CA1276139C - 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 production of cephalosporins in which a substituted or unsubstituted 2,3-dioxo-1,2,3,4-tetra-hydropyrazinyl, 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 atached 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 sutstituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, hererocy-clic group or a hydroxyl-protecting group or a group of the formula, (each of R19 and R20, which may be the same or different, represents a hydroxyl, alkyl, aralkyl, aryl, alkoxy, aralkyloxy or aryloxy group), and the bond

Description

~l2~6~3~

This invention relates to novel cephalosporins, processes for producing said cephalosporins, an antibacterial agen-t containing said cephalosporins. In particular the present invention relates to intermediates for the producting of said cephalosporins and a process for producing said intermediates.

This applica-tion is a divisional application of copending application No. 441,286 filed November 16, 1983 which is directed to the novel cephalosporins and their preparation.
1~
The present inventors have conducted studies with the ajm of discovering compounds having a broad antibacterial spec-trum, exhibiting an excellent antibacterial activity against gram-position and gram-negative bacteria, being stable to ~.-lactamase produced by bacteria, having a low texicity, being at the same time well absorbable upon oral or parenteral adminis-tration and having an excellent therapeutic effect on ~he diseases of human beings and animals. As a result, it has been found that novel cephalosporins characterized in that a 2~ substituted or unsubstituted 2,3-dioxo-1,2,3,4-te-trahydropyra-zinyl, 2-oxo-1,3-dihydropyrazinyl, 3,6-dioxo-1,2,3,6-tetra-hydropyridazinyl or 6-oxo-1,6-dihydropyridazinyl group is attached to the exomethylene group at the 3-positlon of the cephem ring through a carbon-nitrogen bond and the following ~5 group is attached to the amino group at the 7-position, have the above-mentioned excellent properties:

' .; .
:`

-, ~

,- ' . . . .' ': ., ~2'~

5 ~ N ~ A-CO-1 wherein A, R~ 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 5 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 j 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.
lS It is a still further object of this invention to provide intermediates for the production of said novel cephalosporins and to provide a process or producing said intermediates.
Other objects and advantages of this invention will become apparent from the following description.
According to this inven~ion, there is provided a novel cephalosporin, particularly a cephalosporin re-presented by the following formula, or a salt thereof:

- ~ ' ':'': - '. ' " ''. ' ' , - . -; ., :
~: .
'- . ' ': ', ~

~2~6~3~

N ~ A--CONH ~1~ ~ 2 R5--l~ S R4 ~N~ CH2R [ I ]
COOR
1 wherein Rl represents a hydrogen atom or a carboxyl-protecting group; R2 represents a group of ~he formula, ~ N ~--R9-~ ~ 12 J~Rl 4 i I in which R6 represents a hydrogen atom~
-N ~ `R15 a hydroxyl groupj 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, aryl, aralkyl, acyl, alkoxy, alkylthio, acyloxy, cyclo-alkyloxy, aryloxy, alkoxycarbonyl, cycloalkyloxycarbonyl,acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclic sulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyl-sulfonylthiocarbamoyl, arylsulfonylthiocarbamoyl, alkylsulfamoyl, dialkylsulfamoyl, alkoxythiocarbonyl, ` . ' . ~ . : , '' . ' .
.
' ~

~2~

1 alkylideneamino, cycloalkylmethyleneamino, arylmethylene-amino, heterocyclic me-thyleneamino, or heterocyclic group, or a group of the formula, -M < 17 ~each o~

R16 and R17, which may be the same or different, re-presents a hydrogen atom or an alkyl group or R16 and R17 together with their adjacent nitrogen atom may form a ring); each of R7, R8 R9 R10 Rll 12 14 and R15r which may be the same or different, represents a hydrogen atom, a halogen a~om or a substituted or unsubstituted alkyl, aralkyl or aryl group; R13 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-thiocarbamoyl or arylsulfonylthiocarbamoyl group; R3represents 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; and A represents a group of the formula~

--C---CH2- or a group of the formula, N in which R
~R18 .: . ~ -, . . : . .
.. ", ' ' " ' ~ ", ,...... ' : . , :~2~ L39 1 represents a hydrogen atom, a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, heterocyclic group or a hydroxyl-pro-tecting group;

or a group o the formula, ~P \ 20 (each of Rl9 and R , which may be the same or different, represents a hydroxyl, alkyl, aralkyl, aryl, alkoxy, aralkyloxy, or aryloxy 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 o said cephalosphorins and a process for producing said intermediates.
This invention will be further illustrated in detail ~elow.
Herein, unless otherwise speciied, 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 deined above; the term "lower alkyl" means a straight or branched chain Cl 5alkyl and includes, ~or 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 :.. , -, . .
- , ~ ~ .

-: . . , ;
- ~ .
- - : ~ . .
- -. ' ~ . :: .
- . .

1 alkyl is as defined above, the term "acyl" means a formyl grou~; a C2 5alkanoyl group which includes, for example, acetyl, propi.onyl, isovaleryl, pivaloyl, pentanecarbonyl and the like; a C5 8cycloalkanecarbonyl group which includes, for example, cyclopentylcarbonyl, cyclohexylcarbonyl and the like; an aroyl group which includes, for example, benzoyl, toluoyl, 2-naphthoyl and the like; and a he~erocyclic 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 ~3 7cycloalkyl and includes, for example, cyclopropyl, cyclobutyl, cyclo-pentyl, cyclohexyl, cycloheptyl and the like; the term "alkadienyl" means C4 1Oalkadienyl 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, cyclohexadieny~
and the like; the term "aryl'' includes, for example, phenyl, naphthyl, indanyl and the like; the term "aralkyl"
includes, for example~ benzyl, phenethyl, 4-methylbenzyl, ' .
, . . ' ', . , ., ' '`" ',, ' .
'. ~ ' ~ ~ ' ' ' ,~ ' ' . ' , ~;27~
1 naphthylmethyl and -the like; the ~erm "heteroc~clic group"
means a heterocyclic yroup containing at least one he-tero atom selected from oxygen, nitrogen and sulur and in~
cludes, for exàmple r furyl, thienyl, pyrrolyl, pyrazolyl, imidazol~l, thiazolyl, isothiazolyl, oxazolyl, lsoxazol~l, thiadiazolyl, oxadiazolyl, thiatriazolyl, oxa-triazolyl, triazolyl, tetrazolyl, pyridyl, 4-~5-metyl-2-pyrrolinyl), 4-(2-pyrrolinyl), N-methylpiperidinyl, quinolyl, phenazinyl, 1~3- benzodioxolanyl, benzofuryl, benzothienyl, benzoxazolyl, ben20thiazolyl, 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 iodine.
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.

.- , . . . . .
.
,: . , .
.. , ~ .

~:7~ 3~

1 Amon~ these protecting groups, preferable groups are as follows:
(a) alkyl groups, for example, Cl 4alkyl, (b) substituted lower alk.yl groups wherein a~ least one of the substituents is selected from a halogen atom, or a nitro, acyl, alkoxy, oxo, cyano, hydroxyl, cyclo-alkyl, aryl, alkylthio, alkylsulfinyl, alkylsul~onyl, alkoxycarbonyl, 5-alkyl-2-oxo-1,3-dioxol-4-yl, l-indanyl, 2-indanyl, ~uryl, pyridyl, 4-imidazolyl, phthalimido, succinimido, azetidino, aziridino, pyrrolidino, piperidino, morpholino, thiomorpholino, N-lower-alkylpiperazino, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiatriazolyl, oxatriazolyl, tria~olyl, tetrazolyl, quinolyl, phenazinyl, lS benzo~uryl, benzothienyl, benzoxazoly~, benzothiazolyl, coumarinyl, 2,5-dimethylpyrrolidino, 1,4,5,6-tetrahydro-pyrimidinyl, 4-methylpiperidino, 2,6-dimethylpiperidino, 4-(S-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 yroup substitu~ed by a halogen atom, a lower alkyl or lower alkoxy ~roup, - :.- . , . . :
' - :, ' .~ .: .
.. :

. .

~276~L3~
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 aryl groups such as groups represented by the formula:

_~yl 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 tpe substituents are selected from those specifically mentioned in above (b), or groups represented by the formula:

~ ~ 2 lS wherein -Y - is a lower alkylene group such as -tCH2)3-or -ICH2)4-, or a substituted derivative thereof wherein the substituents are selected from those specifically mentioned in above (b), (g) aralkyl groups su¢h 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 speciically mentioned in above ~b), _ g _ : . - .
`' ~ :' ' , ' ' ~
: . , ' :.
- . . ::. , .

3~

1 ~i) indanyl or phthalidyl groups or substituted deriva~ives thereof wherein the substituents are methyls or halogens; tetrahydronaphthyl groups or substituted derivatives thereof wherein the substituents are methyls s or halogens; trityl, cholesteryl, bicyclo[4,4,0]decyl;
or the like, (j) phthalidylidene-lower-alkyl groups or substituted derivatives thereof wherein the substituents are haloyens 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 literature: U.S. Patent Nos.
3,499,909, 3,573,296 and 3,641,018; DT-OS Nos. 2,301,014, 2,253 r 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 yroups, phthalidyl group, indanyl group, phenyl group, substituted or ur.substituted phthalidylidene lower alkyl groups or those groups which can easily be removed in a living body such as groups represented by the ollowing formulas: -CH(CH2)mOR21, -CHOCOOR 1, and -CH(CH2)mCOOR21 wherein R21 represents a known substituted l23 or unsubstituted alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group; R22 represents a hydrogen atom or a , ~
.: : . , . :, .. .. . : , .

~7~i~3~

1 known substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group; R23 represents a hydro~en atom, a halogen atom or a known substituted or unsubstituted alkyl, cycloalkyl, aryl or heterocyclic group, or -(CH2) COOR (R has the same meaning as defined above, and n represents 0, 1 or 2); and m repre-sents 0, 1 or 2.
More specifically, there may be used 5-lower alkyl-2-oxo-1,3-dioxol-4-yl-methyl groups such as S-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-yl-methyl and the like; acyloxyalkyl groups such as acetoxy-methyl, pivalovloxymethyl, propionyloxymethyl, butyryl-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-chlorobenzoylthiometh~l, l-acetylthioethyl, l-pivaloylthioethyl, 1-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, propoxycarbonyloxymethyl, iso-propox~carbonyloxymethyl, n-butoxycarbonyloxymethyl, tert.-butoxycarbonyloxymethyl, 1-methoxycarbonyloxyethyl, 1- ethoxycarbonyloxyl~hyl 3 l-vropoxycarbonyloxyethyl, l-isopropoxycarbonyloxyethyl, l-tert.-butoxycarbonyl--- 11 ~
., . . . . .: . ~, . . -,; ~ :
.. . , :, .
-': :. ' ,. ,' .... : ':
, ' .: '. . . :
, ' . . .
. : ..

~7~3~

- 1 oxyethyl, l-n-butoxycarbonyloxyethyl and the like;
alkoxycarbonylmethyl groups such as methoxycarbony].-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 ~ 6 \~N \N~ N~

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, cycloalkylsulfo~yl, 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 , - ~
' ~ , ' ' ': , ~- ~ .,..... , , ' . . . . . .
.
.. ' . . - ' . .
: ~, -- - ., , ' .

-~ l heterocyclic group; a group of the formula, -N\ R17 (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 ing), each of R , R8, ~9, R10 Rll Rl~ Rl4 15 which may be the same or different, represents a hydrogen atom, a halogen atom, or a sub~tituted or unsubstituted alkyl, aralkyl or aryl group; Rl3 represents a hydrogen atom, a halogen atom, a carboxyl group, a sulfo group, a carbamoyl gxoup, a thiocarbamoyl group, or a substituted or unsubstituted alkyl, aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxy-carbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkyl-sulf~nyl, arylsulfon rl, heterocyclic sulfonyl, alkvl-carbamoyl, dialkylcarbamoyl, alkvlthiocarbamoyl, dialkyl-thiocarbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkyl-sulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonyl~
thiocarbamoyl or arylsulfonylthiocarbamoyl group. ~n each of the groups for R6 and R13 mentioned above, the term ~0 "cycloalkyloxy" means -O-cycloalkyl, the term "aryloxy"
means -O-aryl, the term "alkoxycarbonyl" means ~ O-alkyl, the term "cycloalkyloxycarbonyl" means -Il-O-cycloalkyl, the term "acyloxycarbonyl" means -C-O-acyl, the term "aralkyloxycarbonyl" means -~-O-aralkyl, the term "alkylsulfonyl" means -S02-alkyl, the term "cycloalkyl-sulfonyl" means -S02-cycloalkyl, the term "arylsulfonyl"

-. ~ ' . ,'' .' .

, 3~
1 means -S02-aryl, the term "heterocyclic sulfonyl" means -S02-heterocyclic ring, the term "alkylcarbamoyl" means alkyl -C-NH-alkyl, the term "dialkyl carbamoyl" means -C-N
O O
the term "alkylthiocarbamoyl" means -C-NH-alkyl, the term alkyl "~ialkylthiocarbamoyl" 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 O
-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, ~ , , . ~ ~ . . . .

~7 6i~

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 represen-ted by alkyl -NH-alkyl, dialkylamino groups represented by -N\
alkyl and groups represented by the formulas -N~ , -N~, -N 0, -N NH, -N ~-alkyl, -N ~ , -N ~ , ~ /N~l /N=N
-N ' -N~G~)=O ' -N S, -N S2 ~ -N~ -N~ or f N=N
0 -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, sul~amoyl group, alkylamino groups represented by -NH-alkyl, dialkyl-/alkyl amino groups represented by -N . , acylamino groups \ alkyl :- 15 -. \

.
- :: . . , , . :
. . :.:
, 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-aminoalkyl groups such as N-methylaminomethyl, N-methyl-aminoethyl and the like, N,N-dialkylaminoalkyl groups such as N,N-dimethylaminomethyl, N,N-dimethylaminoethyl and the liXe, 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, ethoxycar~onylmethyl, ethoxycarbo-nylethyl and the like, aralkyloxycarbonylalkyl groups such as benzyloxycarbonylmethyl, benzyloxycarbonylethyl and the like, sulfoalkyl groups such as sulfomethyl, sulfo-ethyl and the like, sulfamoylal.kyl 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 4 in which R 4 represents 0~0 :

- . . . , , :

: ~, - . . . : . :
~ . . : . . , : - ~ .

3~

1 a lower alkyl group, etc. The above-mentioned various groups as to R6, R7, ~8, R9 R10 Rll R12 R13 Rl~ a d R15 may be substituted by at least one of the above-mentioned substituents. Among the above substituents, the hydroxyl group, the amino group and the carbaxyl group may be protected by ~ suitable protecting group usually a~ailable in the art. The hydroxyl-protecting groups include all hydroxyl~protecting groups which can be usually used, such as easily remo~able acyl groups, ln for e~ample, ben~yloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxy-carbonyl, 4-(4-methoxyp~enylazo)benæyloxycarbonyl, 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 ; ~' ' ~ '; ' , "' ' :

.

1 as easily removable acyl groups, fo~ example, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, benzyloxycarbonyl, p-toluenesul~onyl, 4-nitrobenzyloxy-carbonyl, 2-bromobenzyloxycarbonyl, acetyl, (mono-, di-, tri-)chloroacet~l, trifluoroacetyl, formyl, tertO-amyloxy-carbonyl, tert.-butoxycarbonyl, 4-methoxybenzyloxycarbo-nyl, 3/4~dimethoxybenzyloxycarbonyl, 4-(phenylazo)-benzyloxycarbonyl, 4-(~-methoxyphenylazo)benzyloxycarbo-nyl, pyridine-l-oxide-2-yl-methoxycarbonyl, 2-furyloxy-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-nitrophen~lsulfonyl, 2,4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-l~naphthylmethylene, 3-hydroxy-4-pyridylmethylene, 1-methoxycarbonyl-2-propyli-dene, l-ethoxycarbonyl-2-propylidene, 3-ethoxycarbonyl-2-butylidene, 1-acetyl-2-propylidene, 1-benzoyl-2-pro-pylidene, 1-[N-~2-methoxyphenyl)carbamoyl]-2-propylidene, l-[N-I4-methoxyphenyl)carbamoyl]-2-propylidene, 2-ethoxy-carbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5-oxocyclohexylidene, 4~ ni~rofurfurylidene 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, ter-t.-butyl, n-butyl, benzyl, diphenylme.thyl, .

- ' ' ':

l t.rilyl, ~-nitrobenzyl, 4-methoxybenzyl, benzoylmethyl, acetylmethyl, 4-nitrobenzoylmethyl, p-bromobenzoyl-methyl, ~-methanesulonylbenzoylmethyl, 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, dimethylaminomethyl, quinoline-l-oxide-2-ylmethyl, pyridine-l-oxide-2-ylmethyl, b.is(p-mathoxyphenyl~methyl l~ 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 dimethylchlorosilane as described in Japanese .Patent Application Kokai (laid-Open) No. 7073/71 and Dutch 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 groups 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 --C--a group of the formula, N in which Rl8 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 .:: - 1 9 : . .
, ` . ' . ~ ~ . ' ' '. ' ' ' . - . . . . .
' . .: : . '':' :
.

3~

1 of the formula, ~P / 20 (each of Rl9 and R20, which may be the same or dif~erent, represents a hydroxyl, alkyl, aralkyl, aryl, alkoxy, aralkyloxy or aryloxy group) and the bond ~A~ means that the compound may be a syn-isomer or an anti-isomer or a mixture thereof. The said hydroxyl-protecting group includes the hydroxyl-protecting groups mentioned as to R2. In addition, the above~mentioned various yroups 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 ~roups and groups of the formulas -COORl, -CON ~ 25' -N ~ R226 , -NHCoR25 and -Il<oR26 wherein Rl has the same meaning as defined above, and each of R25 R26 a d R27 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 R2 and the carboxyl-protecting group mentioned as to Rl.

The oximes of the Eormula, N include syn-and anti-isomers and mixtures thereof.

' - , .~ ' ' ' ' . ''' . , ,~
.
-~276~

l In the R5~ ~ 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:

R ~S ~ ~ S ~ 4 wherein R4 and R5 have the same meanings as defined above, and RSa represents a protected or unproteGted imino group.
In the above formulas, the imino-protecting group for R5a includes those groups used in the fields of penicillihs and cephalosporins, and specifically, same groups as the monovalent groups among the amino-protecting groups mentioned above as to R2.
When the -CH2R2 group in the formula [I] is a group of the formula:

-CH2-N N-R6 R - N ~ wherein R6, R , 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 includ~ed in this invention:
O O ~ O OH

-CH2-N Na = -CH2-N N

... . . . . . . .

. .
. : .: .
: ~, ':: . : :, . .
~.;, : ' 3~

R

-CH2-N 12 ~ -- -CH2--N R12 O O

1 The ~alts of ~he compounds of formul~ [I] include sal-ts at the basic group and the acidlc group which are well-known in the fields o~ penicillins and cephalosporins. The salts at the basic group include salts with mineral acids such as hydrochloric acid, nitric acid, sul~uric acid and the like; salts with organic carboxylic acids such as o~alic acid, succinic acid, ~ormic acid, trichloroacetic acid, trifluoroacetic acid and the like; ànd salts with sulfonic acids such as methanesulfonic acid, ethanesulfo-nic acid, benzenesulonic acid, toluene-2-sulfonic acid, toluene-~-sulfonic acid, mesitylenesul~onic acid ~2,4,6-trimethylbenzenesulfonic acid), naphthalene-l-sulfonic acid, naphthalene - 2-sulfonic acid, phenylmethanesulfonic acid, benzene-1,3-disulonic acid, toluene-3,5-disulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid, napthalene-2,7-dis~l~onic acid, benzene-1,3,5-trisulfonic acid, ~enzene-1,2,~-trisulfonic acid, naphthalene-1,3,5-trisulonic 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 me~als such as calcium, magnesium and the like;
ammonium salts; and salts with nitrogen-containing organic bases such as procaine, dibenzylamine, N-benz~
phenethylamine, l-ephenamine~ N,N-dibenzylethylenediamine, .. . . . , :. . . . .
-. . ' -:~ . , .: . , : .
- - ., : .. ' - . - -:: . . . ~ : . , ' ' ' , ' . .

~2~ 3~

1 triethylamine, trimethylamine, tr.ibutylamine, pyridine, NrN-~imethylaniline, . 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 o the said compounds. More specifically, pre-ferable examples of the compounds represented by the formula --C--[I] are~ oximes in which A is a yroup of the formula, N

particularly syn-isomers thereof, in which R18 is preferably an alkyl group, especially methyl, ethyl; or a substltuted alkyl group, especially -CX2COORl or -C-COORl (Rl has the same meaning as defined abo~e).
Preferable examples of R2 are groups of the formula, -~=J_R6 in which R is a hydrogen atom, a sub-stituted or unsubstitute~?lower ~kyl ~roup or a ~roup o~ the ormula, -N/ 17 (R and R have the same meanings as defined above); groups of the formula, R ~ N

N~ ` R9 in which each of R7, R8 and R9, which may be the same .

. .
. , . . . . ' .

1 or different, represents a hydrogen atom or an alkyl R10 o R~1 group; groups of the formula, N~ in which o each of R10, Rll and R12, which may be the same or dif-ferent, represents a hy ~ gen atom, a halogen atom or an alkyl groupt 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].

1) Antibacterial activity ~Table 1~
According to the standard method of Japan Society of Chemotherapy l'iCHEMoTHERAPY", Vol. 23, pp. 1-2 (1975)], a bacterial solution obtàined by culturing in Heart Infusion broth (manufactured by Elken Kagaku) at 37C for 20 hours was inoculated onto a Heart In~usion agar containing a drug and cultured at 37C ~or 20 hours, after which the growth ~of the bacteria was observed, to determine the minimum concentration at which the growth o the bacteria:was inhibited a~ MIC l~g/ml). The amount ~'~7~

- 1 of the inoculated bacteria was 104 cells/plate (106 cells/ml~. The MIC values of the following test compounds are as shown in Table 1:
(A) trifluoroacetic acid salt of 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{~1-(2,3-dioxo-1,2,3,4-tet~ahydropyrazinyl)]methyl}-~3-cephem-~-carboxylic acid, ~B) trifluoroacetic acid salt of 7-[2-(2-amino-thiazol-4-yl~-2-(syn)-methoxyiminoacetamido]-3-{[1-(4-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}--cephem-4-carboxylic acid, (~) trifluoroacetic acid salt of 7-[2-(2-amino~
thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylic acid, (D) trifluoroacetic acid salt of 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(4-isopropyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylic acid, (E) trifluoroacetic acld salt of 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(4-dimethylamino-2,3~dioxo-1,2,3,4-tetrahydropyrazinyl)]-methyl}-~3-cephem-4-carboxylic acid, (F) 7-[2-(2~aminothiazol-4-yl)-2-(syn)-carboxy-methoxyiminoacetamido]-3-~[1-(2,3-dioxo-1,2,3,4-tetra-hydropyrazinyl)]methyl}-~3-cephem-4-carboxylic acid, (G) trifluoroacetic acid salt of 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-carboxymethoxyiminoacetamido]-3-.
: . .
.

, -- :
, 6~

1 {[1-(4-methyl-2,3-dioxo-1,2,3,4--tetrahydropyrazinyl)]-methyl}-~3-cephem-4-carbo~ylic acid, IH) 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}-~3-cephem-4-carboxylic acid, (I) ~rifluoroacetic 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}-~3-cephem-4-carboxylic acid, (J) txifluoroacetic 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) tri~luoroacetic acid salt of 7-[2-(2-amino-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(3,6-dioxo-1,2,3,6-tetrahydropyridazinyl)]methyl}-Q3-cephem-4-carboxylic acid, (L) formic acid salt of 7-[2-~2-aminothiazol-4-yl)-2-lsyn)-carboxymethoxyiminoacetamido~-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-1,6-dihydropyridazinyl)]methyl}-Q3-cephem-4-carboxylic acid, and (N) formic acid salt.of 7-[2-~2-aminothiazol-4-yl)-2-tsyn)-carboxymethoxyiminoacetamido]-3-- , . :. ~ ...... . . .
.. ~ . . . .

- . . , ~ . . .:
: .

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

: :

3~

_ _ _ _ _ _ a~ co co ,~ ~ ,~ ~ ,~,-, ~ ,_ ,, . .. l l . . . . . . , o o o o oo o C~ o 1Vll _ Vll Vll Vll_ __ _ ~J
_ __ _ _ __ __ ~D _ O
C~ ~ ~ ~ ~ ~ r~ r~ ,_~ r-l ~~ Lr~ ~
H H . . . . . . . . . . .
~ O O O O O O O O O O ~ ~
vn Vll VllVllVllVll Vll ~1 _ _ _ _ _. . ~9 In r~ r~ ~ r~ ~ r~ r~ r~ ~ r~ I
. . . . . . . . . . .
O O O O O O O O O O ~ U~
_ Vll Vll Vll Vll Vll Vll Vll V
~ D
r~ r~ r~ r~ r~ U~
. . . . . . ~ . . . .
OO O O O O O O O O r-l vn _ vn VllVllVllVllVO
a~ co r-~r-l r-l ~) ~`1 r-l r-l r-~ r~ r-~
. . . . . . . . . . .
OO O O O O O O O O O
VllVllVll VllVllVllVllVll _ _~ CO
,~ ,~ ,~ ,~ ,~ ,~ ,~ ,~ n ,_ ~ ~ . . . . . . . . . . .
-rl O O O O O O O O O r-l O
vn Vll vn Vll Vll Vll Vll Vll Vll ~r~ _ __ ~n ~9 r~ r~ r~ r~ ~ ~ r~ r~ ~ ~ In r-l ~'1 ~ . . . . . . . . . . .
O O O O O O O O O O r-l ~D r-~ Vll vn Vll vn_ vu Vll Vll _ r~ __ __ _ _ _ __ `~ r~ r~ r~ r~ r~ r~ r~ r~ r~ ~D ~ In C~ . . . ., . . . . . . . .~
O O O O O O O O O r-l O ~9 Vll Vll Vll Vll Vll Vll Vll Vll Vll _ _ ~r~ r~ r~ r~ r~ ~ r~ r~ r~ r~ ~ L~
m . . . . . . . . .. . ~
O O O O O O O O O O ~I
'¢ VU Vll VllVll Vll vnvu Vll _ _ _ ~ _ r~ r~ r~ r~r~ r~ r~ ~ ~r~ ~U~
. . . . . . . . . . . .
O O O O O S~ O O O O O~1 \'D VU vn vnVllVll vnvn vnvn ~

*
o *
'Cl er ~ ~ r~ ~ 0 O r~ * ~ ~D ~ ~~D r~
n er~r ,~ ~ ~ r~I` r~cn O ~ l l l H l l Z l Z
Q. ¦ ~ ~ ~ 3 HE~ E-l ~ Zt~
E31 u~ u~
U~
~C (1~ 1~1 11~ (U (I) .,1 ~r~ U~ ~r~ Ul ~ ) ~r~ ~rl ~r-l O O ~rl r~l ~rl .,1 O
m l ~ ~ ~ u~ u~ ~ ,~ h ~a ~:
¦ ~ H E~ ~ ~ ~J S-l h O ~ ::1 .
1.~ ro ,o Q s:: ~ E~ E3 ~ E~ ~ ~ ~
I~ c~ O . . . . . .
I t~ . . . ~ ~ O O O ~) .
I s~ . . ~1 ,~ ,~ a~ a) s~ ~ ~ .,, u~
_ K _ u~ _ ~ _ ~ ~ _ , .:
- :
. ' : ' ' , .
. : .
... .

3~

U~ ~
.,, ~ ~, .,, ~
~, o o s~ ~
~n f~
U~ ,, 5~
o .,, ~ U~
,, o .,. ..
C) .,, .~ .
a U
*
~C
.. .
~ .
Z;

~ _ ~_ ___, ~ ~ ,, I~ _ ' Z; . . . , , . . : . . . .
o o oo o o o o o _ _ Vll _ __ Vll Vll Vll Vll Vll .
~ 1-1 t~ t~l~I ~I C~ ~ CO .
~ ~ . . . ~ l i . . . . . . l ~0 _ 01~ C~ O _ O O Cl O O O _ :~ CO : ~O :
~11~ ~ ~1 U~ ~1 ~ ~ ~
~ ~. . . l l . . . . . ~ l O O O O r-~ O O O ~
.4 vn _ vn _ vn vn vn co _ ~I ~ ~I ~I ~ :,~ ~I ~ I~
E~ K . . . l l . . . .. . i o o o o o o o o o Vll Vll ~ Vll VII Vll Vll Vll ~ - 29 -`: `. ,` - : -. . . : ., .. . : . , .' ... .
. . , , . ~ , , .. . :

3~31 1 2) Urinary recovery A test compound was orally administered to mice ~ICR, male, 4 weeks old) in an amount of 1 my/mouse, and a urinary recovery was determined. The results obtained are shown in Table 2.
In the test compounds (No. 1 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 orall.y administered.
Quantitative measurement method: The amount of free carboxylic acid was measured by bioassay ~a paper-disc methodj usi~g the test organism mentioned in Table 2.

~ - 30 -, - : , : .

~7~3~
.
# . .
~ ~ ~ .. , ,, ,~ ~ _ +, ~, ~, ~ ~ o~o ~ O~ a~ . ~
~ a~ ~ o o ~ ~i R . o ~n ~ ~ ~ ~
" U~ ~ ~ o a) ~ ~ o a E~ ~ U _~ .

/~ ~ ~ ~ ~=C t~

~,~
~;~n ~ u ~ ~û~ ~
D

U : O .q l ' ~ , .

~ ~ ~ u~

-z = ,~ ~ Z
:

: . ` , . : .
. :. . ` , ` . .
- ~- . : . . ~ . ` ., ` . ` . .

:, : ` ` ` . : `. :
`` . , ~ . : ` . . .
:' : '' ,` ,.. ~ : ~ . , . . . . .

12'76~3~

1 3) Acute 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-t2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(2,3-dioxo-1,2,3,4-tetra-hydropyrazinyl)]methyl}-~3-cephem-4-carboxylate, o sodium 7-[2-~2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(4-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-a3-cephem-4-carboxylate, o sodium 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(3,6-dioxo-1,2,3,6-tetra-hydropyridazinyl)]methyl}-a3-cephem-4-carboxylate, and o sodium 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(3-methyl-6-oxo-1,6-dihydro-pyridazinyl)]methyl}-Q3-cephem-4-carboxylate.
Next, an explanation is made below of production processes.
The compound of this invention can be preparéd by the following proces~e~:

~ ~.

; `
`: :

~ - 32 -- . . .- .- : - .. . . ... .. . . .

~76~3~

H h ~;
U~ X
,_ O O
~ O H O ~ O ~
m ~ X u~ o `--æ r_ ~, h ~__ _~, H L
~ æ '' cz) _~ m \~ ~
~ I I ~ ~ o ~
m o~
m \\ ~ m Z o o rd o C~ o _ s~
~ ~ Z =\~n z;"~,~q ' P~ ~
/ ~ m~ ~
~Y ~ /~o ~ ~
o ~ ~ ' ~ o o ~ 1 ~ ~ ~ . u o ~ ~ 1,~ Pæ o ~ *
o ~ 1~ o u a)I t) U
X U~ o 1~H rl I-- ~ H
I U ~ ~ h O I o a z u~ I _~ u ~~ a) 5~ I p ~ o ~
~ I _ U
1~; 0 ~ I ~ol X .~.
. ¦ go h ~, m U
H ~ ~~ ~ 5~ 0 \\
H I I~ h h a) ~\\
H H~0 0 ~3 ~\\
\\ \\
H H ~ \\ ~

~; O ` ` O ~\ t`l O h o c~ O \\ m P:; IY; .C ~ t)M O O rl \\ V 1:~ H rC
_ o ~ I 1~ J o r O H H 1~) rl /~\ O
o ~ `~ U ~I H H ~ O tl~ U ~ O ~ O
~ H H S-l .C U ~IJ O ~ / r-l ~ rl h ~ ~t Z ~ ~~ ~ o ~ ~æ

5-1 ~ O ~ ~ O S~ h al 13 P. ~; O P:; O O ~ ~d -- ' - .
. .
.

~7~i~3~

o ,_ O R
O 1~ h u~
X
x m o .~, '' 0 X I ~ h O
.,~
`~ h ~ 1 O ~ ~
OU ~ X X ~1 o ,~ o a~~1 o o ~ r~ o4~
~ O .~ ~ O ~ ~ o U3 ~ C~ ~ a) Q, ~ u~ ~ tn o ~ ~J h ~) ~r ~H S~
~ =~ ~ ~ ~0 ~ mJ`~o ~ ~
Z ~ Z ~ ~) O O ,1 0 ~r V P; V ~ U~
~= Z~O o V=Zv~ O
o o V U H O Z U~
x ~ ~ XI ~ X c ~

~ I ~=( V~ o O C~ ~1(1) I z U ,,~ ~0~I ~o U~ o o ~
H u~ h ¦ 0 fi 0 m~ 1 ~
oo~l ~ D 0 mO
o o C) _ Z---mO
~,~-- o u~ O H ~ ~>
~ ~ m ~ 0 ~ u V ~ ~ ~ ~ O V 0 . o O O ~ h O a ~rl a) ~ h.C:~
~ 0 .~: '; ' ' ' ~ -. : . . ~ . : .
, 3~

a~
U~
" ~ ,. . .
co~o ~ ~ k~
Z o o P~ o ~'`~ ~P:;/ ~ ~z--~ Z--Z

R O ~
H H H H
H H H H
H H H H

O O O O

.. . .
a) O
Z
.

- . . -... .. ..

: :, .. . ., . ~ ......... . ..
, - : :
, . . ; .,,: ' ., .. . ~.
: , , , . - ,, 3~

Production Route 2 R30-CoNH t ~S~[XVI]
~ N ~ CH2X
COORl or a salt thereof 3~
(conver- HN NR [III-a]
sion at ~=J
3-position) or a salt thereof R -CONH t ~S~ o o I
N ~ CH2N NR6 COOR

~ _ [XVII]

R30-CoNH~ S~ O O

O N ~ CH2N~ NR
COORl J
or salts thereof -¦ (conversion into ~3-cephem) R30-CoNH ~
N ~ CH2N~==JNR [XVIII]
COoRl or a salt thereof deacylation) (Cont'd) : - 36 -.

,. ~ -:
, - : : . ' ': . : ' - , , . ; .

~276~3~

Production Route 2 (Cont'd) `I
R,3 N ~ CH2N~=~NR [XIX]
COOR

or a salt thereo~

3~

``~ 1 In the above formulas, R 9 R , R , R , R , R , 7 8 9 R10 Rll R12 R13 R14, R15, R , ~ and the bond ~~~ have the same meanings as defined above; R18a represents the groups for R18 except a hydrogen atom; R28 represents an amino group, or a group of the formula, 32> C=C-NH- in which each of R31, R and R , which may be the same or different, represents a hydrogen atom or an organic residue not participating in the reaction, or a group o the formula, 35> C=N- in which each of R34 and R35, which may be the same or different, 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 ~ ~ A in which R4, R5 and A have the same S `R4 meanings as defined aboveS 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.
R28 represents an amino group, a group of the formula, . , - - . :
.. . . .
- '~ -~ , .
- . . .
:. . . :

- ~ ', ': ' ' ' R31 R34\
1 32/ C=C-NEI- or a group of the ~ormula, 35/ C=N~, and the group of the formula, 32> C=C- H- includes the group of the formula, 32/ CH-f~N- which is i~s isomer. The organic xesidues not participa-ting in the reaction for R31, R32, R33, R34 and R35 include those well-known in the art, speciically substituted or unsubstituted aliphatic residues, alicyclic residues, aromatic residues, aromatic-aliphatic residues, heterocyclic residues, acyl groups and the like. More specifically, the following groups are included:
(1) aliphatic residues: alkyl group5t alkenyl groups, ~2) alicyclic residues: cycloalkyl groups;
cycloalkenyl groups, ~3) aromatic residues~ aryl groups, l4) aromatic-aliphatic xesidues: aralkyl groups, ~5) heterocyclic residues: heterocycllc groups, ~6) acyl groups: ac~l groups which can be derived rom 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, h~erocyclic aliphatic carboxylic acids, heterocyclic-oxyaliphatic carboxylic acids, and heterocyclic-: - . . .
.
, ' ' -' , - . - ,. ~ ' . . :
., ~ . ,:
., 1 thioaliphatic carboxylic acids, in which an arvma-~c residue or a heterocyclic group is bonded, directly or through an oxygen or sulfur atcm, 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; aromatic carboxylic acids; heterocyclic carboxylic acids; and the like.
The above aliphatic carboxylic acids include formic acid, aceti~ 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 cyclopentaneace-tic acid, 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 o~ the groups constituting these organic carboxylic acids may be ~urther 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 : , . . ' ' : .
, l groups such as acetoxy, propionyloxy, butyryloxy and the like; alkenoyloxy groups such as acryloyloxy and -the like; aroyloxy groups such as benzoyloxy, naphthoyloxy and the like; and carbamoyloxy group. These yroups may be substituted by one or more substituents such as halogen atoms, nitro group, amino group, alkyl groups, alkoxy groups r alkylthio groups, acyloxy gxoups, acylamino groups, hydroxyl group, carboxyl group, sulfamoyl group, carbamoyl group, alkoxycarbonylcarbamoyl groups, aroyl-carbamoyl groups, alkoxycarbonylsulamoyl 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 carboxylic acid of the formula [IV] or a salt thereof can be produced in a high yield with a high 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 o the \

. .
- '- , , - . ~ . . - ~ : , , ': :- ' .......... . .
.
:: ., . .
: , , ~76~3~

1 formula [III-d], or a salt thereof with a cephalosporanic acid represented by the foxmula [II] or a salt thereof in the presence of an acid or a complex compound of an acid, then if desired, remo~ing the pro-tecting group, protecting the carboxyl group or converting the obtained co~pound 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-position can be removed in a conventional manner to form a 7-unsubstituted amlno compound. According to this procedure, not only Q -cephem compounds but also a2-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 [III-c] or the 6-oxo-1,6-dihydro-pyridazine of the formula ~ d] which is used as ~' ' . ' ': ' .

, , .

] a ~actant in the reaction, has a basic or acidic(~roup as the substituentr these compounds may, if necessary, be applied in the form of the corresponding salt to the reaction. In this case, the sal-ts at the basic groups and the salts at the acidie groups include those mentioned as to the salts of the eompounds of the formula [I].
Also, the salts of the compounds of the formulas [II] and [IV] inelude salts at the basie groups and at the aeidie groups, and these salts inelude those mentioned about the salts of the compounds of the formula [I]. The salts of the eompounds of the formula [II] may be pre-viously isolated and then used, or may be prepared in situ.
As the aeids or the eomplex eompounds of aeids used in the reaetion, there are mentioned, for example, protonic aeids, Lewis aeids or eomplex eompounds of Lewis aeids. The protonie aeids inelude sulfurie aeids, sulfonie acids and super aeids (super aeids means aeids stronger than 100~ sulfurie aeid and ineludes some o the above-mentioned s~f~ic aeids and sulfonie aeids).
More speeifically, the protonie aeids inelude sulfurie aeids sueh as sulfurie aeid, ehlorosulfurie aeid, fluorosulfurie aeid and the like, sulfonie aeids, for example, alkyl lmono- or di-)sulfonie acids sueh as methanesulfonic aeid, trifluoromethanesulfonie aeid and the like, aryllmono-, di- or tri-)sulEonie acids such as p-toluenesulfonie aeid and the like, super aeids, such as perehlorie aeid, magie aeid ¦FSo3H-SbF5), FSO3H-AsF5, CF3SO3H-SbF5, HF-BF3, H2SO4 SO3 , , :, . .
'- ' ~:, . :' ' ' ' ~ ' ,,' ' ' ' ' . ' The Lewis acids include, for example, boron tri-fluoride, and the cornplex 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-propylarnine, n-butyl-amine, triethanolamine and the like; with esters such as 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.
1~
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, nitro-alkanes such as nitromethane, nitroethane, nitropropane and the like; organic carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, dichloroacetic acid, propionic acid 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 ~0 dimethyl ether, anisole, 1,2-dimethoxyethane and the like;
esters such as ethyl forrnate, diethyl carbonate, methyl acetate, ethyl acetate, ethyl chloroacetate, butyl acetate and the like;
niiriles such as acetonitrile, butyronitrile and the like; and sulfolanes such as sulfolane and the like. These solvents may ~5 be used in admixture of two or more. In addition, complex compounds formed from these organic solvents and Lewis acids can be used as the solvent. It ~ 4 -` ~ ~ ' ' ' ' `'`, ' - , ; ` ~

3~

l is sufficient that the amount of the acicl 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-lO moles per mole of the compound of the formula [II] or a salt thereof is preferred. Where the complex compound of the acid is used, it can be used per sa as a solvent, and two or more of the complex compounds ma~ 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 ormula ~III-b], the 3,6-dioxo-1~2,3,6-tetrahydropyridazine o'f lS the formula [III-c] or the 6-oxo-1,6-dihydropyridazine of:the formula [III-d] or a salt thereof is at leask equimolar to the amount of the compound represented by the formula [II] or a salt thereof, and particularly, the use in an amount of about 100-5.0 m~les Fer m~le is pre~erred This raaction is usually carried out at 0-80C, and completes in ten minutes to thirty hours. The pre-sence of water in the reaction system may cause undesirable side reaations such as lactonization of the starting material or products and cleavage of ~-lactam 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-5 ing agent such as NrO-bis(-trimethylsilyl)acetamide, trimethylsilylacetamide, trimethylchlorosilane, dimethyl-dichlorosilane or the like; an organic acid chloride such as acetyl chloride, p-toluenesulonyl chloride or the like;
an acid anhydride such as acetic anhydride, trifluoroacetic anhydride or the like; an inorganic dehydrating agent such as anhydrous magnesium sulfate, ~nhydr~us 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 Letters, No. 46, pp. 3991-3994 ~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 `.

, '~; ,` :

3~

1 halogenated compound represented by -the formula ~XVI] or a salt thereo with a 2,3-dioxo-1,2,3,4--tetrahydro-pyrazine of -the ~ormula ~III-a] or a salt thereof in the presence of a base. The base includes ~k~i ~-~l carbona~
(~or example, so~um carbonate, potasslum ~rbonate, or ~e like);
alkali metal hydrogencarbonates ~for example, sodium hydrogencarbonate, potassium hydrogencarbonate and the like); alkali metal hydroxides (for example, sodium hydroxide, potassium hydroxide, and the like); nitrogen-containing organic bases, or example, triethylamine,pyridine, N,N-dimethylaniline and the like.
The conversion at 3-position is generally carried out in a suitable solvent. The solvent includes 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 therevf.
In this case, the compound represented by the formula [III-a] or a salt ther~of is preferably used in an amount of about 1.0-2.0 moles per mole of the compound represented by the ormula ~XVI] or a salt thereof. The reaction is generally carried out at a temperature of 0-50C fox 30 minutes to 10 hours.
The mixture of a ~- and ~3-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 .: .
. : . .. .
. ~ .. .
.
. : , . ,- ~ ~ -' '.

~.;27~

: 1 converted into the compound of the formula [XIX] or a salt thereof by the deacylation. Said convexsion reaction and deacylation are known in -the fields of penicillins and cephalosporins and are speciically described in khe Journal of Organic Chemistry, Vol. 35, No. 7, pp. 2430-2433 ~1970) and "Cephalosporins and Penicillins" Iby Flynn, Academic Press), pp. 56-64.
If the substituents o the 2,3-dioxo-1,2,3,4-tetrahydropyrazine of the ormula [III-a], the 2-oxo-1,2-dihydropyrazine of the formula [III-bj, 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 compoundO
Also~ the compound represented by the formula [IV] or [XIX] can, i~ 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 b~ the formula [IV] wherein R28 represents an amino group can be converted into a reactive derivative at the amlno group or the compound represented by the formula [XIX] as mentioned here.inater by a conventional method.

- ,.
.
.
- ' , ~ . ' : . .: ' , ' .

.

~2~
1 ~b) Acylation When the compound represenked by the ~ormula [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 ccmpound represented by the formula [V], tVI], [VII], [VIII] or [XIII] include salts at the basic group or the acidic group, which specifically include those mentioned as to the salts o~ the compound rspresented 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 example, an isocyanate; a Schiff base produced by the reaction of the compound represented by the formula [IV]
or a salt thereof ~ith a carbonyl compound such as an aldehyde, a ketone, or the like Iketimine type or its isomer, namely, enamine type); a silyl derivative, a phosphorus derivative or a tin derivative, produced by the reaction o~ a compound represenked by the ~ormula ~IV] or a salt thereof with a silyl compound such as ~5 bisltrimethylsil~l)acetamide, trimethylsilylacetamide, trimethylsilyl chloride, or the like, a phosphorus com-pound such as phosporus trichloride~ [ \PCl, L PCl,O/ CH3 O/

- . . . : . -: ,; , . . : , . ..
.

- - . . . . .
: . . , .
, . . ' :. ' ' ~' ,' ' ' ' . :

ro\
~ O/ 3 2 )2PCl~ (CH3CH2)2PCl or -the like, or a -tin compound such as (C4Hg)3SnCl or the like.
The reactive deri~atives 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 derivativPs obtained by reaction of the compounds represent-ed by the formulas [V], [VI], [VII], [VIII] and [XIII] with a Vil~meier reagent. The mixed acid anhydride includes a mixed acid anhydride with a monoalkyl carbona-~ 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, tr'i-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, substituted phenyl esters, substituted benzyl esters, substituted thienyl esters and the like.
Tha 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 halogenati~g agent such as phosgene, thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, phosphorus pentachloride, trichloromethyl chloroformate, o~alyl chloride or the like.
~ 50 .

.
- . . ~ - .

- .
- ~ .
:. . . .
- . .

~7~ L3~ `
1 I~ each of the compounds represented by the formulas [V], [VI], [VII], [VIII] and [XIII] is used in the ~orm 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; azolide compounds such as N,N'-thionyldiimidazole; dehydrating agents such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, alkoxyacetylenes and the like; 2-halo-genopyridinium salts such as 2-chloropyridiniummethyl iodide and 2-fluoropyridiniummethyl 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, ~or example, a halogenated hvdro-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 thereo~. 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, trlethyl-amine, tributylamine, pyridine, N-methylpiperidlne, N-methylmorpholine, lutidine, collidine or the like; or a secondary amine such as dicyclohe~ylamine, diethy-lamine or the like.

~ 51 ~

: ~ . . : . . . . .
.. . ~. . .... ..
~: : :, ~.. - . :. , .

3~
The compound represented by the formula [IX]
or a salt thereof which can be converted into the compound represented by the formula ~Ial or [lb] 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-bu~yryl halide which is obtained by the xeaction of diketene with a halogen such as chlorine or bromine [Journal of the Chemical Society, 97, 1987 (1910)] may be reacted with the compound re-presented 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 reac-tion. 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 xepresented by the for- -mura [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 reac-tion is usually carried out at a temperature ranging from -. ~ . : - ~ .

~6~3~

1 -50 to 40C. The reaction time is usually 1~ minutes to 4~ hours.
Furthermore, the compounds represente~ by the formulas [I], [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 formulas [I], [~X], [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 group 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 Rl, R and R contain groups active to the reaction, these groups can suitably be protected with conventional protecting groups prior to the reaction, and the protecting groups can also be removed b~ a usual method after the reaction.
The compound represented by the formula [I] or a salt thereof of this invention obtained by the above-mentioned method can be isolated by a conventional method.

(c) Nitrosation Subse~uently, 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 rea~ted with the compound , . , : , .
.

. ~ , ~. :' ' .' ' , ;
- - ~ ' '' . ~ -:
.: . ', : . . .

~L27~

1 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 ex~mples 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. I~ 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 or~anic acid such as hydrochloric acid, sulfuric acid, formic acid, acetic acid or the like. I an alkyl nitrite is used as the nitrosating agent, it is preferable to carry out the reaction in the presence of a stron~ 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 [~] 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]. Althou~h 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.

.

, . :, .
- . . . : . ~ .

~:7~

- l (d~ Etherifica-tion and phosphorylation In order to obtai.n 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 etherifica~ion reaction and the phosphoryla-tion reaction can be carxied 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, for example, tetrahydro- .
uran, 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 . - , . . . ... . . .
- -.. . : -- ~ .- , . .

. . ' : ~ Y ..
'-- . . ~: : ', . :

~.~76j~

1 is used, the reaction is carried 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 repre.sented 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~

le) 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 IIX], [X] or [XI] or a salt thereof with the thioformamide or thiourea represented by the formula [XII]. Thls reaction is usually carried out in a solventO As the solvent, there may be used a solvent inert to the reaction, for example, water, methanol, ethanol, acetone, tetrahydrofuran, ~, - ., , "

: , .
.: . .
- ~ - . " .

~;~7~3~

1 dioxane, N,N dimethylformamide, N,N-dimethylace-tamide, N-methylpyridone, alone or in admixture of two or more.
Although it is not essential to add an acid-removing agen-t, the reaction sometimes proceeds smoothly by adding an ~cid-removing agent in such an amount that the cephalosporin skeleton will no~ 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 tem-perature of 0-100C. Thioformamide or 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, preerably 1-10 hours. Furthermore, in the compound represented by the ~ormula [Ia] or [~b], the pr~tection of the carbonyl group and removal of the c~xyl-protectm~ 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 objective compound. If Rl, R , and R in 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 objective compound represented by the formula [Ia] or [Ib] or its salt thus obtained can be isolated by a usual method.

- - : . . . ., .: .
- . . . , . ... :

- `- ' - '' ' ' .', ; .' ;~ '~' ' ' :, . --' '- : ~: , :
i , ., ,: , . :.

1 (f) Qximina-tion The compound represented by the formula [Ib]
or a salt thereof is obtained by reactirlg the compound represented by the formula [XIV] or a salt thereoE 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 tQ
several moles per mole of the compound represented by the formula [xIvJ or a salt thereof. Although the salt of the compound represented by the formula [XV]
~ can be usad 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 hydro~ide, calcium hydroxide or the llke3, 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 . . : . . : .
' ` '' " ~ . '` ` ' ~ `" ' 1 hydrogencarbonate (for example, sodium hydrogencarbonate, potassium hydrogencarbonate or -the like~, an alkaline earth metal ~hosphate (for exampl~, magnesium ~hosphate, calcium phosphate or the like), an alkali metal hydro-genphosphate (for example, disodium hydrogenpho~phate,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), picoline, N-methylpyrro~idine, N-methylmorpholine, 1,5-diazabicyclo-[4,3,0]-5-nonene, 1,4-diazabicyclo[2,2,2]octane, 1,5-diazabicyclo[5,~,0]-7-undecene or the like. The com-pound represented by the formula [Ih] or a salt thereof of this invention thus obtained can undergo convers~on 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 compoun~ 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 repres~ented by the formula [I], [Ia], [Ib], ~IX], [X], [XI] or ` [XIV] wherein R3 :. ., . ,. ,: . : .......... ..

- ' : . ' ' ': . . .
- .
- . : . -3~

1 is a hydrogen atom in a manner known per se, fox example, the method described in Japanese Pa~ent Application Kokai (Laid-Open~ Nos. 24,888~79 and 103,889/79.
The compound represented by the formula [I~ or a salt thereof thus obtained can be adminis-tered to human beings and animals in the form of a free acid or in the ~orm of a pharmaceuticall~ acceptable salt or ester for the purpose of the treatment of and protection against bacterial inections. It is pxeferable to parenterally administer the compound in the orm 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 sufflcient that the compound is formed into a dosage form usually used in cephalosporin medi-cines, for example, tablet, capsule, powder, fine granule,granule, syrup, injection lincluding drip), 5uppository or the like. When the abo~e-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, carboxymethyl cellulose, hydroxy-propyl cellulose or the like; lubricants such as talc, magnesium stearate or the like, disintegrating agents such as carboxymethyl calcium, talc or the like.

.
.

.
' ~ ;27~

1 When the compound represented by the formula [I] or a salt thereof is administer~d, the dosage~
the administra~ion time and the administration method can be varied depending on the symptoms of patient, S and generally it is sufficient to administer orally or parenterally to an adult in a dose of abou-t 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.

Referential Example 1 (1~ To a solution of 20.0 g of ethyl N-(2,2-di-;
ethoxyethyl)oxamate in 60 ml o ethanol was added 6.1 ml o 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'-f2,2-diethoxyethyl)oxamide having a melting point of 131~132C.
IR (KBr) cm 1 vc O 1650 In a similar manner, the compounds shown in Table 3 were obtained.

- :. .. . . . .
.

. .:. ; ~ , ,' ' -., ~7~

Table 3 (CH3CH20) 2OElcH2NHcocoNHR6.

_ -1 Compound Solvent for m.p. IR (KBr) cm recrystal- ( C) vc=o R6 lization -H Ethyl141-142 1650, 1635 acetate -CH3 Ethanol135-136 1645 __ -~CH2)2CH3 Acetone 84-85 1645 / CH3 .

\ CH Acetone145-146 1650, 1635 -(CH2)3CH3 n-Hexane111-112 1645 -(CH2)4CH3 n-Hexane 92-93 1650 .
-(CH2)5CH3 n-Hexane 87-88 1650 _ `-~CH2~7CH3 n-Hexane110-111 1645 -(CH~ CH3 n-Hexane 83-84 1645 _ E~thanol154-155 1640 _ _ _ -CH2- ~ n-Hexane113-114 1655 _ _ _ -CH2CH2OH Ethanol 118-119 _ N / C 3 . Ethanol 157-158 1645 `~-~ _ 128-129 1655 -CH2- ~ -ocH3 . ~ _ - . , ,~ , ~. ..

.
,," . ~ , ' ' ,.,, : " "' ~ ..
"

3~

1 (2) To a solution o the 17.0 g of N-ethyl-N'-(2,2-diethoxyethyl~oxamide 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 completion 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 rom 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.

\

.
.
- ' ' . ~ ~ ~. ,'' , '' . -.~ .
. ' ', ~ ' ' - Table 4 ~0 Compound Solv n for (ocPj IR (KBr) cm 1 R6 lizationC=O
, _.
-H _ >280 1680-1640 -CH3 Ethanol 220-231 1690-1635 .
tCH2)2CH3 Acetone 182-183 1680-1640 ~CH3 _ _ CH ~ CH Acetone215-219 1680, 1625 _ -(CH2)3CH3 Acetone149-150 1680, 1640 -(CH2)4CH3 Acetone171-172 1685, 1660, l , ``(CH2)5CH3 Acetone141-142 1620 . _ .
`(CH2)7CH3 Acetone145-146 1670, 1635 _ _ _ -~CH2)llcH3 Ethanol145-146 1660, 1625 - cetone254-255 1670, 1635 -CH2 ~ Acetic acid 225 1665, 1635 CH2CH2OCOCH3 Methanol178-180 1720, 1675, _ _ .
< CH3 Ethanol229-230 1700-1625 OCH3 = _ \r-~ _ 175-176 1740-1620 .-.CH2 ~ OCH3 __ .

- : . . , . ,: : ~ . .
- - ; . - ..... . . ..

' - ~: ' , . .

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 NrN-dimethylformamide was added 4.1 g of potassium carbonate, and the mixture was stirred at room 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 ~y a column chromatoqraphy (Wa~o Silica Gel C-200 (a'.trademark), eluent;
chloroform) to obtain 4.9 g (yield, 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 ~oint of 154-156C.
IR (KBr) cm 1 vc=O 1820, 1675, 1630 In a similar manner, the compounds shown in Table 5 were obtained.

, . ~. .
. .
, . , : , , : : . '.

.
, , ~ .
. . . - .:
.. . .

~7~3~

Table 5 3 ~ CH2-N -R6 _ .
Compound m.p. (C) IR ~KBr) cm : VC_O
R6 .
.

~ 188-190 1775, 1700, 1650 .

-CH2OCOCICH3)3 100-101 1750, 1690, 1660, -CH2COOC¦CH3)3 105-L06 1740, 1690, 1650 .

-:66 -`' ' . ` ' ` '` `.

7~3~

1 (4) In a mixed solvent of 37 ml of trifluoroacetic acid and 10.8 g of anisole was dissolved 3.7 y of 1-(2,4-dimethoxybenzyl3-4-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-2,3-dioxo-1,2,3,4-tekrahydropyrazine 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.

.. , : . . .. .. .
- ''' ' ' .. : ~. . , . '~ , . -- - - :'. -, .: . . : ~

' ' ' . ;., ~ ' ' ", ' : ' ' ~. ' .

~1.27~

Table 6 0~,0 HN N_R6 Compound -1 R6 m.p. (C) IR (KBr) cm : VC=O
. _ ~ >270 1790, 1775, 1730, _ ' .

-CH2OCOC(CH3)3 166-167 1740, 1700, 1660 , -CH COOH 282 1730, 1670-1630 2 (decomp.) 1 (S) To a solu-tion o 2.6 g of 1-carboxymethyl-2,3~
dioxo-1,2,3f4-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 S or 10 minutes. Tha raactlon 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 cr~7stals were collected by iltration, and washed with 10 ml of ethyl acetate and 10 ml of diethyl ether in this order to obtain 2.9 g - - . . ~ .- , ~ . .-- ~ . :., .: . , - . : . ~ , . .. :

1 lyield, 80.4%) of l-diphenylmethyloxycarbonylmeth~l-2~3 dioxo-1,2,3,4-tetrahydropyrazine having a meltiny point of 97-98C.
IR(KBr)cm 1 ~C=O 1750, 1675, 1645 Example 1 (1) To a solu'cion of 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 completion 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 fiItration, 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}-~3-cephem-4-carboxylic acid having a metling point of 191-195C
(decomp.).
IR (KBr) cm : vC=O 1795, 1670, 1620 NMR (CF3COOD~ ~ values:
1.44 (3H, t, J=7Hz, `~NCH2CH3), 3.69 (2H, bsj 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)j ~ 2 ,, ~ ............... . , , , . :

.: . . ..
- : ' . ~ ., ' ' . .' ' ~ `

~ ~2~7~;~L3g3 1 6.74, 7.00 (2H, ABq, J-6Hz, ~ ) H H

t2) 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-{[1-14-ethyl-2,3-dioxo-1,2,3,4-te-trahydropyrazinyl)]methyl}-~3-cephem-4-carboxylic acid in the yi.elds shown in Table 7.

: - 70 -.. . . . . . . .
. ~ , , , . .: , . : . . . .
- ~ :

- , ~ : .
. . ~

3~9 Table 7 Starting material Acid or Reaction Amount No. Solvent complex condi- (Yield) 7-ACA HN N-CH2CH3 . of acid tions _ _ _ Sulfo- Boron Room 2.6 g 1 2.72 g 1.54 g lane tri- tempera- (73.9%) 10 ml fluoride ture 2.71 g 2 hours _ .

. Nitro- Boron Room 2.85 g 2 2.72 g 1.54 g methane tri- tempera- (81.0~) 14 ml fluoride- ture ether 16 hours 5Co7mplex .

l 13) In a similar manner to that in above ll), the compounds shown in Table 8 were obtained.
(In this case, the obiective compounds were obtained by pouring into ice-water the reaction mixture after completion of the conversion at 3-positlon and adjusting to pH 3.5 with 28~ by weight aqueous ammonia solution with ice-cooling.) .
.. - : :
': - . . ' , ' :
' - ~ . .

~.~76~3~

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1 ~4? The conversion reaction at 3-position mentioned in above (13 was carried ouk under the reaction conditions shown in Table 9 to obtain 7-amino-3-{[1-(3,6-dioxo-1~2~3~6-tetrahydropyridazinyl)]methyl}-a3 -cephem-4-carboxylic acid in the yields shown in Table 9.

Table 9 Starting Acid or Reaction Amount No. material Sol- complex condi- (Yield) . compound tions 7-ACA hyldeeiac 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.
complex ___ Sul- Boron tri- Room 2.75 g 2 2.72 g 1.23 g folane fluor de temper- (84.9~) 3 hours _ .

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

- - ,:, . , - , : :- . . -: - . , - , . ,- , .
. '- '. ~ ' " ' ', -~ -- ~ , : . . :
- -~

~ ~7~

Table 10 H 2N ~ S ~ CH R2 COOH

No Compound . _ _ . _ 1 -N N-H * 1 _ _ . __ 2 O~,O
-N N-CH
~ 3 ;
_ _ .
0~0 _ _ _ 4 ~ 3 _ _, .
O~
-N N ~CH2 ) 3CH3 6 ~ 4 :
-N N{~
. ~

7 . C~ .
-N~C~N (CH2 ) 11CH3 _ - Cont ' d - 76 ~

- . ~ - . . . .~ , . .
,, .. ,~ ,. . . . ..
, ... ..
- : , . . .. - :, . .. .

7~35~

` Table 10 (Cont 'd) 8 0~0 ~ C 2 2 3 ~ ¦ 0~,0 12 ~C1~3 _ , *2 N~ Cl - Cont ' d -- 77 ~

3~

Table 10 (Cont'd) 14 N ~ N~`C~

~ t ~
`

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 o~
insolubles and addition of pyridine into the filtrate.
*2: The representat~on was taken because it was not confirmed whether the chlorine atom was ~placed at 4- or S-position, and whether the product was composed of a single compound or a mixture. (Such representations in Tables ~ ~ 78 -,. ~'' . : - ' ,`~ '....... ., .. , , . ::
: - . . ' :, ~ , ' : . .

`- : , . . ' '. . ' ' ~ ' . , :
,.

1 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 compound. (Such repxesentations in Tables appearing hereinafter have khe same meaning.) Example 2 To a suspension of 3.0 g of the 7-amino~3-{[1-l4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylic acid obtained in ~xample 1-(1) 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 solvenk of 20 ml of 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 (yleld, 70.3%) of diphenylmethyl 7-amino-3-{[1-- 7g -:
; .

, ~27~3g l ~4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cevhem-4-carboxylate having a melting point of 183-186C (decomp.).
IR (KBr) cm : VC o 1765, 1730, 1680, 1630 In a similar manner, the compounds shown in Table ll were obtained.

:

~ : - 80 -3~

Table 11 H2Nr~ S ~

0~ ~CH2R

COOCH( ~ )2 Compound m.p. (C) IR ~Ksr) cm : VC=O
. . _ ~4 -N NH 129-130 1765, 1725, ~=J (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 ) 2OE13 (decomp.) 1685, 1635 . .__ _ ~ ~ CH3 179-180.5 1760, 1720, -N~ NCH~ (decomp.) 16O5, 1635 . ... __ .. :
O~O lôO-lB9 1760, 1725, -N N (CH2)3CH3 (decomp.) 1680, 1630 ~ ~ . , .
O ~ O 185-194 1765, 1730, -N N (CH2)4cd3 Idecomp.) 1685, 1630 :~AA._ - Cont'd -- : . . , ' . ' ' ' `' ' ` ` ` ' ' ' ' ' . ' ' ~ ~ ,. ... .
.. . . .. .

~;27~;~3~

" Table 11 (Cont'd) .
Compound m.D. (C) IR (KBr) cm : v O
.. __ . . C--O O ~ '' ~ 170-174 1765, 1730, -N~ N(CH2)5CH3 (decomp.) 1685, 1635 ~ 186-188 1765, 1730, -N ~'(CH2)7CH3 (decomp.) 1685, 1635 .. _ .
O O
~ 164-172 1765, 1730, -N ~(CH2)11CH3 (decomp.) 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~ NCH2cH2OcocH3 tdecomp.) 1678, 1623 . ...... __ O O ~
~ CH3 172-175 1760, 1720, -N N-N ~ . 1680) 1630 _ _ _ ~ N 82-85 1775, 1720, -N ~ (decomp.) 1650 O __ - Cont'd -- - ' ~ ~ . - .
- ~ ' -. ~ ' _ ' ' , - ,~ .' ' ,'. ~ - ~ .

;~7~

` Table 11 (Cont'd) . . _ Co~.pound m.p. (C) IR (~CBr) cm : v C=O

C ~ HN 108-114 1765, 1725, -N ~ (decomp.) 1650 .
O 132-135 17~0, 1730, (decomp.~ 1665 O ' --- .... ..... __ _ H ~ 178-181 1780, 1730, Cl (decomp.) 1660 O ~ O ~
HN ~ CH3 HN ~ 137-139 1780, 1730, ~ ~ + -h ~ CH (decomp.) 1660 O O, _ _ _ _ ____ _ N ~ 90-93 1770, 1720, -N ~ ~ (decomp.) 1660 ~ 2CH3 138-143 1770, 1720, -~ ~ (decomp.) 1660 _ O _ ~ _ - 83 ~

' , '; ~ . , ' ., . ~ ''' , , . .

.. . .. ...
~ ` ~' ' " ', :
.. ~ . : : .. .. . .

~7~3~3 1 Example 3 In a mixed solvent of 25 ml of trifluoroacetic acid and 10 ml of anisole was dissolved 4.9 y of diphenylmethyl 7-amino-3-[1-(2,3-dioxo-1,2,3,4-tetra-hydropyrazinyl)methyl]-~ -cephem-4-carboxylate and the 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, and 50 ml of diethyl ether was added to the residue, after which crystals were collected by filtration. The crystals were suficiently washed with 40 ml o diethyl ether and then dried to obtain 4.25 g (yield, 97.0%) of trifluoroacetic acid salt of 7-amino-3-{[1-(2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-methyl}-~3-cephem-4-carboxylic acid having a melting point of 105-106C (decomp.) IR (KBr) cm : vC=O 1780, 1700-1630 NMR (CF3COOD) ~ values:

3.72 (2H, bs, C2-H), S
5.14, 5.52 (2H, ABq, J=15Hz, ~CH
5.44 (2H, s, C6-H, C7-H), 6.78, 6.g8 (2H, ABq, J=6Hz, ~ ) In a similar manner, the compounds shown in Table 12 were obtained.

' '' : ' '. , : ' :. `.

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.
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- 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-diazabicyclo[5,4,0]-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 in~roduced into a mixed solvent of 50 ml of watex and 50 ml of ethyl 10 acetate, and the organic layer was separated, washed with water and then dried over anhydrous magnesium sulfate.
Subsequently, 10 ml of an ethyl acetate solution containing 1.40 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-1,6-dihydropyridazinyl)~methy1}-~3-cephem-4-carboxylate having a melting point of 145-147C (decomp.).
IR (RBr) cm 1 vc=O 1790, 1750, 1660 NMR ~d6-D~1SO) ~ 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, S~ ), ~LCH2-5.14 (lH, d, J=5Hz, C6-H), 5.76-6.23 (3H, m, C7-H, -OC~2O-~, .

: ~

` . , -1J~

-- 1 7.01, 7.53 (2E~, ABq, J=lOHz, ~ ), 7.44 (3H, bs, -NH~

E~ample 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 mlxed 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.
Subseqùently, the solvent was remo*ed 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 xesidue were added 100 ml of 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, -. . . , ... : . .

.. . , . , , ~ , ~ . . .

~ ~7~i~3~

1 eluent; chloroform) to obtain 2.70 g ~yield, 43.2% o~
tert.-butyl 7~phenylace-tamido-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 vc_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 of tert.-butyl 7-phenylacetamido-3-{~ 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. 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 t 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.).

.. . .
- . ~ ' ~ ' , : ' ' , '' : ' `

~76~3~

1 IR (KBr) cm 1 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, ABg, J=18Hz, C2-H), 3.77 (2H, s, ~ CH2-)' 4.53, 5.13 (2H, ABq, J=15Hz, ~ ), ~ CH2 4.71 ~2H, s, ~NCH2-), 5.03 (lH, d, J=5Hz, C6-H), 5.93 (lH, dd, J=5Hz, J=8Hz, C7-H), 6.53, 6.89 (2H, ABq, J=ÇHz, ~ ), 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 15 (2), the compounds shown - in Table 13 were obtained.

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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]]methyl}-~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 or 1 hour. The reaction mixture was cooled to -40C, 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 o~ ethyl ~o 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-.

.
.: . . . - :
.

~.27~

1 4-carboxylate having a melting point of 185-188C (decomp.).
IR (KBr) cm 1 vc O 1820, 1765, 1705, 1690, 1635 NMR (CDC13+d6-DMSO) ~ values:
1.52 (9H, s, -C(CH3)3), 2.24 (3~, s, -CH3), 3.46 (2H, bs, C2-H), 4.35, 5.08 (2H, AB~, J=15Hz, S~ ), 4.76-5.09 (4H, m, ~NCH2-, C6-H, C7-H), 6.74 (2H, s, ~ ) H
In a similar manner, the compounds shown in Table 14 were obtained.

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1 Example 6 (l~ In 2.29 ml of N,N-dimethylacetamide and 4.58 ml of acetonitrile 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-1,2l3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylate was added ~o the reaction mixture, and the mixture was subjected to reaction at -5 to 0C for l 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 hydrogencarbonate. 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-formamldo-thiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~ -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, J=7Hz, >N-CH2CH3), ~- 105 -.

~.2~3~

l 3.97 (3H, s, -OCH3), 4.42, 5.04 (2H, ABq, J-15Hz, S~ ), ~ 2 5.30 (lH, d, J=5Hz, C6-H), 6.02 (lH, dd, J=5Hz, J=8Hz, C7-H), 6.50, 6.62 (2H, ABq, J=6Hz, ~ ), H H
7.04 (lH, s, -CH~ ), N

7.17-7.82 (llH, m, ~ x2, ~ ), 8.63 (lH, s, HCo-j, 9.89 (lH, d, J=8Hz, -CONH-), 12.68 (lH, bs, HCONH-) In a similar manner, the compounds shown in Tables 15, 16 and 17 were obtained.

- 106~-~

~ .

.

'7~;~3~

Table 15 HCONH ~ ~ C- --CONH ~ ~ CH2R
\ OCH3 COOCH( ~ )2 (syn-isomer) Compound -~ - m.p. (C) VC=O

O ~ O 120-125 1780, 1720, -N N-CH3 H ~decomp.) 1680-1640 . - _ O O 154-156 1785, 1720, ,~ H (decomp.) 1685, 1645 -N N-~CH234C~3 .
O O H 131-136 1783, 1725, . ~ (decomp.) 1680, 1645 -N N(CH2)5CH3 .
. _ ,.
H 180 182 1780, 1720, O~ O (decomp.) 1680-1640 -N~=~h(CH2)7CH3 .
_ _ O O H 158-166 1780, 1725, ~ (decomp.) 1675, 1640 .
-N N-(CH2)11CH3 . .
_ _ ~ H 126-138 1685, 1650 -N N-CH2 ~

~- l ~ ~ 1 - Cont'd -. - , . . .
. ~ -, .~. .
-, . . . .

~ ;~7~

Table 15 (Cont' d) O~O sr ( dec omp . ) 1675, 1640 O 171-173 1780t 1720, HN ~ H ~decomp . 1690 - 650 _ _ 148-151 1780, 1730, N~ H ~decomp. ~ 1690 1660 _ ~
. ~ 191-195 1775, 1720, ~C~3~l L~ ~

. . \ .

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: : , , -6~

Table 16 ICH3 M C-CONH- ~S~
3 2 1 OCONH ~S ~ ¦¦ / ~ N ~ CH~R
OR COOCH( ~ )2 (syn-isomer) .
CompoundRl8 m.p. tC) . IR (KBr) cm O~ O 176-179 1780, 1720, -N~=~NH . -CH3(decomp . ) 1680, 1640 . _ .
O O CH 152-155 1780, 1720y ~ - 3 (decomp. ) 1680, 1640 -N N- (CH2 ) 2CH3 .
... _...... .... _ . .
. 158-160 1780, 1720, ~ / 3 -CH3 (decomp.) 1680, 1640 -N NCH \
.. . . ` .' 166-167 1780, 1720, O ~ O -CH3 (decomp.) 1685, 1645 -N~=~N- (CH2)3CH3 .
. _ ~ . _ 162-165 . 1780, 17~0, ~=~ ~ -CH3 (decomp. ) 1680, 1640 , , _ 145-147 1780, 1720, O ~O -CH3 tdecomp , ~ 16S2, 1640 -N N-cH2cH2ococH3 ~ ,~ _ ,- ' .. .
.
- Cont'd -- : . .. .

~7~3~

Table 16 (Cont' d) . 138-144 1780, 1715, O~ -CH 3 ( decomp . ) 1690, 1620 -N~N- (CH2) 7CH3 .
88-90 1780, 1720, ~ / 3 -CH3 1690-1620 -N~-N

_ ................................. _ ~
O O -CH C: ~ 131 1786, 1723, ~ 2 3 (decomp. ) 1684, 1645 -N N-CH2CH3 .

CH CH -CH 118-120 1780, 1720, 2 3 3 ~decomp. 1660 . _ O -CH 190-192 1780, 1720, ~e~

- Cont ' d -, : . .
- . . . . .

:
- . -': . -' , . , : ' ` ' " :` ','` ~ : , Table 16 (Cont' d) . -CH 183-185 1780, 1720, O 3 (decomp. ) 1670 --N ~ \ CE~

. ..... ... _ .
-CH 128-131 1780, 1720 , `N~l 3 (decomp. ) 1~80, 1 6 :, . . , . , :, : .
- . -. . : : . ,, . . ,: ~ . . .
, ~ . : :

. - , : ,.
,. ~ ;.' , : , - Table 17 CH
1 3 N C CONH ~ S~
CH 3CH2f -OCONH~S~ 1I J,_ N ~ CH2R
CH3 OCH3 COOC(CH3~3 (syn-isomer) Compound m.p (C) IR (KBr) cm :

~ 141-1~3 1815, 1775, -N N - CH CH (decomp.) 1710, 1680, ~=~ ~ O 3 1640 ____ _ ~
154-156 1775, 1710, O O (decomp.) 1700, 1680, ~ /O\ O 1650 -N N ~

_ 85-88 1785, 1730, O ~ O (decomp.) 1715, 1660 -N N-CH2OCOC(CH3)3 .
_I
144-146 1775, 1745, O O (de~omp.) 1715, 1690, -N N-CH2COOC~( ~ )2 1650 - 1l12 -- , . , ~ . . . ~ . . .
:
.
- , : . . . . , . ~.

. . ~
, .' : ;' "'' ' : ~ ' ' ' ' ` : !, ~2~3~

1 (2) To a solution of 6.05 g of diphenylmethyl 7-[2-(2-formamidothiazol~4-yl)-2-(syn)-methoxylminoace-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 concentra-ted hydrochloric acid, and the mixture was subjected to reaction at 35C
for 2 hours. After completion of the reaction, -the sol-vellt was removed by distillation under reduced pressure.
To the residue were added 100 ml of ethyl acetate and 100 ml of water, and the resulting 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~) o diphenylmethyl 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido~-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydro~yrazinyl)]methyl}-~3-cephem-4-carboxylate 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 ~ ~, ~ CH2-5.26 ~lH, d, J=5Hz, C~-H), ~- ' . ' : " ' , , ,''.' ~.Z7~g~3~

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

, ` - 114 -. ~

- . . . , .. : . .

3~

Table 18 N ~ C-CONH ~ ~ ~

\OCH30 COOCH( ~ )2 (syn-isomer) .
R2 R4 m.p. (C3 IR (KBr) cm :
_ O~ O 158-166 1780, 1720, -N N-CH3 H (decomp.) 1680, 1640 151-156 1780, 1720, O O H (decomp.) 1680, 1640 -N N-(cH2)4cH~ . . .
. .
150-156 1780, 1720, O O EI (decomp.) 1680, 1640 -Nr-~N-~cH2)scH3 .

O~ O H 168-175 1775 1723, -N N-(CH2~llcH3 .
. _ . _ O~ O H 161-166 1680, 1640 -N NCH2 ~

_ 146 1780, 1720, 0~0 , Br Idecomp . ) 1680, 1640 -N NCH2CH3 : . .
.. , . . . _.
: .
- ~ont'd -.

31.Z7~3~

Tabl e 18 I Cont ' d ) 175_1781780, 1720, HN~ I H Idecomp. )685 - 1660 __ d 146-148 1780, 1720, (deao~p . )166 :
- ~116 -3~

1 (3) In a mixed solvent of 25.5 ml of trifluoroace-tic~
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-5 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 lQ 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 td6-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=lSHz, S ~ ), ~LCH2-5.21 (lH, d, J=5Hz, C6-H), 5.83 (lH, dd, J=5Hz, J=8Hz, C7-H), 5.86 (3H, bs, -NH36~), 6.71 (2H, bs, ~ ), H H

. .. . . ~ .
.

-., : .

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

~ 118~

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1 (4) In 30 ml of water was dissolved 6.35 g of trifluoroace-tic acid salt of 7-[2~(2-aminothiazol-4-yl)-~-(syn)-methoxyiminoacetamido]-3-{[1-(2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylic acid, and the resulting solution wasadjusted to pH 7.4 with sodium hydrogencarbonateO Subse-quently, this solution was purified by passing through an Amberlite ~N~2 (a trademark) col ~ bo botain 4.7 ~ (yield, 86.6%) of sodium 7-[2-(2-aminothiazol-4-yl)-2-~syn)-methoxyimino-acetamido]-3-{[1-(2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-methyl~-~3-cephem-4-carboxylate having a melting point of 200C or more.
IR (KBr) cm : VC O 1763, 1670, 1650-1620 In a similar manner, the ~ollowing compounds were obtained:
o Sodium 7-[2-(2-aminothiazol~4-yl)-2-tsyn)-methoxyiminoacetamido]-3-{[1-(4-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylate.
m.p.: 190-195C ~decomp.) IR ~KBr) cm o vC=O 1760, 1670, 1650, 1630 o Sodium 7-[2-(2~aminothiazol-4-yl)-2-lsyn)-methoxyiminoacetamido]-3-~[1-(3,6-dioxo-1,2,3,6-tetra-hydropyridazinyl)]methyl}-~3-cephem-4-carboxylate O Sodium 7-[2-~2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-l3-methyl-6-oxo-1,6-dihydrO_ pyridazinyl)]methyl}-~3-cephem-4-carboxylate.

-- 13g --:. - .
' .. -: - , .
.
-- --- . ` ' ~7~i~3~

-- 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}-~ -cephem-4-carboxylic acid and Z.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 30 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. Subsequently, the organic layer was separated and washed twice with S0-ml portions o 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 puriied by a column ' .
, , -, -~ ;~7~;~3~

1 chromatography (Wako Silica Gel C-200, eluent; benzene:
ethyl acetate=3:1) to ob~ain 1.6 g IYield, 27.8%) of diphenylme~hyl 7-~2-(2-tritylaminothiazol~4-yl)-2-(syn~-tert.-butoxycarbonylmethoxyiminoacetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-te-trahydropyrazinyl)]methyl}-Q3-cephem~
4-carboxylate having a melting point of 98-100C (decomp.).
IR (KBr) cm : VC O 1780, 1720l 1680~ 1630 NMR (d6-DMSO) ~ values:
1O17 (3H, t, J=7Hz, >N~l2~l3), 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 (2H, ABq~ J=15Hz, S~ ), -lS 5.27 (lH, d, J=5Hz, C6-H), 5~87 (lH, dd, J=SHz, J-8Hz, C7-H), 6.55 (2H, bs, ~ ), H H
6.80 (lH, s, -CH<), N~r 6.97 [lH~ s, S~ ~)' 7.05-7.67 (25H, m, ~ x 5), 8.86 (lH, bs, ( ~ )3C-NH-), 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 (2) In a mixed solvent of 8 ml of trifluoroace~ic acid and 3 ml of anisole was d~ssolved 1.6 g of diphenyl-methyl 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, 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 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 1 vc=O 1775r 1695, 1680, 1635 NMR (d6-DM~O) ~ values:
1.22 (3H, t, J=7Hz, ~NCH2CH3), 3.53 (2H, bs, C2-H), _ 146 -, . '' . "`.. " ~. ' ' . ~ ' -''', ' ', .', . ~

.
" :' . , ' ~' . ', ' ' 6~39 1 3.74 (2H, q, J=7Hz, ~NCH2CH3), 4.70 (2H, s, -OCH2CO-), 4.45, 5.10 (2H, AB~, J=15Hz, S ), ~L CH2-5.23 (lH, d, J=5Hæ, C6-H), 5.90 (lH, dd, J=5Hz, J=8Hz, C7-H), 6.69 (2H, bs, ~ ), H H

6.94 (lH, s, ~ ), 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 8O40 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 subjected to reaction at -30 to -20C for 30 minutes. The thus obtained reaction mix~ure 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 -30 to -20C ~or 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, ana the thus obtained crystals were collected by filtration to obt~in 5.85 g (yield, 85.6~) of diphenylmethyl 7_(4-bromq_3~ butyramido ) 3-{[1-(4-ethyl-2,3 28 dioxo-L~2~3~4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylate having a melting point of - - ' .
. - : . : ~ -- ~ . .. `:

.
.. ;
.

3~1 1 138-142C (decomp.).
IR (KBr) cm 1 vc 0 1778, 1720, 1680, 1640 NMR (d6-DMSO) ~ values:
1.22 (3H, t, J=7Hz, `NCH2CH3), 3.40 (2H, bs, C2-~), 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 ~ ), ~C~12-5.04 (lH, d, J=SHz, C6-H), 5.90 (lH, dd, J~5Hz, J=8Hz, C7-H), 6.15, 6.50 (2H, ABq, J=6Hz, ~ ), 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:
4.09 g ~yield, 62.6%) of diphenylmethyl 7-14-bromo-3-oxo-bUtYr ~ d )-3-{[1-(3,6-dioxo-1,2,3,6-tetra-~0 hydropyridazinyl)]methyl}-Q3-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 1i ~
3.49 (4H, bs, C2-H, -CCH2C-~, ,. , : ~ . ... , : . .

~ . - . , . :. , .

1 4.52 ~2~I, s, BrCH2C-), 5.06 (lH, bs, S ), ~)--CH2-5.26 (lH, d, J=5Hz~ C6-H), 5.90 (lH, dd, J=SHz, J=8Hz, C7-H), 7.01~ 7.25 (2H, ABq, J=lOHz, ~ ), 7.09 (lH, s, -CH< ) 7 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 7j-(4-10 brm-3~xobu ~ amido )-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-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 o water to precipitate crystals. The crystals were collected by filtration, washed sufficiently with water, and dried. Thenj 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-oxobutyramido ~)-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetra-; '.''. ' ', .:' ' . ~ .

. -. , : .: , , . - . , -. , . -.- '-.. ~, ~: ' : ' . - . . , . ., . - .: ~. . : . . , ~l~7;:~3~

1 hydropyrazinyl)]methyl}-A3-cephem-4-carboxylate having a melting point of 127-132C (decomp.) IR (KBr) cm : VC O 1778, 1720, 1680, 1635 NMR (CDC~3) ~ values:
1.26 (3H, t, J=7Hz, >NCH2CE13), 3.47 (2H, bs, C2-H), 3.81 (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 2), 9.20 (lH, d, J=8Hz, -CONH-) In a similar manner, the following compound was obtained:
4.71 g (yield, 75.1%) of diphenylmethyl 7-(4-bromo-2-hydroxyimino-3-oxobutry ~ do :~-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 : vc_O 1780, 1720, 1660 NMR (d6-DMSO) ~ values:
3.46 (2H, bs, C2-H), 4.62 (2H, s, BrCH2CO-) - . :: ' : ' .' ' "' ' ~ - . , , .. . . .. . . .
.

:. . :

~.~7~

1 4.96 (2H, bs, S~ ), 5.18 (lH, d, J=5Hz, C6-H), 5.93 (lH, dd, J-5Hz, Ja~Hz, 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 lO 3.00 g of the diphenylmethyl 7-(4-bromo-2-hydroxyimino-3-oYobu~yramido) :-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 o 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 aqueous sodium chloride solution in this order. After the organic layer was dried over anhydrous magnesiam sulfate, 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 ~ .

.- , . - . . . . ~ . .
.. ~ ~ , . . . ... . . .

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1 (yield, 72.3~) oE diphenylmPthyl 7-[2-(2~aminothiazol-4-yl)-2-(syn)-hydroxyiminoacet~mido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-c~phem-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), 3.48 (2H, bs, C2-H), 3.68 (2H, q, J=7Hz, >NCH2CH3), 4.46, 5.04 (2H, ABq, J=15Hz, S~ ), ~J~CH2 -5.28 (lH, d, J=5Hz, C6-H), 5.97 (lH, dd, J=5Hz, J=8Hz, C7-H), 6.57, 6.75 (2H, A~q, J=6Hz, ~ ), H H

6.79 (lH, s, N ~ ), 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 trifluoroacetic acid and 2.0 ml of anisole was dissolved 2.00 g of the 20 diphenylmethyl 7w[2-(2-aminothiazol-4-yl)-2 (syn)-hydro-xyiminoacetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetra-hydropyrazinyl)lmethyl}-~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, tha solvent was removed by . ~ , .

: . :

~ ;276~35~

1 distillation 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 (yield, 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 IdecomP.).
IR (KBr) cm 1 vc 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

Example 9 (1) To a solution of 7.1 g of diphenylmethyl 7-(4-bromo-2-hydroxyiminO-3-oxobutyramido 3_3_ {[1-~4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-methyl}-~3-cephem-4-carboxylate in 70 ml of anhydrous methylene chloride was slo~ly added a solution of diazomethane in diethyl ether at -5 to 0C, and the resulting solution was subjected to reaction at the same temperature for 30 minutes. After confirming the . . . -: . , : . . .

' ` '`. .: .: . :

1 disappearance of diazomethane, the solvent was removed by distillation under reduced pressure. The~, the obtained residue was purified by a column chromatoyraphy (Wako Silica Gel C-200, eluent; benzene O ethyl acetate=3:1 by volume) to obtain 2.32 g (yield, 32.0%) of diphenylmethyl 7-[4-bromo-2-(syn)-methoxyimino-3-X~butrYa~i~ ]-3-{[1-~4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~ -cephem-4-carboxylate having a melting point of 135-140C ¦decomp.).
IR (KBr) cm : Vc O 1778, 1720, 1682, 1638 NMR (CDC13) ~ values:
1.25 (3H, t, J=7Hz, >NCH2CH3), 3.48 (2H, bsr C2-H), 3.84 ¦2H, ~, J=7Hz, ~NCH2CH3), 4.00 (3H, s, -OCH3), 4.10 (2H, s; BrCH2CO-), 4.48, 4.67 (2H, ABq, J=15Hz, ~CH2-5010 (lH, d, J=5Hz, C6-H), 6~05 (lH, dd, J=5Hz, J=8Hz, C7-H), 6.38, 6.73 12H, 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 ~ 163 -. : ~ . : . .
.: . . . .
- . . :. . ~

. .: :

1 7-[4-bromo-2-(syn)-me-thoxyimino-3 ,oxobu~do ]-3-{[1-(3,6-dioxo-1,2,3,6-tetrahydropyridazinyl)]methyl}-~3-cephem-4-carboxylate having a melting point o~ 145-148C
(dec.).
IR (KBr) cm : vc=O 1780, 1730, 1660 NMR td6-DMSO) ~ values:
3.49 (2Hs bs, C2-H), 4.03 (3H, s, -OCH3), 4.60 (2H, s, BrCH2CO-), 5.02 (2H, bs, S~ ), 5.30 (lH, d, J=5Hz, C6-H), 6.02 (lH, dd, J=SHz, J=8Hz, C7-H), \~H
6.92, 7.16 (2H, ABq, J=lOHz, 6.99 (lH, s, -CH ~), 7.17-7.78 (lOH, m, ~ x 23, 10.16 (lH, d, J=8Hz, -CONH-~
(2) In 14 ml of N,N dimethylacetamide were dissolved 2.3 g o~ diphenylmethyl 7-[4-bromo-2-(syn)-methoxy-imino-3-oxO~utYraridO :~]-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 o~ SO~ml of water and 150 ml of ethyl acetate. Then, sodium hyc~ gencarbonate was added there-.
. . ..
-. : . , .

~ ~7~;~3~

1 to adjust the mixture to pEI 6.7, and then the organic layer was separated. The aqueous layer was further extracted twice with 100-ml portions o~ ethyl acetate.
The combined or~anic 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 ~ Iyield, 86.3~) of diphenylmethyl 7-[2-t2-aminothiazol-4-yl~-2-tsyn)-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.
IRtKBr)cm 1 vc O 1780, 1720, 1680, 1640 In a similar manner, the ~ollowing compound was obtained:
o Diphenylmethyl 7-[2~t2-aminothiazol-4-yl~2-tsyn)-methoxyiminoacetamido]-3-{[1-(3~6-dioxo-1~2,3~6-tetrahydropyridazinyl~]methyl}-~3-cephem-4-carboxylate, m.p., 175-178C tdecomp.) IR (KBr) cm 1 vc 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 ohtain the compounds shown in Tables 24, 25 and 26.

, - ~ ' ':
. ~ .. . . . .
. . - . ~ . ~ . :.... . .
- ~., , . .: , :
' . .,: ~: ',:, ~ . , , . , ~ . . . .
- .
.
. .

~ ~7~ 3~

o ¦ N ~ =o U ~=

- Z

- 166 -:

.
- .`. :: , - . ~ . , . . . , , , .: ,.

~ ~76~.3~

r ~.

~ m : ~

-~ 167 - ~ -~: :

.. ~ . .. . .. ...
: ~; .~ ` ,. , :
: . ` . ` ` . : : ` , , . . . : `
: - ~ .

- ` .. `: , , :, , `
.

:~ ~7~3~

_ m m u" ~

~Z~D o~z~D o~ I ~D

. .. _ D

U ~ O U
0~~ ~ 0~ ~ ~ 0~ ~ ~

. . . .. _ U U

U C~
~Z~l oX~ ~

-- 168 -- ~
\

.. . . . . . . .
.. . .: , :
: . ., ` : ' ' .,: ' ' .

'- ~ . . .

~.~76~3~3 . . . . ......

~ ~o ; ~

~ '~

U~ Or~

.. . . :. , ~ :, .
:.
.
:. .: . . - ~ ., .. `. ., . : ~` :
. ` .

~. . : ` . ~, ;.
` .
- . .. , . , : : .
. .. ., ` . .

~ ~'7~

Table 25 S ~r N O~ ~ 2 (syn-isomer) - - --......... ...... .

0~0 . . _ _ --N NCH2C~3 NH2- -CH2COOH

__ .. .. ...

--N~NCH2cH3 CP3COOH~NH2- -C-COOH

O O _ , --N N~3 NH 2 - -CH 2CH
lo~o ~ ~ ~

. ,~, . ___ , . . _ ..

--N,=,N-N~ 3 ¦ CF3COOH~ NH2- ¦ CH2COO

- Cont ' d .- , , , - ,, . , . , .:

6~3~

Table 25 (Cont ' d1 ~
j~j N~ 3C130 3 ~ N 32--CH2COOEI

l~c32c=cc33 ~ ~

. ....... ~ .. _ _.... . .

--N N ~) N12- -CH2COOH

O O ._ ....... _ --N NCH20COC (CH 3 j 3 NH2- -CH2COOH

1 ~ . _ _ .
- Cont'd -- ~- 171 ` ' , - ~,' - - - ,, , :: . ' , . :
-, . :' ~2~

Table 25 (Cont ' d) --N~C 2COOH ~ NH2- ~-C}l COOH

~ . . _ _ .

--N ~NCH2CH3 HCOOH NH2~ CH2COO~) 2 3 HCOOH~NH2-- -CH ~<OO~

'0~0 _ . .__ . _ ~ _.. _ ~__.

~;
- .. . ~

. : . : ' .: , ' ' ':: ' . : . . ' ., ' : . , ' ''' -, ' ~ '- . '' . :
. .

3~

Table 26 H N~ CH R2 OCH3 O l I
COOR
(syn-isomer) ._. .
._ ._ . ___ . .
0~,0 -CHOCOC(CH3)3 -N NCH2CH3 CH3 .

-fHOCOC(C~3)3 - N NCH3 .

. _ . ............ . ._ . ., ~ 0~,0 -fHococ(cH3)3 - N N-(CH2)4CH3 _ _ .
~
-fHOCOC(CH313 ~N N-(CH2)5CH3 - Cont'd -:

.

\ ~

' ~ . ', ' ' .', '' . . .. , , -' `' ~ ' ~ ' ' ,- ,` ' '., . , ' : , ~ . , .

3~

Table 26 (Cont 'd) -C30COC ~C~3) 3 --N 2 ~C~12) 7CH3 _ ..

--fHOCOC (CH3) 3 ~ ( 2)11CH3 0~0 -CH20COC (CH3) 3 --M~ICH2CH3 ... _ . .. . . _ 0~,0 -cHocooc (CH3~ 3 --N~NCH2CH3 . . __ _ . _......... _ ~ ; --~1NC1~2CI{3 .__ _ ... ---- - --- .

2 ) 3 ~3 --NNCH2CN3 . .__- .. .. , - Cont'd -- - - '. . ~ .. - - - , ' ' ' : .
` - ` - ` ' ~ ' , ' ~ ' ~ ' ' ' ' ' . . , , ~ ~7~3~

Table 26 tCont~d~

-CH~=C-CH3 0~<0 ~ --N~NCH 2CH 3 --CH20COC (CH3) 3 ~D
.

--C}120COC (CH3) 3 ¦--N~JJ

_ _ . . .

-C 3 20COC ( C 3 ) 3 3 IN ~

.. .. _ ~n ~ . ....... _ .. __ ~ ~C (CH3 ) 3 ~
: .
- Con t ' d '.

--~ 175 --:::

- - . ~ . .... .
- -. -: ~ . - .
- : . i . . .

~.~7;~39 Table 26 (Cont'd) CHococlcH3)3 CU~

. . . ...
0~,0 . -CH20COC(CH3)J -N N

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

:: :
:

.

- ~ . . . .

,.. ~ . ..
-- . - : ~: . . : . :
.. ... - . : . ~ ,. : , - :

3.~7~3~3 - 1 E~ample 10 (1) To a suspension of 2.2 g of 2-(2-formamido-thiazol 4-yl)glyoxylic acid in 11 ml of N,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 added 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-~-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 _he reaction, 70 ml of water and 50 ml f methylene chloride ~ere added to the reaction mixture. Then, sodium hydrogencarbona~e 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 pressureO The residue was purified by a column chromatography ~Wako Silica Gel - 177 ~

.

.
, . . . .
. ~ ~ . . . . .
-' ' ' ' : ' ' ~ ~'7~3~

1 C-200, eluent; chloroform:methanol=20:1 by volume) to obtain 1.4 g (yield, 20.0~) of diphenylme-thyl 7-[2-(2-formamidothiazol-4-yl)glyoxylamido]-3-{[1-~4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]me-thyl}-~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=SHz, 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 diphenylm~thyl 7-[2-(2-formamidothiazol-4-yl)glyoxylamido~-3-{[1-(3,6-dioxo-1,2,3,6-tetrahydropyridazinyl)]methyl}-~3-cephem-4-carboxylate, -.

.
: .. : . . . .~ . - ., . . , ~. . . . .

3~
1 m.p.: 153-154C (decomp.).
IR (KBr) cm 1 ~C O 1780, 1725, 1690, 1665 NMR (CDCl3+d6-DMSOJ ~ values:
3.42 (2H, bs, C2-H), 4.96-5.40 (3H, m, S ~ , C6-H), 5.95 (lH, dd, J=5Hz, J=8Hz, C7-H), 6.72-7.78 (13H, m, -CH~ , ~ , ~ x 2~, 8.66 (lH, s, N
S H

8.73 (lH, s, HCO-), 9.86 llH, 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-lS 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 .: ~ ' .'; ' ', , ' : ' ' , . . ' , ~ 27~i~3 1 reduced pressure. To the residue 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)-methoxy-iminoacetamido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,4-tetra-hydropyrazinyl)]methyl}-Q3-cephem-4~carboxylate having a melting point of 165-168C.
IRtKBr) cm 1 VC O 1780, 1720, 1680, 1640 In a similar manner, the following compound was obtained:
Diphenylmethyl 7-[2-(2-formamidothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(3,6-dioxo-1,2,3,6-tetrahydropyridazinyl)]methyl}-Q3-cephem-4-carboxylatet m.p. 171-173C (decomp.).
The 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 Tri~luoroacetic acid salt of ~-E 2-(2-amino-5-bromothiazol-4-yl)-2-(syn)-methoxyiminoacetamidoJ-3-{~1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)~-methyl}-~-cephem-4-carboxylic acid m.p.: 147C (decomp.) 25 IR(KBr) cm 1 vc~O 1775, 16~0, 1640 - . : ,:, ~- , ~ , ; , -.
,, , ` ,', :,'', ', ' ' : ' ' ~
. : ~ . .: .: . : , . .

~ ~7~

,'`'~'' ,~1/ l I

n ~ . ~ ~ ~
~: ~0 ~0 U
~ L

, ~ ~

. . .. , . ~ . ` ` .
.` . ~. . . . . . . . .

.

~ ~7~

. ... _ _ .~ . o~ .

o ~3 ~C ~
L~

: ` , : ... : .. .~ . . . .-- . . . . . .

.. : ,, ,. , . : .. . . ,, , :
. : : . :: . : . . . ..

3~

.. .. . ._ ~ ~, m D~ . ~

o~z~ o~z~ o~z3 . ..... _ ~o ~
u m . u ~ o~cO o~ ~o, ..

Q ~ 0 ~J~ ml .
o~z~D 0~ 1 ~ 0 :
_ _ _ . . .' ~Z~I ~ ~ ~ oX~

::

\

35~

_ 1 ~o ~ I

, Xr~ V

3~

Table 28 N\ O ~\CH2R
OR 1 ~ COOH
(syn-isomer) F . ~ RS ~ R1 8 --N NCH2CH3 NH2-- --CE~2CH

_ _ _ ~ 2C113 CF 3Coo ~ ' ~3 2 ~ =

--N NH NH 2 ~ -CE~ 2COOH

--N~CH3 CE'3COOEI ~ NH2- -CH2COOH

W-N~ 3 C~3COOi3~ N~ n 2~00~l ¦

- Cont ' d - - . -: . . .: .
. . - -. - : .
' ' Table 28 (Cont ' d) o ~HCOOH NH2- -CH2COOH

. ~ ..

--N ~ HCOOH: NH2- -CH 2CH

0~0 ...,, '-- ''---N NCH2C=C-CH , J ~ 3 NH2- -CH2COOH

O O - : . .... . I
--N N ~ NH2- -CH2COOH
~ ' . . _ __ . _ --N CH20cOc ~CH ) 3 NH2- -CH~COOH
:1 I . . . . __ - Cont'd -~ 186 -. .
-, . , , . , ' - , . . , ., .: . ..

3~

.
Tabl~ 28 (Cont 'd) --N NCH2cooH ~ NH2- ~ -Cl[2COOH

I .. . .. ~ ..... _. .. _. .
--N ~NCH2CH3 HCOOH- NH2- -CH2COO~) -0~0 ~ ~ ... __ .
--N~CH2CH3 HCOOH~NH2-- --CH2COO &1 0~0 . _ --~ NCH2CH3 HCOOH~ NH2-- --CH2COOCH2CH3 . . . . .. .. .
-.
- ~:

~276~3~

.
Table 29 2 ~ CH2R
OCH3 O l 1 COOR
(syn-isomer) Rl . . .~ .
. , 0~,0 -CHOCOC(CH3)3 -N NCH2CH3 CH3 .
__ _ .
' 0~,0 ` `
-CHOCOC(CH3)3 -N NCH3 . : O

-fHOCOC(CH3)3 ~ ~ N-(CH2)4CH3 C~3 . . . _. : , ' ~ 'OC~CH3i~ N N ~CH2)5CH3 :
: ~ - Cont'd -, .

~ 8 -- . ... i , ... "............. .. . ..

Table 2 9 (Con t ' d ) 0~/0 -FHOCOC (CE~3) 3 --N N (CE~2) 7CH3 .~ . . .. ___ 0~ ,0 -I ~OCOC (CH3) 3 --N N [C~12)11CH3 _ - . . .
0~<0 --CH20COC (CH3) 3 --N~NCH2CH3 . _ 0~,0 -CHOCOOC (CH3) 3 --N~NCH2CH3 .. . . _ .

. .
: 3~
- (CH2) 3CH3 --N NCH2CH3 . _ ._ ~: .. - ,, - Cont'd -.
, ~
., , ~ ~ ..'; ' ' ' .

~7~3~

Table 29 :(Cont'd~

-CH2C=C--CH3 0~,0 l~o --N~NCH2CH3 --CH20COC ~CH3 ) 3 --I ~11 .

CH 20COC ~ CH3 ) 3 t 1120C ~ (CH 3 ) 3 HN~

-CH20COC (CH3) 3 f~
. ~ _ .~

- Cont'd -.
. : .
, . ~ . .

~ ~ , ``.' '. ." ,, -~7~i~3 Table 29 (Cont'd~

-CIIOCOC ~CH3) 3 N ¦`~

_. . ._ ~ O
-C~20COC(CH3)3 -N N ~

Note: * Hydrochloride ~

1 Physical properties Im. p ., IR and NMR spectra) of the above compounds were the same as those obtained in Examples 6, 7, 11 and 12.
.

.
,' . ' ' ~ ' . ' .~;,, `, ' ' :

~. . . . . . .
~ ~ , - . .

6~3 1 Example 11 (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)-m~thoxyiminoacetamido]-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-{ E 1-(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]-methyl}-~3-cephem-4-carboxylic acid having a melting point of 155-158C Idecomp-)-IR (KBr) cm 1 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=7HZr ~NCH2CH3), 3.91 (3H, s, -OCH3), 4.42, 4.95 t2H, ABq, J-15Hz, S~ ), ~lCH2-5.2I (lH, d, J=5Hz, C6-H), 5.89 (lH, dd, J=5Hz, J=8Hz, C7-EI), 6.65 (2H, bs, H~

'. ','' , ,, ',1 .

3~3 N lT-1 7.46 (lH, s, ~ ~, S H

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

.

~:

: ~
~ 193~
::

Table 30 N C CONH ~ `~
HCONH ~ ~N~--CH2R

OCH COOH
3 (syn-isomer) Compound _IR (KBr ) . . m ~. (C) -1 _R2 .~ cm : VC=O
(~ O 195-198 1775, 1720, )?~ (decomp.) 1680-1640 .

. .. _ .
O O
-N N- (CH2)4CH3 122-125 1775, 1680, \~ (decomp.) 1640 .... _ . ~ ... ..
,0~0 l -N N-~CH2)5CH3 165-170 1775, 1680, (decomp. ) 1640 -. ......... _ . , 0~0 -N N--~ ~O 195-198 1775, 1685, \=~ ~decomp.) 1650 .. ~ .... ... __._ _ .. __ .
O O
~4 ' (CH2) 7CH3 155-158 1780, 1720, .
\~/ (decomp.) 1680-1640 .. _ ..... ___ _ .
0~0 ~ ~
(C 2) 11CH3 144-147 177 8, 1685, ~=~ (decomp. ) 1660 j 1645 _ , : ' - Cont'd -.
,, , . - . . . .

.. . , . :.
- . ;... .. . : :, - , : : , ~6~3~

Tablf~ 30 (Cont'd) N ~ ~ .86-188 ~ 1775, 710, -N (decomp. ) 1690, 1650 ~C~3 N 218-221 1775, 1670, -h~l ~decomp . ) 1 165 0 .

: ~ - 1 95 -:.. . .,: .. .. , : . , ~7~9 1 (2) To a solution of 5.63 g oE 7-[2-(2-formamidothiazol-4-yl)-2-(syn)-methoxyiminoace-t-amido]-3-{[1-(4-ethyl-2,3-dioxo-1,2,3,~-te-trahydro-p~razinyl)]methyl}-~3-cephem-4-carboxylic acid in 25 ml of N,N-dimethylacetamide were added 1.52 g o~
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 minu~es. After completion of the reaction, the reaction 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 water, and then dried over anhydrous magnesium sulfate. The sol~ent was removed 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 (yield, 79.6%) of l-pivaloyloxyethyl 7-[2-(2-~ormamido-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 melting point o~
140-142C~
IR (KBr) cm 1 vc 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 ~or the diphenylmethyl esters.

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1 (3) To a solution of the 5.5 g of l-pivaloyloxy-ethyl 7-[2-(2-formamidothiazol-4-yl)-2-(synl-methoxy-iminoacetamido]-3-{[1~(4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)lmethyl}-~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 res~lting mixture was subjected to reaction at 35C for ~ 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 hydrogencarbonateO Subsequently, the organic layer was separated and dried over anhydrous magnesium sulfate, ater 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-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-t4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~ -cephem-4-carboxylate having a melting point of 148-150C.
IR tKBr) cm 1 vc O 1780, 1740, 1680, 1640 NMR (d6-DMSO) ~ values:
0.90-1.3g (12H, m, -C~CH3)3, > NCH2CH3), 1.52 (3H, d, J=5Hz, -OICHO-), 3.52 (2H, bs, C2-H), 3.76 (2H, q, J=7Hz, ,~NCH2CH3), .
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l 3.88 (3H, s, -OCH3), 4.38, 5.04 (2H, ABq, J=15Hz, ~ ~, ~LCH2-5.21 (lH, d, J=5Hz, C6-H~, 5.87 (lH, dd, J=5Hz, J=8Hz, C7-H), 6.61 ~2H, bs, ~ ), H H

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

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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 reackion at 35C 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 o~ 7-~2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(2,3-dimethyl-6-oxo-1,6-dihydropyrazinyl)]methyl}-~ -cephem-4-carboxylic acid having a melting point of 250C or more.
IR(KBr) cm 1 vc=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, -oCH33, 4.94, 5.24 (2H, AB~, J=15Hz, ~ CH - )' 5.10 (lH, d, J~5HZ, C6-H), 5.78 (lH, dd, J=5Hz, J=8Hz, C7-H), 6.89 (lH, s, SN ~ H)' 7.82 (lH, s, ~ H), 9.79 (lH, dd, J=8Hz, -CONH-) ~, , '' ' ' ~`' ~' . ~. ~ ; . - , . :
,, : . - :
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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.

H ~ S ~ N
\OCH2COOR
(starting material, syn-isomer) NH2~ S ~ 0~0 N ~ CH2N N-CH2CH3 COOCH( ~ )2 \ /

0~ 1 2 ~=~ 2 3 OCH2COO~1 COOCH( ~ )2 (objective compound, syn-isomer) - . . . . .

.. . , ~ . . .
- . . . , .. ~ ~ , . , .. , . .:

.. .: .

.. . .. .

Table 33 __ . . _ .. . . . _ __ ¦ Objective Compound m.p. (C) IR (KBr) Rl cm : VC O
__ .. _ . ._ f-~ 127-130 1780, 1720, (decomp.) 1685, 1645 , _ ,, , _ A. __ _ 127-130 1~80, 1720, ~ (decomp.) 1685, 1635 _ 150-152 1780, 1720, -CH2CH3 (decomp.) 1680, 1645 1 ~2) The compounds shown in Table 34 were obtained by reacting the above-mentioned compounds in a similar manner as in Example 7-~2).

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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. Subsequen-tly, 1.12 y 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 water.
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-caoling.
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-tetrahydropyrazinyl1methyl}-~3-cephem-~-carboxylate ' ' '' "~. :. ,, ,` .
.
.'~ ' :. `

7~

1 having a mPlting point o~ 152-154C (decomp.).
IR (KBr) cm : VC o 1780, 1720, 1685, 1640 In a similar manner, the following compound was obtained: 6.15 g (yield, 82.7~ o~ diphenylmethyl 7-[2-(2-tert.-amyloxycarboxamidothiazol-4-yl)acetamido]-3-{[1-(3,6-dioxo-1,2,3,6-tetrahydropyridazinyl)]methyl}--cephem-4-carboxylate, m.p.: 136-139C (decomp.) IR (KBr) cm 1 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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~ N

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1 Example 14 In 48 ml of N,N-dimethylacetamide ~ere dissolved 6.82 g o~ diphenylmethyl 7-(4-brOmo-3-oxobut~r~o ~-3-{[1-(4-ethyl-2,3-dioxo-1,2~3,4-tetrahydropyrazinyl)]-methyl}-~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 reaction mixture was poured into a mixed solvent of 500 ml of water and 500 ml of ethyl acetate, and the n 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 reduaed 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 crystal5 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~ ,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylic acid having a melting point of 109-115C
(decn).
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-, ' ' ' ~ , ', ' , '.
, 3~

l hydropyridazinyl)]methyl}-~3-cephem-4-carboxylic acid, m.p.: 200C or more.
Physical properties (IR, NMR values) of this compound were identical with those in Example 13-(2).

::

.
~ 23:2~

: : , , ~ . . .. ...

;~ ~7~3~

1 Preparation Example 1 An aqueous sodium salt solution of 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-{[1-(2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)]methyl}-~3-cephem-4-carboxylic acid was treated in a conventional manner 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 1 was dissolved in 4 ml of 0.5% (WlV) aqueous lidocaine hydrochloride solution to obtain a dilutable injection.

lS Preparation Example 3 One gram (potency) of the freeze-dried product obtained in Preparation Example 1 was dissolved in 20 ml o~ 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 1 to 3.

, . .

., ' : ' : '

Claims

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

1. A 7-amino-3-substituted methyl-.DELTA.3-cephem-4-carboxylic acid represented by the following formula or a salt thereof:

wherein R1 represents a hydrogen atom or a carboxyl-protecting group; R2 represents a group of the formula:

or 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, alkadienyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl, aralkyl, acyl, alkoxy, alkylthio, acyloxy, cycloalkyloxy, aryloxy, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkyl-sulfonyl, arylsulfonyl, heterocyclic sulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, acylcarbamoyl, acylthio-carbamoyl, alkylsulfonylcarbamoyl, arylsulfonyl-carbamoyl, alkylsulfonylthiocarbamoyl, arylsulfonyl-thiocarbamoyl, alkylsulfamoyl, dialkylsulfamoyl alkoxythiocarbonyl, alkylideneamino, cycloalkyl-methyleneamino, arylmethyleneamino, furylmethylene-amino, thienylmethyleneamino, pyrrolylmethyleneamino, pyrazolylmethyleneamino, imidazolylmethyleneamino, thiazolylmethyleneamino, isothiazolylmethyleneamino, oxazolylmethyleneamino, isoxazolylmethyleneamino, thiadiazolylmethyleneamino, oxadiazolylmethyleneamino, thiatriazolylmethyleneamino, oxatriazolylmethylene-amino, triazolylmethyleneamino, tetrazolylmethylene-amino, pyridylmethyleneamino, 4-(5-methyl-2-pyrrolinyl)-methyleneamino, 4-(2-pyrrolinyl)methyleneamino, N-methylpiperidinylmethyleneamino, quinolylmethylene-amino, phenazinylmethyleneamino, 1,3-benzodioxolanyl-methyleneamino, benzofurylmethyleneamino, benzothienyl-methyleneamino, benzoxazolylmethyleneamino, benzo-thiazolylmethyleneamino, phthalidylmethyleneamino, coumarinylmethyleneamino, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiatriazolyl, oxatriazolyl, triazolyl, tetrazolyl, pyridyl, 4-(5-methyl-2-pyrrolinyl), 4-(2-pyrrolinyl), N-methylpiperidinyl, quinolyl, phenazinyl, 1,3-benzodioxolanyl, benzofuryl, benzothienyl, benzo-xazolyl, benzothiazolyl, phthalidyl or coumarinyl 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, dialkyl-amino groups, acylamino groups, alkoxycarbonyl groups, acylalkyl groups, aminoalkyl groups, N-alkylaminoalkyl groups, N,N-dialkylaminoalkyl groups, hydroxyalkyl groups, hydroxyiminoalkyl 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 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);
each of R7, R8, R9, R10, R11, R12, R14 and R15, 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 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, hydroxyiminoalkyl groups, alkoxyalkyl groups, carboxyalkyl groups, alkoxy-carbonylalkyl groups, aralkyloxycarbonylalkyl groups, sulfoalkyl groups, sulfamoylalkyl groups, carbamoyl-alkyl groups, carbamoylalkenyl groups, N-hydroxy-carbamoylalkyl groups and a group of the formula in which 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, cycloalkoxycarbonyl, acyloxycarbonyl, aralkyloxy-carbonyl, alkyisulfonyl, cycloalkylsulfonyl, aryl-sulfonyl, furylsulfonyl, thienylsulfonyl, pyrrolyl-sulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, thiazolylsulfonyl, isothiazolylsulfonyl, oxazolyl-sulfonyl, isoxazolylsulfonyl, thiadiazolylsulfonyl, oxadiazolylsulfonyl, thiatriazolylsulfonyl, oxatriazolyl-sulfonyl, triazolylsulfonyl, tetrazolylsulfonyl, pyridylsulfonyl, 4-(5-metyl-2-pyrrolinyl)sulfonyl, 4-(2-pyrrolinyl)sulfonyl, N-methylpiperidinyl-sulfonyl, quinolylsulfonyl, phenazinylsulfonyl, 1,3-benzodioxolanylsulfonyl, benzofurylsulfonyl, benzothienylsulfonyl, benzoxazolylsulfonyl, benzothiazolylsulfonyl, phthalidylsulfonyl, coumarinylsulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, acyl-carbamoyl, acylthiocarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonylthiocarbamoyl or arylsulfonylthiocarbamoyl 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-alkylamino-alkyl groups, hydroxyalkyl groups, hydroxyiminoalkyl 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; R3 represents a hydrogen atom or an alkoxy group; R28 represents an amino group, a group of the formula or a group of the formula, in which each of R31, R32, R33, R34 and R35, which may be the same or different, represents a hydrogen atom or an alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, 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, 1,3-benzodioxolanyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, phthalidyl, coumarinyl or acyl group, which acyl can be derived from formic acid, acetic acid, propionic acid, butanoic acid, isobutanoic acid, pentanoic acid, methoxyacetic acid, methylthioacetic acid, acrylic acid, crotonic acid, cyclohexanoic acid, cyclo-pentaneacetic acid, cyclohexaneacetic acid, cyclohexanepropionic acid or cyclohexadieneacetic acid and the said acyl may be substituted by at least one substituent selected from the group consisting of halogen atoms, a hydroxyl group, a protected hydroxyl group, alkyl groups, alkoxy groups, acyl groups, a nitro group, an amino group, a protected amino group, a carboxyl group and a protected carboxyl group.
2. A 7-amino-3-substituted methyl-.DELTA.3-cephem-4-carboxylic acid or a salt thereof according to claim 1, wherein R3 is a hydrogen atom.
3. A 7-amino-3-substituted methyl-.DELTA.3-cephem-4-carboxylic acid or a salt thereof according to claim 2, wherein R28 is an amino group.
4. A 7-amino-3-substituted methyl-.DELTA.3-cephem-4-carboxylic acid or a salt thereof according to claim 3, wherein R2 is a group of the formula, in which R6 has the same meaning as defined in claim 1.
5. A 7-amino-3-substituted methyl-.DELTA.3-cephem-4-carboxylic acid or a salt thereof according to claim 3, wherein R2 is a group of the formula, in which R6 is a hydrogen atom, a 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, 1,3-benzodioxolanyl, benzofuryl, benzothienyl, benzoxazolyl, benzo-thiazolyl, phthalidyl or coumarinyl group or an alkyl, aralkyl or cycloalkyl group which may be substituted by the same substituent as defined in claim 1 or a group of the formula, in which R16 and R17 have the same meanings as defined in claim 1.
6. A 7-amino-3-substituted methyl-.DELTA.3-cephem-4-carboxylic acid or a salt thereof according to claim 3, wherein R2 is a group of the formula, in which R6 is a dialkylamino group or a hydrogen atom, or an alkyl, aralkyl or cycloalkyl group which may be substituted by an alkanoyloxy or carboxyl group or a group of the formula (wherein R24 represents a lower alkyl group).

7. A 7-amino-3-substituted methyl-.DELTA.3-cephem-4-carboxylic acid or a salt thereof according to claim 3, wherein R2 is a group of the formula, in which R6 is a hydrogen atom or an alkyl, aralkyl or cycloalkyl group which may be substituted by the same substituent as defined in claim 1 or a group of the formula, in which R16 and R17 have the same meanings as defined in claim 1.
8. A 7-amino-3-substituted methyl-.DELTA.3-cephem-4-carboxylic acid or a salt thereof according to claim 3, wherein R2 is a group of the formula, in which R6 is a dialkylamino group or a hydrogen atom, or an alkyl, aralkyl or cycloalkyl group which may be substituted by acyloxy.
9. A 7-amino-3-substituted methyl-.DELTA.3-cephem-4-carboxylic acid or a salt thereof according to claim 3, wherein R2 is a group of the formula, in which R7, R8 and R9 have the same meanings as defined in claim 1.

10. A 7-amino-3-substituted methyl-.DELTA.3-cephem-4-carboxylic acid or a salt thereof according to claim 3, wherein R2 is a group of the formula in which R7, R8 and R9, which may be the same or different, is a hydrogen atom or an alkyl group.
11. A 7-amino-3-substituted methyl-.DELTA.3-cephem-4-carboxylic acid or a salt thereof according to claim 3, wherein R2 is a group of the formula, which R10, R11 and R12 have the same meanings as defined in claim 1.
12. A 7-amino-3-substituted methyl-.DELTA.3-cephem-4-carboxylic acid or a salt thereof according to claim 3, wherein R2 is a group of the formula, in which R10, R11 and R12, which may be the same or different, is a hydrogen atom, a halogen atom or an alkyl group.
13. A 7-amino-3-substituted methyl-.DELTA.3-cephem-4-carboxylic acid or a salt thereof according to claim 3, wherein R2 is a group of the formula, in which R13, R14 and R15 have the same meanings as defined in claim 1.
14. A 7-amino-3-substituted methyl-.DELTA.3-cephem-4-carboxyllc acid or a salt thereof according to claim 3, wherein R2 is a group of the formula, in which each of R13, R14 and R15, which may be the same or different, is a hydrogen atom or an alkyl group.