3 and R4 are hydro-gen, R5 is amino and R2 is as in claim 20 and R6 is as in claim 22.

40. A cephalosporin derivative represented by the for-mula I given in claim 1 or a pharmaceutically acceptable salt thereof wherein R1 and A are as in claim 1, R3 and R4 are hydro-gen, R5 is amino and R2 is as in claim 23.

41. A cephalosporin derivative represented by the for-mula I given in claim 1 or a pharmaceutically acceptable salt thereof wherein R1 and A are as in claim 1, R3 and R4 are hydro-gen, R5 is amino and R2 15 as in claim 23 and R7, R8 and R9 are as in claim 24.

42. A cephalosorin derivative represented by the for-mula I given In claim 1 or a pharmaceutically acceptable salt thereof wherein R1 and A are as in claim 1, R3 and R4 are hydro-gen, R5 is amino and R2 is as in claim 25.

43. A cephalosporin derivative represented by the for-mula I given in claim 1 or a pharmaceutically acceptable salt thereof wherein R1 and A are as in claim 1, R3 and R4 are hydro-gen, R5 is amino and R2 is as in claim 25 and R10, R11 and R12 are as in claim 26.

44. A cephalosporin derivative represented by the for-mula I given in claim 1 or a pharmaceutically acceptable salt thereof wherein R1 and A are as in claim 1, R3 and R4 are hydro-gen, R5 is amino and R2 is as in claim 27.

45. A cephalosporin derivative represented by the for-mula I given in claim 1 or a pharmaceutically acceptable salt thereof wherein R1 and A are as in claim 1, R3 and R4 are hydro-gen, R5 is amino and R2 is as in claim 27 and R13, R14 and R15 are as in claim 28.

46. A process according to claim 1, in which R5 is amino, R4 is hydrogen, A is (syn)methoxy lmlno methylene, R3 is hydrogen, R2 is 1-(2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) and R1 is hydrogen or an ester group.

47. A process according to claim 1, in which R5 is amino, R4 is hydrogen, A is (syn)carboxy methoxy lmlno methylene, R3 is hydrogen, R2 is 1-(2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) and R1 is hydrogen or an ester group.

48. A process according to claim 1, in which R5 is amino, R4 is hydrogen, A is (syn)methoxy lmlno methylene, R3 is hydrogen, R2 is 1-(4-methyl-2,3-dioxo-1,2,3,4-tetrahydropy-razinyl) and R1 is hydrogen or an ester group.

49. A process according to claim 1, in which R5 is amino, R4 is hydrogen, A is (syn)carboxy methoxy lmlno methylene, R3 is hydrogen, R2 is 1-(4-methyl-2,3-dioxo-1,2,3,4-tetrahydropy-razinyl) and R1 is hydrogen or an ester group.

50. A process according to claim 1, in which R5 is amino, R4 is hydrogen, A is (syn)methoxy lmlno methylene, R3 is hydrogen, R2 is 1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) and R1 is hydrogen or an ester group.

51. A process according to claim 1, in which R5 is amino, R4 is hydrogen, A is (syn)carboxy methoxy lmlno methylene, R3 is hydrogen, R2 is a 1-(4-ethyl-2,3-dioxo-1,2,3,4,-tetrahy-dropyrazinyl) and R1 is hydrogen or an ester group.

52. A process according to claim 1, in which R5 is amino, R4 is hydrogen, A is (syn)methoxy lmlno methylene, R3 is hydrogen, R2 is 1-(4-isopropyl-2,3-dioxo-1,2,3,4-tetrahydropy-razinyl) and R1 is hydrogen or an ester group.

53. A process according to claim 1, in which R5 is amino, R4 is hydrogen, A is (syn)methoxy lmlno methylene, R3 is hydrogen, R2 is 1-(4-dimethylamino-2,3-dioxo-1,2,3,4-tetrahy-dropyrazinyl) and R1 is hydrogen or an ester group.

54. A process according to claim 1, in which R5 is amino, R4 is hydrogen, A is (syn)carboxy methoxy lmlno methylene, R3 is hydrogen, R2 is 1-(4-dimethylamino-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) and R1 is hydrogen or an ester group.

55. A process according to claim 1, in which R5 is amino, R4 is hydrogen, A is (syn)methoxy lmlno methylene, R3 is hydrogen, R2 is 1-(2-oxo-1,2-dihydropyrazinyl) and R1 is hydrogen or an ester group.

56. A process according to claim 1, in which R5 is amino, R4 is hydrogen, A is (syn)methoxy lmlno methylene, R3 is hydrogen, R2 is 1-(3,6-dioxo-1,2,3,6-tetrahydropyrldazinyl) and R1 is hydrogen or an ester group.

57. A process according to claim 1, in which R5 is amino, R4 is hydrogen, A is (syn)carboxy methoxy lmlno methylene, R3 is hydrogen, R2 is 1-(3,6-dioxo-1,2,3,6-tetrahydropyrldazinyl) and R1 is hydrogen or an ester group.

58. A process according to claim 1, in which R5 is amino, R4 is hydrogen, A is (syn)methoxy lmlno methylene, R3 is hydrogen, R2 is 1-(3-methyl-6-oxo-1,6-dihydropyrldazinyl) and R1 is hydrogen or an ester group.

59. A process according to claim 1, in which R5 is amino, R4 is hydrogen, A is (syn)carboxy methoxy lmlno methylene, R3 is hydrogen, R2 is 1-(3-methyl-6-oxo-1,6-dihydropyrldazinyl) and R1 is hydrogen or an ester group.

60. 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-methoxy-lmlno-acetamido]-3-[[1-(2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl)-.DELTA.3-cephem-4-carboxylic acid, an ester thereof or a salt thereof.

61. 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-carboxymethoxy-lminoacetamido]-3-([1-(2,3-dioxo-1,2,3,4-tetrahydropy-razinyl)]methyl]-.DELTA.3-cephem-4-carboxylic acid, an ester thereof or a salt thereof.

62. 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-methoxylminoac-etamido]-3-([1-(4-methyl-2,3-dioxo-1,2,3,4-tetrahydropy-razinyl)]methyl)-.DELTA.3-cephem-4-carboxylic acid, an ester thereof or a salt thereof.

63. 7-[2-(2-aminothiazol-4-yl)-2-(syn)-carboxymethoxy-lminoacetamido]-3-1[1-(4-methyl-2,3-dioxo-1,2,3,4-tetrahydropy-razinyl)]methyl)-.DELTA.3-cephem-4-carboxylic acid, an ester thereof or a salt thereof.

64. 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-methoxylminoac-etamido]-3-([1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropy-razinyl)]methyl)-.DELTA.3-cephem-4-carboxylic acid, an ester thereof or a salt thereof.

65. 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-carboxymethoxy-lminoacetamido]-3-([1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropy-razinyl)]methyl)-.DELTA.3-cephem-4-carboxylic acid, an ester thereof or a salt thereof.

66. 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-methoxylminoac-etamido]-3-([1-(4-isopropyl-2,3-dioxo-1,2,3,4-tetrahydropy-razinyl)]methyl)-.DELTA.3-cephem-4-carboxylic acid, an ester thereof or a salt thereof.

67. 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxylminoac-etamido]-3-([1-(4-dimethylamino-2,3-dioxo-1,2,3,4-tetrahydropy-razlnyl)]methyl)-.DELTA.3-cephem-4-carboxylic acid, an ester thereof or a salt thereof.

68. 7-[2-(2-Amlnothlazol-4-yl)-2-(syn)-carboxymethoxy-lminoacetamido]-3-([1-(4-dimethylamino-2,3-dioxo-1,2,3,4-tetrahy-dropyrazinyl)]methyl)-.DELTA.3-cephem-4-carboxylic acid, an ester thereof or a salt thereof.

69. 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-methoxylminoac-etamido]-3-[[1-(2-oxo-1,2-dihydropyrazinyl)]methyl)-.DELTA.3-cephem-4-carboxylic acid, an ester thereof or a salt thereof.

70. 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-methoxylminoac-etamido]-3-[[1-(3,6-dioxo-1,2,3,6-tetrahydropyridazinyl)]-methyl)-.DELTA.3-cephem-4-carboxylic acid or a pharmaceutically acceptable ester or salt thereof.

71. 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-carboxymethoxy-lminoacetamido]-3-([1-(3,6-dioxo-1,2,3,6-tetrahydropyrl-dazinyl)]methyl)-.DELTA.3-cephem-4-carboxylic acid or a pharmaceuti-cally acceptable ester or salt thereof.

72. 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-methoxyiminoac-etamldo]-3-[[1-(3-methyl-6-oxo-1,6-dihydropyridazinyl)]-methyl}-.DELTA.3-cephem-4-carboxylic acid or a pharmaceutically acceptable ester or salt thereof.