FR2536074A1 - NEW CEPHALOSPORINS, PROCESSES FOR PREPARING THEM, ANTIBACTERIAL AGENTS CONTAINING SAME, INTERMEDIATES FOR THEIR PREPARATION, AND PROCESS FOR THE PREPARATION OF INTERMEDIATES - Google Patents

Abstract

NEW CEPHALOSPORINS IN THE FORMULA OF A RADICAL 2,3-DIOXO-1,2,3,4-TETRAHYDROPYRAZINYL, 2-OXO-1,2-DIHYDROPYRAZINYL, 3,6-DIOXO-1,2,3,6-TETRAHYDROPYRAZINYL OR 6-OXO-1,6-DIHYDROPYRIDAZINYL, POSSIBLY SUBSTITUTED, IS FIXED TO THE EXOMETHYLENE GROUP IN POSITION 3 OF THE CEPHEM CORE VIA A CARBON-NITROGEN BOND, AND THE FOLLOWING GROUP IS FIXED IN THE 7 AMINO GROUP: CF DRAWING IN BOPI) FORMULA IN WHICH -A- REPRESENTS A GROUPING OF FORMULA -CH- OR A GROUPING OF FORMULA: (CF DRAWING IN BOPI) IN WHICH R REPRESENTS A HYDROGEN ATOM OR A RADICAL ALKYL, ALKENYL, ALCYNYL, CYCLOALKYL , CYCLOALCENYL, ARALKYL, ARYL OR HETEROCYCLIC, POSSIBLY SUBSTITUTED, A PROTECTIVE GROUP OF HYDROXYL FUNCTION, OR A GROUP OF FORMULA: (CF DRAWING IN BOPI) (EACH OF THE R AND R SUBSTITUTES, WHICH ARE IDENTIFIED OR ARE DIFFERENT HYDROXYL GROUP OR A RADICAL ALKYL, ARALKYL, ARYL, ALCOX Y, ARALKYLOXY OR ARYLOXY), AND THE BINDING MEANS THAT THE COMPOUND MAY BE A SYN ISOMER OR AN ANTI ISOMER OR A MIXTURE OF THE TWO; R REPRESENTS A HYDROGEN OR HALOGEN ATOM; AND R REPRESENTS A HYDROGEN ATOM OR A POSSIBLE PROTECTED AMINO GROUP. THESE CEPHALOSPORINS HAVE A WIDE ANTIBACTERIAL SPECTRUM, ARE STABLE TO B-LACTAMASE PRODUCED BY BACTERIA, HAVE LOW TOXICITY, AND ARE WELL ABSORBED WHEN DELIVERED ORAL OR PARENTALLY.

Description

New cephalosporins, processes for their preparation, agents

  The present invention relates to new cephalosporins, processes for their preparation, agents for the preparation of

  antibacterial agents containing said novel cephalosporans

  intermediates for the preparation of said cephalosporins, and a process for preparing said intermediates. The present inventors have conducted research in order to discover compounds having a broad antibacterial spectrum, demonstrating excellent antibacterial action against gram-positive and gram-negative bacteria, stable against B. lactamase produced by bacteria, of low toxicity, and at the same time capable of being well absorbed by oral or parenteral administration and having an excellent therapeutic action on the diseases of humans and animals. As a result of this research, it has been discovered that new

  cephalosporins, characterized in that a 2,3-dioxo radical

  1,2,3,4-tetrahydropyrazinyl, 2-oxo-1,2-dihydropyrazine

  yl, 3,6-dioxo-1,2,3,6-tetrahydropyridazinyl or 6-oxo

  1,6-dihydropyridazinyl, optionally substituted, is attached to the exomethylene group in the 3-position of the cephem ring via a carbon-nitrogen bond, and in that the following radical is attached to the amino group in the 7-position, possessed the excellent properties mentioned above:

R 5 N A-CO-

  formula in which A, R and R meet the

definitions below.

  It is an object of the present invention to provide novel cephalosporins having the above-mentioned chemical constitution features

  and having a broad antibacterial spectrum, stable vis-à-

  the β-lactamase produced by the bacteria, having low toxicity, which can be well absorbed by oral or parenteral administration, and having an excellent therapeutic action on the diseases of the

human beings and animals.

  It is another object of the present invention to provide a method for preparing said

new cephalosporins.

  It is another object of the present invention to provide an antibacterial agent containing a

said cephalosporins.

  It is yet another object of the present invention to provide intermediates for the preparation of said novel cephalosporins, and

  provide a process for preparing said intermediates.

  Other goals and benefits of this

  invention will emerge from reading the description

who will follow.

  According to the present invention, there is provided a novel cephalosporin, especially a cephalosporin represented by the following formula, or a salt thereof, wherein R 1 represents an atom of hydrogen or a protecting group of the carboxyl function; R 2 represents a radical of formula:

O R 8 O

R 13 R 14 N

R 156

  In which R 6 represents a hydrogen atom, a hydroxyl, nitro, carbamoyl, thiocarbamoyl or sulphamoyl group, or an alkyl radical,

  alkenyl, alkynyl, alkadienyl, cycloalkyl, cycloalkyl,

  alkenyl, cycloalkadienyl, aryl, aralkyl, acyl, alkoxy,

  alkylthio, acyloxy, cycloalkyloxy, aryloxy, alkoxy-

  alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclic sulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, acylcarbamoyle, acylthiocarbamoyle, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonylthiocarbamoyle, arylsulfonylthiocarbamoyle, alkylsulfamoyl, dialkylsulfamoyl, alkoxythiocarbonyl,

  alkylideneamino, cycloalkylmethyleneamino, arylmethylene-

  amino, heterocycle-methyleneamino, or heterocyclic, optionally substituted, or a group of formula R 16 -N 17

R 17

  (Each of the substituents R 6 and R 17, which may be the same or different, represents a hydrogen atom or an alkyl radical, or R 16 and R 17 may form a ring with the nitrogen atom which is adjacent to them. ); each of R 7, R 8, R 9, R 10, R 11, R 14 and R 15, which may be identical or different, represents a hydrogen or halogen atom or an alkyl, aralkyl or aryl radical, optionally substituted; R 13 represents a hydrogen or halogen atom, a carboxyl, sulfo, carbamoyl or thiocarbamoyl group, or a radical

  alkyl, aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxy-

  carbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyl

  oxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocycle-sulfonyl, alkylcarbamoyl,

  dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthio-

  carbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkyl

  sulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulphonyl-

  thiocarbamoyl or arylsulfonylthiocarbamoyl, optionally substituted; R 3 represents a hydrogen atom or an alkoxy radical; R 4 represents a hydrogen or halogen atom; R 5 represents a hydrogen atom or an optionally protected amino group; and A represents a group of formula -CH 2 or a group of -C- formula 18 in which R 8 represents an atom 18 OR

  hydrogen, an alkyl, alkenyl, alkynyl, cycloalkyl,

  alkyl, cycloalkenyl, aralkyl, aryl, or heterocyclic,

  optionally substituted, or a protecting group of the hydroxyl function; or a group of

O R 19

  19 20 u evn formula -P (each of R 19 and R 20, which can

R 20

  be identical or different, represents a hydroxyl group or an alkyl, aralkyl, aryl, alkoxy, aralkyloxy or aryloxy radical); and binding means that the compound can be a syn isomer or an anti isomer or a

mix of both.

  The present invention also provides a process for preparing said cephalosporins and their salts,

  antibacterial agents containing said cephalosporins

  spores, intermediates for the preparation of said cephalosporins, and a method of preparation

said intermediates.

  The invention will be described in more detail below.

after.

  Throughout this description,

  unless otherwise specified, the term "alkyl" means a straight or branched straight chain C1-C14 alkyl radical and

  includes, for example, methyl, ethyl, n-methyl,

  propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, dodecyl, lauryl, and similar radicals; the term "alkoxy" means an -O-alkyl radical in which the alkyl radical is defined as above; the term "lower alkyl" refers to a straight or branched chain C 1 -C 5 alkyl radical and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso, butyl, sec- butyl, tert-butyl, pentyl, and similar radicals; the term "lower alkoxy" means an O-lower alkyl radical in which the lower alkyl radical is defined as above; the term "acyl" refers to a formyl radical, a C 2 -C 5 alkanoyl radical including, for example, radicals

  acetyl, propionyl, isovaleryl, pivaloyl, pentane

  carbonyl and similar radicals; a C 5 -C 5 cycloalkane carbonyl radical comprising, for example,

  cyclopentylcarbonyl radicals, cyclohexyl-

  carbonyl and similar radicals; an aroyl radical comprising, for example, benzoyl, toluoyl, 2-naphthoyl and similar radicals; or a heterocycle-carbonyl radical including, for example, thenoyl, 3-furoyl, nicotinoyl and similar radicals; the term "acyloxy" refers to an -O-acyl radical in which the acyl radical is defined as above; the term "alkylthio" refers to a -S-alkyl radical in which the alkyl radical is defined as above; the term "alkenyl" refers to a C 2 -C 10 alkenyl radical and includes, for example, vinyl, allyl, isopropenyl, 2-pentenyl, butenyl and similar radicals; the term "alkynyl" refers to a C 2 -C 10 alkynyl radical and includes, for example, ethynyl, 2propynyl and similar radicals; the term "cycloalkyl" refers to a C 3 -C 7 cycloalkyl radical and

  includes, for example, cyclopropyl, cyclopropyl,

  butyl, cyclopentyl, cyclohexyl, cycloheptyl and similar radicals; the term "alkadienyl" refers to a C 4 -C 10 alkadienyl radical and includes, for example, 1,3-butadienyl, 1,4-hexadienyl and similar radicals; the term "cycloalkenyl" refers to a C 5 -C 7 cycloalkenyl radical and includes, for example, cyclopentenyl, cyclohexenyl and similar radicals; the term "cycloalkadienyl" refers to a C 5 -C 7 cycloalkadienyl radical and includes, for example,

  cyclopentadienyl radicals, cyclohexane

  dienyl and similar radicals; the term "aryl" includes, for example, phenyl, naphthyl, indanyl and similar radicals; the term "aralkyl" includes, for example, benzyl, phenethyl, 4-methylbenzyl, naphthylmethyl and similar radicals; the term "heterocyclic radical" means

  a heterocyclic radical containing at least one hetero

  atom selected from oxygen, nitrogen and sulfur and includes, for example, furyl, thienyl,

  pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, iso-

  thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxa-

  diazolyl, thiatriazolyl, oxatriazolyl, triazolyl,

  Tetrazolyl, pyridyl, 4- (5-methyl-2-pyrrolinyl), 4-

  (2-pyrrolinyl), N-methylpiperidinyl, quinolyl,

  phenazinyl, 1,3-benzodioxalanyl, benzofuryl, benzo

  thienyl, benzoxazolyl, benzothiazolyl, phthalidyl, coumarinyl and similar radicals; the term "heterocyclic alkyl" denotes a radical composed of the heterocyclic radical defined above and the alkyl radical defined above; and the term "halogen atom" includes, for example, fluorine, chlorine, bromine and iodine atoms.

  In the formulas of this description, the

  symbol R 1 represents a hydrogen atom or a group protecting the carboxyl function, and the protective group for the carboxyl function comprises those conventionally used in the penicillin and cephalosporin domains, for example a forming group an ester which can be removed by catalytic hydrogenation, chemical reduction, or treatment under other mild conditions; an ester-forming group that can be easily removed in a living body; or an organosilyl radical, an organophosphorus radical, or an organotin radical, or a similar radical, which can be easily removed by treatment with water or with an alcohol; as well as

  various other well-known ester-forming groups.

  Among these protective groups, the following are preferred: (a) alkyl radicals, for example a C 1 -C alkyl radical, (b) substituted lower alkyl radicals in which at least one of the substituents is a halogen atom, a

  nitro group, or an alkyl, alkoxy, oxo, cyano radical,

  hydroxyl, cycloalkyl, aryl, alkylthio, alkylsulfinyl,

  alkylsulfonyl, alkoxycarbonyl, 5-alkyl-2-oxo-1,3-

  dioxol-4-yl, 1-indanyl, 2-indanyl, furyl, pyridyl, 4-imidazolyl, phthalimido, succinimido, azetidino, aziridino, pyrrolidino, piperidino, morpholino, thiomorpholino, N-lower alkylpiperazino, pyrrolyl, pyrazolyl, thiazolyl , isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiatriazolyl, oxatriazolyl, triazolyl,

  tetrazolyl, quinolyl, phenazinyl, benzofuryl, benzo

  thienyl, benzoxazolyl, benzothiazolyl, coumarinyl, 2,5-

  dimethylpyrrolidino, 1,4,5,6-tetrahydropyrimidinyl, 4-

  methylpiperidino, 2,6-dimethylpiperidino, 4- (5-methyl)

  2-pyrrolinyl), 4- (2-pyrrolinyl), N-methylpiperidinyl, 1,3-benzodioxolanyl, alkylamino, dialkylamino, acyloxy,

  acylthio, acylamino, dialkylaminocarbonyl, alkoxycarbonyl-

  amino, alkenyloxy, aryloxy, aralkyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycleoxy, alkoxycarbonyloxy,

  alkenyloxycarbonyloxy, aryloxycarbonyloxy, aralkyl-

  oxycarbonyloxy, heterocycle-oxycarbonyloxy, alkenyloxycarbonyl,

  aryloxycarbonyl, aralkyloxycarbonyl, cycloalkyloxy-

  carbonyl, cycloalkenyloxycarbonyl, heterocyclic oxy

  carbonyl or alkylanilino, or an alkyl radical

  anilino substituted with a halogen atom, a lower alkyl radical or a lower alkoxy radical, (c) a cycloalkyl radical; a cycloalkyl radical substituted by a lower alkyl radical; or a (2,2-di-lower alkyl-1,3-dioxol-4-yl) methyl radical, (d) alkenyl radicals, (e) alkynyl radicals, (f) phenyl radical; a substituted phenyl radical of which at least one of the substituents is selected from those specifically listed in (b) above; or aryl radicals such as those represented by the formula: wherein -Y is -CH = CH-O-, -CH = CH-S-,

  -CH 2 CH 2 S-, -CH = N-CH = N-, -CH = CH-CH = CH-, -CO-CH = CH-CO-,

  or -CO-CO-CH = CH-, or a substituted derivative of these radicals, whose substituents are chosen from those which have been expressly listed in paragraph (b) above, or the aryl radicals represented by the wherein: Y 2 _ is a lower alkylene group such as - (CH 2) 3 or - (CH 2) 4-, or a substituted derivative thereof, the substituents of which are selected from those which have been (g) aralkyl radicals such as optionally substituted benzyl radicals, the substituents of which are selected from those specifically listed in paragraph (b) ) the optionally substituted heterocyclic radicals of which at least one of the substituents is selected from those expressly listed in paragraph (b) above, (i) the optionally substituted indanyl or phthalidyl radicals, the substituents of which are methyl radicals or halogen atoms; optionally substituted tetrahydronaphthyl radicals, the substituents of which are methyl radicals or halogen atoms; trityl, cholesteryl, bicyclol 4,1-decyl and similar radicals, (j) optionally substituted phthalidylidene-lower alkyl radicals, the substituents of which are

  halogen atoms or lower alkyl radicals.

  The above-mentioned carboxyl protecting groups are typical examples, and the carboxyl protecting group may also be selected from the other protecting groups which are described in US Pat. Nos. 3,499,909, 3,573,296 and 3,641,018, and in the German patent applications published under No. 2,301,014,

2,253,287 and 2,337,105.

  Among these protective groups of the function

  carboxyl, diphenylmethyl radicals are preferred, 5-

  lower alkyl-2-oxo-1,3-dioxol-4-yl-lower alkyl, acyloxyalkyl, acylthioalkyl, phthalidyl, indanyl, phenyl, phthalidylidene-lower alkyl optionally substituted, or radicals which can be easily removed in a living body , such as the radicals represented by the formulas:

21 -COOR 21 -C (H 22

  -CH (CH 2) OR 21, -CHOCOR and CH (CH 2) m COOR 2 in

122 122 123

R R R

  which R 21 represents a known optionally substituted alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic radical; R 2 represents a hydrogen atom or an optionally substituted alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic radical; R 23 represents a hydrogen or halogen atom or a known optionally substituted alkyl, cycloalkyl, aryl or heterocyclic radical, or a radical of formula - (CH 2) n COOR 22 (R 22 has the same meaning as 1 1 above and N is 0, 1 or 2); and m is equal to

0, 1 or 2.

  More specifically, it is possible to use lower alkyl-2-oxo-1,3-dioxol-4-yl-methyl radicals such as the 5-methyl-2-oxo-1,3-dioxol-4yl-methyl radicals, ethyl-2-oxo-1,3-dioxol-4-ylmethyl, 5-propyl-2-oxo-1,3dioxol-4-ylmethyl and similar radicals; of the

  acyloxyalkyl radicals such as acetoxy radicals

  methyl, pivaloyloxymethyl, propionyloxymethyl, butyryl-

  oxymethyl, isobutyryloxymethyl, valeryloxymethyl, 1-

  acetoxyethyl, 1-acetoxy-n-propyl, 1-pivaloyloxy-

  ethyl, 1-pivaloyloxy-n-propyl and similar radicals; acylthioalkyl radicals such as

  acetylthiomethyl, pivaloylthiomethyl, benzoyl-

  thiomethyl, para-chlorobenzoylthiomethyl, 1-acetyl-

  thioethyl, 1-pivaloylthioethyl, 1-benzoylthio-

  ethyl, 1- (p-chlorobenzoylthio) ethyl and similar radicals; alkoxymethyl radicals such as the methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, n-butyloxymethyl and similar radicals; alkoxycarbonyloxyalkyl radicals such as

  the methoxycarbonyloxymethyl, ethoxycarbonyl-

  oxymethyl, propoxycarbonyloxymethyl, isopropoxy

  carbonyloxymethyl, n-butoxycarbonyloxymethyl, tert-

  butoxycarbonyloxymethyl, 1-methoxycarbonyloxyethyl, 1-

  ethoxycarbonyloxyethyl, 1-propoxycarbonyloxyethyl,

  1-isopropoxycarbonyloxyethyl, 1-tert-butoxycarbonyl-

  oxyethyl, 1-n-butoxycarbonyloxyethyl and similar radicals; alkoxycarbonylmethyl radicals such

  that the methoxycarbonylmethyl, ethoxycarbonyl-

  methyl and similar radicals; the phthalidyl radical; the indanyl radical; the phenyl radical; phthalidylidenealkyl radicals such as 2- (phthalidylidene) ethyl, 2- (5-fluorophthalidylidene) ethyl radicals,

  2- (6-chlorophthalidylidene) ethyl, 2- (6-methoxy)

  (phthalidylidene) ethyl and similar radicals; etc. R 2 represents a radical of formula:

R 8 3

  O R 7 R R 10 O il R 1 R 7 R -N N-R, I u

N-N A R 9 N 12 -N R 15

  in which R 6 represents a hydrogen atom, a hydroxyl, nitro, carbamoyl, thiocarbamoyl or sulphamoyl group, or an alkyl, alkenyl, alkynyl, alkadienyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl, aralkyl or acyl radical, alkoxy, alkylthio, acyloxy,

  cycloalkyloxy, aryloxy, alkoxycarbonyl, cycloalkyl-

  oxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl,

  heterocycle-sulfonyl, alkylcarbamoyl, dialkyl-

  carbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl,

  acylcarbamoyl, acylthiocarbamoyl, alkylsulfonyl-

  carbamoyl, arylsulfonylcarbamoyl, alkylsulphonylthio-

  carbamoyl, arylsulfonylthiocarbamoyl, alkylsulfamoyl, dialkylsulphamoyl, alkoxythiocarbonyl, alkylideneamino,

  cycloalkylmethyleneamino, arylmethyleneamino, hetero-

  ring-methyleneamino or heterocyclic ring, optionally substituted; a group of formula R

-NOT

R 17

R 16 17

  (each of R 16 and R 17 which may be the same or different, represents a hydrogen atom or an alkyl radical, or R 16 and R 17 form a ring with the nitrogen atom which is adjacent thereto); each of the substituents R 1, R 5, R 7, R 12 R 14 and R 15, which may be the same or different, represents a hydrogen or halogen atom or an optionally substituted alkyl, aralkyl or aryl radical; R 13 represents a hydrogen or halogen atom, a carboxyl, sulfo, carbamoyl or thiocarbamoyl group, or an alkyl radical,

  aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxy-

  carbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocycle-sulfonyl, alkylcarbamoyl,

  dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthio-

  carbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkyl

  sulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyl

  sulfonylthiocarbamoyl or arylsulphonylthiocarbamoyl, possibly

  Substituted in each of the definitions mentioned for R and R 13

  above, the term "cycloalkyloxy" refers to a radical -O-

  cycloalkyl, the term "aryloxy" refers to a radical -O-

  aryl, the term "alkoxycarbonyl" refers to a -C-O-alkyl radical, the term "cycloalkyloxycarbonyl" refers to a -C-O-cycloalkyl radical, the term "acyloxycarbonyl"

  denotes a -C-O-acyl radical, the term "aralkyloxy-

I

O

  "carbonyl" denotes a -C-O-aralkyl radical, the term "alkylsulfonyl" denotes a -SO 2 -alkyl radical, the

  "cycloalkylsulfonyl" means a radical -SO 2 -cyclo

  alkyl, the term "arylsulfonyl" refers to a radical -SO 2-

  aryl, the term heterocycle-sulfonyl "refers to -502-heterocycle, the term" alkylcarbamoyl "refers to a -C-NH-alkyl radical, the term" dialkylcarbamoyl "refers to a radical of formula alkyl _CNX -CN / lix O alkyl term "alkylthiocarbamoyl" refers to a radical of the formula -C-NHalkyl, the term "dialkylthiocarbamoyl" wherein alkyl denotes a radical of the formula -CN, the term "alkyl" acylcarbamoyl "denotes a radical of the formula -C-NH-acyl, the term "acylthiocarbamoyl" denotes a radical of formula -C-NH-acyl, the term "alkylsulfonylcarbamoyl" denotes an II S

  radical of the formula -C-NH-SO 2 -alkyl, the term "aryl-

g

  sulfonylcarbamoyl "denotes a radical of formula -C-NH-SO 2

  As used herein, the term "alkylsulfonylthiocarbamoyl" refers to

  radical of the formula -C-NH-SO 2 -alkyl, the term "aryl-

  "Sulfonylthiocarbamoyl" refers to a radical of the formula -j-NH-SO 2aryl, the term "alkylsulfamoyl" refers to an S

  radical of formula -502-NH-alkyl, the term "dialkyl-

  sulfamoyl "denotes a radical of alkyl formula

-502-N '

  the term "alkoxythiocarbonyl" refers to a radical of formula -C-Oalkyl, the term "alkylideneamino" refers to an II S

  radical of formula -N = CH-alkyl, the term "cycloalkyl-

  methyleneamino "denotes a radical of formula -N = CH-cyclo-

  alkyl, the term "arylmethyleneamino" refers to a radical

  of the formula -N = CH-aryl, and the term "heterocycle-

  methyleneamino "refers to -N = CH-heterocycle.

  R 16 Radicals of formula -N R 17

16 1 R

  in which R 16 and R 17 have the same definitions as above include the amino group, the alkylamino groups represented by the formula -NH-alkyl, the dialkylamino alkyl groups represented by the formula -N alkyl and the radicals represented by the formulas -N -NO, -N NH, -N N -alkyl, N -NO, -O, -NS, -N SO 2, -NQ, N or / N = N

-N |.

  The substituents of the various radicals mentioned above include the halogen atoms, the alkyl, aralkyl, aryl or alkenyl radicals, the group

  hydroxyl group, the oxo group, the alkoxy or alkyl-

  thio, nitro, cyano or amino groups, acyl or acyloxy groups, carboxyl, carbamoyl, sulfo or sulphamoyl groups, alkylamino groups represented by the formula -NH-alkyl, dialkylamino alkyl groups represented by the formula -N alkyl acylamino radicals represented by the formula -NH-acyl, alkoxycarbonyl radicals represented by the formula -CO-alkyl, acylalkyl radicals, such as acetylmethyl, propionylmethyl radicals and similar radicals, aminoalkyl radicals such as aminomethyl, aminoethyl radicals; and similar radicals,

  N-alkylaminoalkyl radicals such as N-radicals

  methylaminomethyl, N-methylaminoethyl and similar radicals, N, N-dialkylaminoalkyl radicals such as

  the radicals N, N-dimethylaminomethyl, N, N-dimethylamino-

  ethyl and similar radicals, hydroxyl radicals

  alkyl radicals such as hydroxymethyl radicals, hydroxyl

  ethyl and similar radicals, hydroxyl radicals

  iminoalkyl radicals such as hydroxyiminomethyl, hydroxyiminoethyl radicals and similar radicals,

  alkoxyalkyl radicals such as methoxy radicals

  methyl, methoxyethyl, ethoxymethyl, ethoxyethyl and similar radicals, carboxyalkyl radicals such as carboxymethyl radicals, carboxyethyl and similar radicals, alkoxycarbonylalkyl radicals such as

  methoxycarbonylmethyl radicals, methoxycarbonyl-

  ethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl and

  similar radicals, aralkyloxycarbonyl radicals

  alkyl such as benzyloxycarbonylmethyl, benzyloxycarbonylethyl and similar radicals, sulfoalkyl radicals such as sulfomethyl, sulfoethyl and similar radicals, sulfamoylalkyl radicals such as sulfamoylmethyl radicals, sulfamoylethyl and similar radicals, carbamoylalkyl radicals such as radicals carbamoylmethyl, carbamoylethyl

  and similar radicals, carbamoyl radicals

  alkenyl such as the carbamoylallyl radical and

  similar radicals, N-hydroxycarbamoyl-

  alkyl radicals such as N-hydroxycarbamoylmethyl, N-hydroxycarbamoylethyl radicals and similar radicals, a radical of formula C = C-R 24 in which R 24 I \ o o

O

  represents the lower alkyl radical, etc. The various groups mentioned above in the definitions of R 6, R 7, R 8, R 9 R, R, R, RR, R, R 3, R 14 and R 15 are optionally substituted. by at least one of the abovementioned substituents Of the above substituents, the hydroxyl, amino and carboxyl groups are optionally protected by a suitable protecting group ordinarily known in the art. The hydroxyl protecting groups include all those which can be used habitually, such as easily removable acyl radicals, for example benzyloxycarbonyl radicals,

  4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-

  methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxy-

  carbonyl, 4- (phenylazo) benzyloxycarbonyl, 4- (4-

  methoxyphenylazo) benzyloxycarbonyl, tert-butoxycarbonyl,

  1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, diphenyl-

  methoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-

  tribromethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyl-

  oxycarbonyl, 1-cyclopropylethoxycarbonyl, 8 quinol-

  eiloxycarbonyl, formyl, acetyl, chloroacetyl, benzoyl, trifluoroacetyl and similar radicals; alkylsulfonyl radicals, for example methanesulfonyl, ethanesulfonyl and similar radicals; arylsulfonyl radicals, for example phenylsulfonyl, toluenesulfonyl and similar radicals; the benzyl radical; The radical

  diphenylmethyl; the trityl radical; the methoxy radical

  methyl; the tetrahydropyranyl radical; the tetrahydrofuranyl radical; leradical 2-nitrophenylthio; the 2,4-dinitrophenylthio radical; and similar radicals. In addition, the protecting groups of the amino function include all those which are usually usable, such as acyl radicals.

  easily removable, for example the radicals 2,2,2-tri-

  chlorethoxycarbonyl, 2,2,2-tribromethoxycarbonyl,

  benzyloxycarbonyl, para-toluenesulfonyl, 4-nitrobenzyl-

  oxycarbonyl, 2-bromobenzyloxycarbonyl, acetyl, (mono-, di-, tri) chloroacetyl, trifluoroacetyl, formyl,

  tert-amyloxycarbonyl, tert-butoxycarbonyl, 4-methoxy-

  benzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,

  4- (phenylazo) benzyloxycarbonyl, 4- (4-methoxyphenyl)

  azo) benzyloxycarbonyl, pyridine-1-oxide-2-yl-methoxy-

  carbonyl, 2-furyloxycarbonyl, diphenylmethoxycarbonyl,

  1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 1-

  cyclopropylethoxycarbonyl, phthaloyl, succinyl, 1-

  adamantyloxycarbonyl, 8-quinolyloxycarbonyl and similar radicals; other radicals easily

  eliminable, for example trityl radicals, ortho-

  nitrophenylsulfonyl, 2,4-dinitrophenylthio, 2-hydroxy-

  benzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-

  1-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, 1-

  methoxycarbonyl-2-propylidene, 1-ethoxycarbonyl-2-

  propylidene, 3-ethoxycarbonyl-2-butylidene, 1-acetyl-

  2-propylidene, 1-benzoyl-2-propylidene, 1-N- (2-methoxy)

  phenyl) carbamoyll-2-propylidene, 1-lN- (4-methoxyphenyl) -

  carbamoyll-2-propylidene, 2-ethoxycarbonylcyclo

  hexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetyl-

  cyclohexylidene, 3,3-dimethyl-5-oxo-cyclohexylidene, 4-nitrofurfurylidine and similar radicals; a di or tri-alkylsilyl radical; and similar radicals. Finally, the protective groups of the carboxyl function include all the protective groups of the carboxyl function which are usually usable, and there are cases where the carboxyl function is protected by a group such as the methyl, ethyl or n-propyl radical. isopropyl, tert-butyl, n-butyl, benzyl,

Diphenylmethyl, trityl, 4-nitrobenzyl, 4-methoxy-

  benzyl, benzoylmethyl, acetylmethyl, 4-nitrobenzoyl

  methyl, para-bromobenzoylmethyl, 4-methanesulfonyl-

  benzoylmethyl, phthalimidomethyl, 2,2,2-trichloroethyl,

  1,1-dimethyl-2-propenyl, 1,1-dimethylpropyl, acetoxy-

  methyl, propionyloxymethyl, pivaloyloxymethyl, 3-methyl-

  3-butynyl, succinimidomethyl, 1-cyclopropylethyl, methyl

  thiomethyl, phenylthiomethyl, dimethylaminomethyl,

  quinoline-1-oxide-2-yl-methyl, pyridine-1-oxide-2

  N-methyl, bis (para-methoxyphenyl) methyl and similar radicals, where the carboxyl function is protected by a metalloid compound such as titanium tetrachloride, and where the carboxyl function is

  protected by a silylated compound such as dimethylchloro-

  silane, as described in Japanese Patent Application Publication No. 1073/71 and in the application for

  Dutch patent published under N 7105259.

  R 5 represents a hydrogen atom or an optionally protected amino group, and the protective groups of the amino group comprise numerous radicals commonly used in the penicillin and cephalosporin field, in particular all the amino protecting groups which have been

  mentioned above in the definition of R 2.

  A represents a group of formula -CH-, or -C- well a group of formula N wherein R 18 OR 18 represents a hydrogen atom; an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl or heterocyclic radical, optionally substituted, or a group protecting the hydroxyl function, or a group

O R 19

  II -, 19 of formula -P (each of R 19 and R 20, which may be the same or different, represents a hydroxyl group or an alkyl, aralkyl, aryl, alkoxy, aralkyloxy or aryloxy radical), and the link "means that the compound may be a syn isomer or an anti isomer or a mixture of both. Said hydroxyl protecting group comprises the hydroxyl protecting groups which have been mentioned in the definition of R 2. the various radicals which have been mentioned above in the definition of R 18 are optionally substituted by at least one substituent chosen from halogen atoms, oxo, cyano and hydroxyl groups, alkoxy radicals, groups

  amino, alkylamino and dialkylamino radicals,

  cyclic radicals, and the radicals of formula: ## STR2 ## 25 and ## STR12 ##

NR 26 '

R 21 R 27 'O 26

  which R 1 has the same definition as above and each of the substituents R 25, R 26 and R 27, which may be identical or different, represents a hydrogen atom or an alkyl, aralkyl or aryl radical. Among these substituents, the hydroxyl, amino and carboxyl groups are optionally protected, respectively, by one of the hydroxyl protecting groups and the amino protecting groups which have been mentioned above in the definition of R 2, and by the protective group of the carboxyl function that was

  mentioned above in the definition of R 1.

C-

  The oximes of formula N include the ORs 18

  syn and anti isomers and mixtures thereof.

  N In the group of formula R t R as it appears in all formulas of the

  present description, there are tautomers represented

  by the following equilibrium formulas, where R is an optionally protected amino group, and these tautomers form part of the present invention. HRTR 5 has Rt formulas wherein R and R have the same definitions as above and R represents an optionally imino group protected In the preceding formulas, the protective group of the imino function which is designated R 5a comprises the groups used in the field of penicillins and cephalosporins, and in particular the monovalent groups forming part of the protective groups of the amino function which have mentioned above in the definition of R When the group of formula -CH 2 of formula (I) is a group of formula oo 10 R 1

-4 R -N

  -CH 6 N-R or -CH 2 -NN-R or -CH 2 -N 12 in which R

R

  R 1, R 2 and R 3 have the same definitions as above, there are tautomers represented by the following equilibrium formulas when each of the substituents R 6 and R 10 is a hydrogen atom, and these tautomers also part d, the present inrention:

0 O O OH

-CH -N NH -CH

0 O H

R R

HNI N

C-CHC 2-N 12H 2 N

2R R 12

O O

  The salts of the compounds of formula (I) include the salts at the basic group and the acid group which are well known in the field of penicillins and cephalosporins. The salts at the basic group comprising salts formed with mineral acids such as hydrochloric acid, nitric acid, sulfuric acid and similar acids; salts formed with organic carboxylic acids such as oxalic acid, succinic acid, formic acid, trichloroacetic acid, trifluoroacetic acid and the like acids; and the salts formed with sulphonic acids such as methanesulfonic acid, ethanesulphonic acid, benzenesulphonic acid, toluene-2-sulphonic acid,

  toluene-4-sulphonic acid, mesitylene

  sulfonic acid (2,4,6-trimethylbenzenesulfonic acid), naphthalenesulfonic acid, naphthalene-2-sulphonic acid,

  phenylmethanesulphonic acid, benzene-1,3-

  disulfonic acid, toluene-3,5-disulfonic acid, acid

  naphthalene-1,5-disulfonic acid, 2,6-naphthalene

  disulfonic acid, naphthalene-2,7-disulfonic acid, acid

  benzene-1,3,5-trisulfonic acid, 1,2,4-benzene

  trisulfonic acid, naphthalene-1,3,5-trisulfonic acid and the like acids The acid level salts include

  salts formed with alkali metals such as -

  sodium, potassium and similar alkali metals; salts formed with alkaline earth metals such

  calcium, magnesium and alkaline earth metals

  similar earthy; ammonium salts; and salts formed with nitrogenous organic bases such as

  procaine, dibenzylamine, N-benzyl-e-phenethyl

  amine, 1-epheniramine, N, N-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridyne, N, N-dimethylaniline, N-methylpiperidine,

  N-methylmorpholine, diethylamine, dicyclo

  hexylamine and similar amines.

  The present invention also encompasses all optical isomers and racemic compounds of the cephalosporins of formula (I) and their salts, as well as all crystalline forms and hydrates of said compounds. More specifically, preferred examples of the compounds represented by the formula (I) are the oximes in the formula of which A is a group of the formula _C-II N, in particular their syn isomers, R 18 being

OR 18

  preferably an alkyl radical, especially a methyl or ethyl radical, or a substituted alkyl radical, in particular a radical of formula -CH 2 COOR or CH

  -C-COOR 1 (R 1 has the same definition as above).

  Preferred examples of R 2 are radicals of the formula -N N-R in which R is a hydrogen atom, an optionally substituted alkyl radical, or a radical of formula

24 2536074

R 16

16 17

  -N (R 6 and R 17 have the same definitions as above

R 7 R 8

  above); radicals of formula -> N in -N R 9 in which each of the substituents R 7, R 8 and R 9, which may be identical or different, represents a hydrogen atom or an alkyl radical; radicals of formula R 10 i

1 O

  Wherein each of the substituents -R 10 12 R 10, R 11 and R 12, which may be the same or different, represents a hydrogen or halogen atom or an alkyl radical; and radicals of formula

R 14

  Wherein each of the substituents R 13, R 14

-N 5 R 1

  and R 15, which may be the same or different,

  represents a hydrogen atom or an alkyl radical.

  The pharmacological effects exhibited by certain standard compounds will now be described.

represented by formula (I).

  1) Antibacterial activity (Table 1) According to the standardized method of the Japan Society of Chemotherapy CHEMOTHERAPY, Vol 23, pp 1-2 (1975) 1, a bacterial solution, obtained by cultivating an infusion broth, was inoculated. of heart (made by Eiken Kagaku) at 37 C for 20 hours, in a drug-containing heart infusion agar, and cultured at 37C for 20 hours, after which growth of the bacteria was observed to determine the minimum inhibitory concentration (MIC) (in pig / ml) for which bacterial growth was inhibited The number of inoculated bacteria was 104 cells per plate (106 cells per ml) The MIC values of the following test compounds were shown in Table i below

  (A) Trifluoroacetic acid salt of the acid 7-

  2 (2-aminothiazol-4-yl) -2 (syn) -methoxyiminoacetamidol

  3- {1- (2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl} -

At 3 _cephemn-4-carboxylic -

  (B) Trifluoroacetic acid salt of the acid 7-

  1 (2-anminothiazol-4-yl) -2 (syn) -methoxyiminoacetamido

  3- {1- (4-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)-

  methyll} to 3-cephem-4-carboxylic acid,

  (C) Trifluoroacetic acid salt of the acid 7

  1 (2-Aminothiazol-4-yl) -2 (syn) -methoxyiminoacetamido I-

  3- {1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) I-

  methyl-3-phenre-4-carboxylic acid,

  (D) Trifluoroacetic Acid Salt of Acid 7-

  2- (2-Aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamidol

  3- {1- (4-Isopropyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) -1-

  Methyl-3-phenre-4-carboxylic acid,

  (E) Acid trifluoroacetic acid salt 7-

  2- (2-Aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamidol

  3- {1- (4-Dimethylamino-2,3-dioxo-1,2,4,4-tetrahydro-

  pyrazinyl) Imethyl} -A 3 -cephem-4-carboxylic acid,

  (F) 7-1-2- (2-Aminothiazol-4-yl) 2- (syn) -

  carboxymethoxyiminoacetamidol-3- {1- (2,3-1,2,3-dioxo)

  Tetrahydropyrazinylmethyl] -A3-cephem-4-carboxylic acid,

  (G) Trifluoroacetic acid salt of the acid 7-

  1 (2-Aminothiazol-4-yl) -2 (syn) -carboxymethoxyimino

  acetamidol-3 {1 - (4-methyl-2,3-dioxo-1,2,3,4-tetrahydro-pyrazinyl) -1-methyl-3-ephem-4-carboxylic acid,

  (H) Trifluoroacetic acid salt of the acid 7-

  1 (2-Aminothiazol-4-yl) -2 (syn) -carboxymethoxyimino

  acetamidol-3- {11- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydro)

  pyrazinyl) Imethyl I-A 3 -cephem-4-carboxylic acid,

  (I) Trifluoroacetic Acid Salt of Acid 7-

  1 (2-Aminothiazol-4-y) -2 (syn) -carboxymethoxyimino

  acetamidol-3- {1- (4-dimethyl) -2-dihydro-2,3-dioxo-1,2,3,4

  tetrahydropyrazinyl) 1-methyl-3-cephemri-4-carboxylic acid, (J) trifluoroacetic acid salt of 7-l 2- (2-

  aminothiazol-4-yl) -2 (syn) -methoxyiminoacetamnido I 3-

  1- (2-Oxo-1,2-dihydro-di-n-yl) -methyl} 3-cephem-4-

carboxylicque,

  (K) Trifluoroacetic acid salt of 7-112- (2-

  aminothiazol-4-yl) -2 (syn) -methoxyiminoacetamidol-3-

  1- (3,6-dioxo-1,2,3,6-tetrahydropyridazinyl) lm

At 3 _chemph-4-carboxylic,

  (L) 7-I 2- (2-amino) formic acid salt of

  thiazol-4-yl) 2 (syn) -carboxymethoxyiminoacetamidol

  3- {1- (3,6-dioxo-1,2,3,6-tetrahydropyridazinyl) methylmethyl)

With 3-cephem-4-carboxylic acid,

  (M) Acid trifluoroacetic acid salt 7-

  1-2 (2-Aminothiazol-4-yl) -2 (syn) -methoxyiminoacetamido;

  3- {1 (3-methyl-6-oxo-1,6-dihydropyridazinyl) methyl}

A 3-cephemn-4-carboxylic acid, and

  (N) Formic acid salt of 7-112- (2-amino)

  thiazol-4-yl) -2 (syn) -carboxymethoxyiminoacetamido

  3-[1 (3-methyl-6-oxo-1,6-dihydropyridazinyl) methyl] -

at 3-ephem-4-carboxylic acid.

1 C D E F G H

é A B

Organization j-C O mpos

"1: 500

  E. coli NIHJ: 50, 1 μg, 1: 5 o, 1 E. coli TK: 50 ° -3 °: 50, 150: 50, 1 Op 2, 50, 1: 50110, 2 Ki pneumoniae Y-50: 50 J 15 o? 15011: 01? 1 9 o 1o'l Oj 2 O r 2 0.2 0.1

39; 50.1

  Ki pneumoniae Y-41 011 O l 5 o'i; 50%, 1%, 50% 1, 50%, 1%, 50%, 0.39%, 50%, 1%, 50%, 0.39% W-134; 50, 1: 50, 1: ## EQU1 ## 50.1 w'1: 50.1 0.39 Ser marcescens IID 620: 50, 1; 50, 1: 50.1: 50.1 1; 50, 1; 5 1: 5011 1: 9011 ProMrganii T-216; 50, 1: 50, 1, 50, 1; : 5011 <- 011 <-o'l Pr o mirabilis T-111 <07 1: 50,1: 50, 1 0,2,: 5011; io, 1 Éo'l: of 1 5 op 1 0,2 Pro vulgaris GN 76 ** 0, 39 1.56, W 1, 50.1 - <Ol <- o'l O 78

1 Y 1

  Cit freundii N-7 0.31; 56 0.78 1156 0.78 0.78 1156 1,, 56 1.56 0.78

  Ps aeruginosa, -GN 918 ** Li 2.5 1 25 6, F 25 6125 12.5 -

TALBEAU 1

  Anti-bacterial activity CIM (pg / ml) p-J M LM w

0% 1

C> 1

at 1 -ON K L m N, 1 Aloi O ,, l '50, 1

0,, 2 0.78 0.2 0.2

/ 1 0.78 Gold 2 0.39

O 1 O 1 0.78 1

: 50 ', 1 1, 56 012: 90, 1

  : 5011; 501 1 O? ## EQU1 ## Figure 1 (continued) Note: * Penicillinase producing strain ** Cephalosporinase producing strain m Ln L 4 l 0% t C>, at, 2) Urinary recovery A test compound was administered orally to mice (ICR, males, 4 weeks old) at a dose of 1 mg / mouse and the urinary recovery was determined. The results obtained are given in Table

2 below.

  In the test compounds N O 1 and N O 2,

  ester group is easily removed in a living body, so that the compounds are transformed into

  the corresponding free carboxylic acids Par-

  therefore, urinary recovery was determined by quantitatively measuring free carboxylic acids

excreted in the urine.

  Method of administration: a test compound suspended in the oral route was administered

  carboxymethylcellulose (CMC) at 0.5%.

  Quantitative measurement method: the amount of free carboxylic acid was measured by bioassay (paper disc method) using the organism

  test mentioned in Table 2 below.

TABLE 2

H N I Nr-F

CH R 2

  (isomer-syn) Compose Organism Recuperated Urine Assay * No R 15 R1 R 2 (% eN Kl u pneumonia 15,9 1, # 6 1 CH 3 -CH 2 OCOC (CH 3) 3 Nr ATCC 10031 O 2 -CH 3 -CH 2 OCOC <CH 3> 3 "i 20, # 4 3,7 3 -CH 2 COOH -H tu 10 4 1,1

  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

  Note * at 6 o'clock, a group of 5 mice (statistical mean and standard) wc: r 4> U 4 3) Acute toxicity The mean lethal doses (LD 50) of the following test compounds were 3 g / kg or more when the compounds were administered to mice intravenously (ICR mice, males, body weight

at 24 g).

Test compounds:

  7-1- (2-Aminothiazol-4-yl) -2- (syn) -methoxy-

  iminoacetamido l-3- {1- (2,3-dioxo-1,2,3,4-tetrahydro)

  sodium pyrazinyl) methyl-3-cephem-4-carboxylate,

  7- [2- (2-Aminothiazol-4-yl) -2- (syn) methoxy]

  iminoacetamidol-3- {t 1- (4-methyl-2,3-dioxo-1,2,3,4-

  sodium tetrahydropyrazinyl) methyl-3-cephem-4-carboxylate,

  7-1- (2-Aminothiazol-4-yl) -2- (syn> methoxy)

  iminoacetamidol-3- {1- (3,6-dioxo-1,2,3,6-tetrahydro)

  sodium pyridazinylmethyl} -A 3-cephem-4-carboxylate, and

  7- [2- (2-Aminothiazol-4-yl) -2- (syn) methoxy]

  iminoacetamidol-3- {1- (3-methyl-6-oxo-1,6-dihydro)

  sodium pyridazinyl) methyl-3-cephem-4-carboxylate.

  We will now explain and describe the

  processes for the preparation of the compounds according to the invention.

  The compounds according to the present invention can be prepared by the following processes: Preparation route No. 1 R 3

R 28 Z

N CH R 29

o 2 or salt of it l "Jl

N A-COOH

  RL IVl or salt or reactive derivative of that ri I 1 (acylation) R 3 s R Rf 4JI CH 2 R 2

COOR 1

or salt of it

or salt of it

  Ci (tranxsformation on position 3) C 2 OHCO ousel or derivative i thereof R O

1 ZCH R 2

o 2

COOR 3-

lVIl -active R 3

XCH 2 COCH 2 CONH

  Lion): e: 4-N% CH R 2 Pr TY COOR 1 o; u Salt thereof (IVl or salt thereof or txi 1 derivative reactive to the same amino group thereof

(nitrosamine

(to be continued)

H NCR '

2 i s lXIIl <cycl isation) V R 3

N CH 2 CON S

R _ // _r 1 CHR 2

S O N 2

COOR 1

  llal or salt thereof lw N ", Ln LM 0% Q RI -% nt Route of Preparation No. 1 (continued)

XCH 2 COCCOOH

  Acylati, salt, or active derivative thereof

CH 2 COCCOOH

R 3 L

18 a OR f CH 2 R 2

COOR 1

lIVl

or salt of it

  ci, or a reactive derivative having a non-reactive derivative thereof or a salt, or a reactive derivative thereof (acylation)

R 5 N COCO (

XCH 2 COCCONH

  N o on) The salt of it (<4therification Iltion)

H NC 1 E

It's

XCH 2 CQCCONH

  N o LR 18) Ho lxiiia or salt, or reactive derivative of acylation

CH 2 R 2

eOOR 1

  lX Itl u sel of it R 3 this one i

N COCONH

R 5 2

COOR 1

lXIVl (cyclization.

=== R 5-

H NCR 5

2 i s lXIIl R 3 r CH

COOR 1

  XVI (cyclization) or a salt thereof loximination) NR 18 or salt thereof Ln Ow, o 'or salt thereof r E -r r%. 1 CD% O 1 PO LM (M T a q SG lP-IIIl glnw 2 og uq (t, 4 s GlD-ilil alnwao 3 eq (E tl '6 ll Il NH N Lm 8' a / l = -

E-M RH

  9 k <q q q q 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91

(1: E) -40 N

  Route of Preparation No. 2 R 3 R 30-CONH s

N CH 2 X

COOR 1 l lCVIl or salt thereof

(trans-

  on the position HN RIII-al '3) or salt thereof lXVIIl or salt thereof (transformation to 3 _cè'phemr)

* R 30-CONH - '<

CH 2 N \, CHRN lXVIIIl

COOR 1

  or salt thereof (deacylation) V (to follow) i

R 30 _CONH-

R 30 _CONH

  + q Preparation route N 2 (continued) H 2 N lXIXl I 1 COOR or salt thereof

37 2536074

1 2 3 4

  In the above formulas, R, R, R, R, R 67, R 17 R 12 13 14 15

R, R ,, R, R, R ,, R, R, R R

  R, A and binding have the same definitions as above; R 18 a has the same definition as R 18 except that it can not represent a hydrogen atom; R 28 represents an amino group, or a group of R 31 formula / C = C-NH in which each of

R 32 R 33

31 32 33

  substituents R, R and R, which may be the same or different, represents a hydrogen atom or an organic radical not participating in the reaction, or a R 34 group of formula C = N in which each R 35

34 35

  substituents R 34 and R 35, which may be the same or different, represent a hydrogen atom or an organic residue not participating in the reaction; R 29 represents an optionally substituted acyloxy or carbamoyloxy radical; R 30 represents a benzyl radical, phenoxymethyl radical or a radical of formula N

R 5 S> A 4 5

  S R in which R, R and A have the same

R 4

  definitions as above; X represents a halogen atom; > z represents> S or S + O; and the broken line of the cycle represents a double bond between positions 2 and 3

or between positions 3 and 4.

  More detailed explanations will now be given. R 28 represents an amino group, a R 31 group of formula C = C-NH or a group of

R 32 R 33

38 2536074

  R formula / C = N-, the group of formula J R 31 C = C-NH comprising the group of formula

32 '/ 33

R R

  R 31 CH-C = N which is its isomer The remains

32 "I'133

R 32 / R

  organic substances not participating in the reaction that are

1 31 32 33 34 35

  R 3, R 3, R 3, R 3 and R 3 include those which are well known in the art, including aliphatic residues, alicyclic residues, aromatic residues, aromatic-aliphatic residues, heterocyclic residues, residues and the like. acyl and similar residues, optionally substituted More specifically, they include the following residues: (1) aliphatic residues: alkyl radicals; alkenyl radicals, (2) alicyclic radicals: cycloalkyl radicals, cycloalkenyl radicals, (3) aromatic radicals: aryl radicals, (4) aromatic-aliphatic radicals: aralkyl radicals,

  (5) heterocyclic radicals: heterocyclic radicals

  cliques, (6) acyl radicals: acyl radicals which can be derived from organic carboxylic acids including aliphatic carboxylic acids, carboxylic acids

  alicyclic and alicyclic carboxylic acids

  aliphatic; they also include aromatic-aliphatic carboxylic acids, aromaticoxyaliphatic carboxylic acids, aromatic-thioaliphatic carboxylic acids,

39 2536074-

  heterocyclic aliphatic carboxylic acids, heterocyclic oxyaliphatic carboxylic acids, and heterocyclic thioaliphatic carboxylic acids, in which an aromatic radical or a heterocyclic radical is bound, directly or via an oxygen or sulfur atom, to a carboxylic acid aliphatic; organic carboxylic acids in which a remainder

  aromatic radical, an aliphatic radical or a radical

  cyclic is bonded to the carbonyl group via an oxygen, nitrogen or sulfur atom; aromatic carboxylic acids; heterocyclic carboxylic acids; etc. The above aliphatic carboxylic acids include formic acid, acetic acid, propionic acid, butanoic acid, isobutanoic acid, pentanoic acid, methoxyacetic acid, methylthioacetic acid, acrylic, crotonic acid and similar acids; the above alicyclic carboxylic acids include cyclohexanoic acid and similar acids; and the above alicycloaliphatic carboxylic acids include cyclopentaneacetic acid, cyclohexaneacetic acid,

  cyclohexanepropionic acid, cyclohexadiene

  acetic acid, and similar acids.

  On the other hand, the aromatic moieties of the aforementioned organic carboxylic acids include phenyl, naphthyl and similar radicals. Each of the groups constituting these organic carboxylic acids may, in addition, be substituted with a substituent such as a halogen atom, an optionally protected hydroxyl group, or an alkyl, alkoxy or acyl radical, with a nitro group or with an optionally amino group. protected, or by

2536074

  an optionally protected carboxyl group.

  On the other hand, the optionally substituted acyloxy and carbamoyloxy radicals which are designated R 29 include alkanoyloxy radicals such as acetoxy, propionyloxy, butyryloxy radicals and similar radicals; alkenoyloxy radicals such as acryloyloxy radicals and similar radicals; aroyloxy radicals such as benzoyloxy, naphthoyloxy radicals and similar radicals; and the carbamoyloxy radical These groups may be substituted with one or more substituents such as halogen atoms, nitro and amino groups, alkyl, alkoxy, alkylthio, acyloxy, acylamino radicals, hydroxyl groups,

  carboxyl, sulfamoyl, carbamoyl, alkoxy radicals,

  carbonylcarbamoyl, aroylcarbamoyl, alkoxycarbonyl-

  sulfamoyl, aryl, carbamoyloxy, etc. In the abovementioned substituents for R 29, the hydroxyl, amino and carboxyl groups and similar groups may be protected by protective groups which are usually employed, and these protective groups include, in particular, the hydroxyl protecting groups, the protective groups. of the amino function and the protective groups of the carboxyl function which have been

  mentioned above in the definition of R 2.

  (a) Transformation reaction at position 3 An optionally substituted 7-amino-3-methyl substituted cephem carboxylic acid of formula (IV), or a salt thereof, can be prepared in high yield and high purity. using a procedure easy to implement at the scale

  by reacting a 2,3-dioxo-1,2,3,4-

  tetrahydropyrazine of formula (III-a), a 2-oxo-1,2-

  dihydropyrazine of the formula (III-b), a 3,6-dioxo

41 2536074

  1,2,3,6-tetrahydropyridazine of formula (III-c) or a 6-oxo-1,6-dihydropyridazine of formula (III-d), or a salt of the above, with a cephalosporanic acid represented by the formula ( II), or with a salt thereof, in the presence of an acid or a complex compound of an acid, then, if necessary, by eliminating the protecting group, protecting the carboxyl group or by transforming the compound obtained in a salt thereof Par

  elsewhere, 2,3-dioxo-1,2,3,4-tetra-

  hydropyrazine mentioned above by the method described in Journal of Chemical Society, Perkin I, pp 1888-1890

(1975).

  On the other hand, if appropriate, the substituent of the amino group at the 7-position can be removed in a conventional manner to form an unsubstituted 7-amino compound. According to this procedure, non-substituted starting compounds can be used. only 3-cephem compounds but also 2-cephem compounds, and in the case where the 2-cephem compounds are used as starting compounds, the 2-cephem compounds produced by the reaction a new

  transformation into 3-Céphem compounds.

  On the other hand, not only compounds in which> Z is> S, but also compounds in which> Z is> S + O can be used as starting materials, and in the latter case it is possible to convert> S + O in> S during the

  reaction or in a post-treatment step.

  If the 2,3-dioxo-1,2,3,4-tetrahydropyrazine of formula (III-a), the 2-oxo-1,2-dihydropyrazine of formula (III-b), the 3,6-dioxo- 1,2,3,6-tetrahydropyridazine of formula (III-c) or 6-oxo-1,6-dihydropyridazine of formula (III-d) which are used as reactants in the reaction are substituted with basic groups or acids, these may be used, where appropriate,

42 2536074

  compounds in the reaction under the form of salt corlespondanrt.

  In this case, the salts at the basic group and the salts at the acid group include those which have been mentioned as salts of the compounds of formula (I). On the other hand, the salts of the compounds of formulas (II) and (IV) include salts at the basic group and salts at the acid group, and these salts include those which have been mentioned as salts of the compounds of formula (I) The salts of the compounds of formula (II) can either be isolated beforehand, then they can be used, or they can be prepared

in situ.

  Acids or complex compounds of acids used in the reaction include, for example, protonic acids, Lewis acids or complex Lewis acid compounds. Protonic acids include sulfuric acids, sulfonic acids and the like. and super acids (super acids are stronger acids than 100% sulfuric acid, especially some of the above-mentioned sulfuric and sulfonic acids). Specifically, protonic acids include sulfuric acids such as sulfuric acid itself, chlorosulfuric acid, fluorosulfuric acid and similar acids, sulfonic acids such as

  alkyl (mono- or di-) sulphonic compounds such as methane

  sulfonic acid, trifluoromethanesulfonic acid and similar acids, aryl (mono-, di- or tri) sulfonic acids such as para-toluenesulphonic acid and similar acids, superacids such as perchloric acid, magical acid (FSO 3 H-Sb F 5), FSO 3 H-As F 5, CF 3 SO 3 H-Sb F 5,

  HF-BF 3, H 2504-503, and similar acids.

  Lewis acids include, for example, boron trifluoride, and the complex compounds of the acids

  Lewis compounds include complex compounds of

  boron fluoride with dialkyl ethers such as diethyl ether, di-n-propyl ether, di-n-butyl ether and the like ethers; with some

  amines such as ethylamine, n-propylamine, n-propylamine,

  butylamine, triethanolamine and similar amines; with carboxylates such as ethyl formate, ethyl acetate and similar carboxylates; with aliphatic acids such as acetic acid, propionic acid and the like acids; and with nitriles such as acetonitrile, propionitrile and

similar nitriles.

  The reaction is preferably carried out in the presence of an organic solvent. The organic solvents used include any reaction-inert organic solvents, for example nitroalkanes such as nitromethane, nitroethane, nitropropane and nitroalkanes. like; organic carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, dichloroacetic acid, propionic acid and carboxylic acids

  like; ketones such as acetone, methyl-

  ethyl ketone, methyl isobutyl ketone and similar ketones; ethers such as diethyl ether,

  diisopropyl ether, dioxane, tetrahydro-

  furan, ethylene glycol dimethyl ether, anisole, dimethylcellosolve and similar ethers; esters such as ethyl formate, diethyl carbonate, methyl acetate, ethyl acetate, ethyl chloroacetate, butyl acetate and similar esters; nitriles such as acetonitrile, butyronitrile and similar nitriles; and sulfolanes such as sulfolane itself and similar sulfolanes. These solvents can be used in a mixture of two or more. In addition, a complex compound formed from these solvents can be used as solvents.

44 2536074

  It is sufficient if the amount of the acid or the complex compound of the acid used is at least equimolar with respect to the amount of the compound represented by the formula (II) or a salt of this, and can vary this amount depending on the situations In particular, it is preferred to use a proportion of 2 to 10 moles per mole of the compound of formula (II) or a salt thereof. a complex compound of the acid is used, it can be used as such as a solvent, and it can be used in

  mix two or more of the complex compounds.

  It is sufficient that the amount of 2,3-dioxo

  1,2,3,4-tetrahydropyrazine of formula (III-a), of the 2-

  oxo-1,2-dihydropyrazine of formula (III-b), of

  dioxo-1,2,3,6-tetrahydropyridazine of formula (III-c) or of 6-oxo-1,6dihydropyridazine of formula (III-d), or of a salt of the above, being at least equimolar to amount of the compound represented by formula (II) or a salt thereof, and it is preferred to use

  in particular, from 1.0 to 5.0 moles per mole.

  This reaction is usually carried out at a temperature of 0 to 800 ° C., and is terminated in ten minutes to thirty hours. The presence of water in the reaction system may cause undesirable side reactions such as lactonisation of the product or products. starting point, and that a cut of the S-lactam ring, so that it is desirable to maintain the system under anhydrous conditions In order to fulfill this condition, it is sufficient to add to the reaction system a suitable desiccant, for example a phosphorus compound such as phosphorus pentoxide, polyphosphoric acid, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride or a similar compound; an organic silylating agent such as

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  N, O-bis (trimethylsilyl) acetartide, trimethylsilyl

  acetamide, trimethylchlorosilane, dimethyldichloro-

  silane or a similar agent; an organic acid chloride such as acetyl chloride, para-toluenesulfonyl chloride or a similar compound; an acid anhydride such as acetic anhydride, trifluoroacetic anhydride or a similar compound; a mineral desiccant such as anhydrous magnesium sulfate, anhydrous calcium chloride, molecular sieve, calcium carbide or the like. If a compound represented by the formula (II) in which R 1 represents a protecting group for the carboxyl function is used as starting material, it is possible, in certain cases, to obtain directly by this reaction a compound represented by the formula (IV) in which R 1 represents a hydrogen atom, or this compound can be obtained by eliminating the grouping

  protector in a classic way.

  We will now describe the reaction of transformation on position 3 which is described in

the preparation route N 2.

  The halogenated compound represented by the formula (XVI) can be prepared according to the method described in Tetrahedron Letters, N 46, pages 3991-3994 (1974) and

  Tetrahedron Letters No. 40, pages 3915-3918 (1981).

  The compound represented by formula (XVII) or a salt thereof can be prepared by reacting a halogenated compound represented by formula (XVI), or a

  salt thereof, with 2,3-dioxo-1,2,3,4-tetrahydro-

  pyrazine of formula (III-a) or with a salt thereof, in the presence of a base This base may be an alkali metal carbonate (for example sodium carbonate or a similar carbonate); an alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate or similar bicarbonate); an alkali metal hydroxide (for example sodium hydroxide, potassium hydroxide or similar hydroxide); an organic base

  azo, e.g. triethylamine, pyridine, N, N-

  dimethylaniline or a similar base.

  Transformation is generally carried out at the 3-position in a suitable solvent. This solvent may be a halogenated hydrocarbon such as chloroform, methylene chloride or a similar compound; an ether such as tetrahydrofuran, dioxane or a compound

  similar; N, N-dimethylformamide; N, N-dimethyl

  acetamide; acetone; the water; or a mixture of

precedents.

  In this case, the compound represented by the formula (III-a), or a salt thereof, is preferably used in an amount of about 1.0 to 2.0 moles per mole of the compound represented by the formula (XVI) or a salt thereof The reaction is generally conducted at a temperature

  from 0 to 50 C for 30 minutes to 10 hours.

  It can easily be transformed into a compound A 3-

  cephem the mixture of compounds 2 and Z 3-cephem thus obtained, ie a compound represented by the formula (XVII) or a salt thereof, to prepare the compound of formula (XVIII), or a salt of the latter, which is then converted into the compound of formula (XIX), or a salt thereof, by deacylation. Said transformation and deacylation reactions are known in the field of penicillins and cephalosporins and are specifically described in Journal of Organic Chemistry, Vol 35, No. 7, pages 2430-2433 (1970) and "Cephalosporins and Penicillins" (Flynn, Academic).

Press), pp. 56-64.

  If the substituents of 2,3-dioxo-1,2,3,4-

47 2536074

  tetrahydropyrazine of formula (III-a), 2-oxo

  1,2-dihydropyrazine of formula (III-b), 3,6-dioxo

  1,2,3,6-tetrahydropyridazine of formula (III-c), or 6-oxo-1,6dihydropyridazine of formula (III-d), or a salt thereof, which are used as reactants in the reaction, are themselves substituted with a hydroxyl group, amino, carboxyl or the like, these groups may be protected with the aid of the above-mentioned protective groups, before the reaction, and then undergo a conventional elimination reaction after completion. of the reaction to get

the desired compound.

  On the other hand, the carboxyl group of the compound represented by the formula (IV) or (XIX) may, if appropriate, be protected or converted into salt by a conventional method, to give the desired compound Other on the other hand, the compound represented by the formula (IV) wherein R 28 represents an amino group may be converted to a reactive derivative at the amino group or the compound represented by the formula (XIX) as

  mentioned below, by a conventional method.

  (b) Acylation When reacting the compound represented by formula (V), (VI), (VII), (VIII) or (XIII), or a salt thereof, or a reactive derivative thereof ci, with a compound represented by the formula (IV) or with a salt thereof or with a reactive derivative at the amino group, there is obtained a compound represented by the formula

  (I), (IX), (X), (XI) or (XIV), or a salt thereof.

  The salts of the compound represented by the formula (V), (VI), (VII), (VIII) or (XIII) include salts at the basic group and salts at the acid group, which specifically include those which have been mentioned for

  salts of the compound represented by formula (I).

48 2536074

  Reactive derivatives at the amino group of the compound represented by the formula (IV) include any 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 with a carbonyl compound such as an aldehyde, a ketone, or a similar compound (such as ketimine or its isomer, namely enamine type); a silylated derivative, a phosphorus derivative or a tin derivative, produced by the reaction of a compound represented by the formula (IV) or a salt thereof with a silylated compound such as bis (trimethylsilyl) ) acetamide, trimethylsilylacetamide, trimethylsilyl chloride, or a similar compound, a phosphorus compound such as phosphorus trichloride, O \ Pci, O \ Pci, Hpcl, O / CH 3 O / (CH 3) CH 2 O) 2 PC 1, (CH 3 CH 2) 2 P Cl, or a similar compound, or a tin compound

  such as (C 4 H 9) 3 Sn Cl or a similar compound.

  The reactive derivatives of the compounds represented by the formulas (V), (VI), (VII), (VIII) and (XIII) specifically include acid halides, acid anhydrides, mixed acid anhydrides, active acid amides, the active esters, the reactive derivatives obtained by reacting the compounds represented by the formulas (V), (VI), (VII), (VIII) and (IX) with a Vilsmeier reagent. mixed acid may be a mixed acid anhydride formed with a carbonate

  monoalkyl such as mono-ethyl carbonate, mono-

  isobutyl carbonate and similar carbonates, a mixed acid anhydride formed with a lower alkanoic acid optionally substituted with a

  halogen, such as pivalic acid, trichloroacid

  acetic acid or a similar acid The active acid amide comprises

  N-acylsaccharin, N-acylimidazole, N-acyl-

492536074

  benzoylamido, N, N'-dicyclohexyl-N-acylurea, N-

  acylsulfonamide and the like compounds The active ester comprises cyanomethyl ester, substituted phenyl esters, substituted benzyl esters,

  substituted thienyl esters and similar esters.

  The reactive derivatives obtained by reaction with a Vilsmeier reagent include those obtained by reaction with a Vilsmeier reagent itself obtained from

  reacting an acid amide such as N, N-dimethyl-

  formamide, N, N dimethylacetamide or an amide -

  similar with a halogenating agent such as phosgene, thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride,

  phosphorus pentachloride, trichlorinated chloroformate

  methyl, oxalyl chloride or a similar agent.

  If one of the compounds represented by the formulas (V), (VI), (VII), (VIII) and (XIII) is used in the form of a free acid or a salt, a Suitable condensing agent This condensing agent comprises N, N'-disubstituted disarbodiimides such as N, N'dicyclohexylcarbodiimide; azolides such as N, N'thionyldiimidazole; desiccants

  such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydro-

  quinoline, phosphorus oxychloride, alkoxy-

  acetylenes, and the like; salts of 2-

  halopyridinium such as 2-chloropyridinium iodide

  methyl and 2-fluoropyridiniummethyl iodide

and similar agents.

  This acylation reaction is usually carried out in a suitable solvent, in the presence or absence of a base. A solvent which is inert to the reaction, for example a halogenated hydrocarbon such as chloroform, may be used as the solvent. methylene chloride or a similar hydrocarbon; an ether such as tetrahydrofuran, dioxane or an ether

  similar; N, N-dimethylformamide; N, N-dimethyl

  acetamide; acetone; the water; or a mixture of the foregoing A base may be used as a base such as an alkali metal hydroxide, an alkali metal bicarbonate, an alkali metal carbonate, an alkali metal acetate or a similar base; a tertiary amine such as trimethylamine, triethylamine,

  tributylamine, pyridine, N-methylpiperidine, N-

  methylmorpholine, lutidine, collidine or an amine

  similar; or a secondary amine such as dicyclo

  hexylamine, diethylamine or a similar base.

  The compounds represented by the formula (IX), or their salts, which can be converted into the compounds represented by the formulas (Ia) and (Ib) and their salts, can be obtained by the following procedure: To obtain the compound represented by formula (IX) or a salt thereof using the compound represented by formula (IV) or a salt thereof,

  can react a halogenide of 4-halo-3-oxo

  butyryl, which is formed by reacting a diketene with a halogen such as chlorine or bromine. The Journal of the Chemical Society, 97, 1987 (1910) 1, with the compound represented by the formula (IV) or with a salt of this, according to a conventional method. Conditions and procedures which are well known in the art can be used for this reaction. The salt of the compound represented by the formula (IX) can be easily prepared according to a usual method. salt comprising the same salts as mentioned above as salts of the compound represented by the formula (I) Although the compound represented by the formula (IX) or a salt thereof can be isolated and purified, can use it for the

  subsequent reaction without prior isolation.

  Furthermore, the compound represented by formula (V), (VI), (VII), (VIII) or (XIII) or a salt thereof or a reactive derivative thereof, is preferably used in a amount of about 1 mole to several moles per mole of the compound represented by formula (IV), or a salt thereof, or its reactive derivative at the group level

  amino The reaction is usually carried out at a temperature

  50 to + 40 ° C The duration of the reaction is

  usually from 10 minutes to 48 hours.

  Moreover, the compounds represented by the formulas (I), (IX), (X), (XI) and (XIV) in which R is a protective group for the carboxyl function can be converted into the compounds represented by the formulas (I), (IX), (X), (XI) and (XIV) wherein R is a hydrogen atom, or their salts, according to the usual method; and likewise the compounds represented by the general formulas (I), (IX), (X), (XI) and (XIV) in which R 1 is a hydrogen atom can be converted into the compounds represented by the formulas (I), (IX), (X), - (XI) and (XIV) wherein R 1 is a protecting group of the carboxyl function, or salts thereof; and the salts of the compounds represented by the formulas (I), (IX), (X), (XI) and (XIV) can be converted to their corresponding free acids, respectively. On the other hand, in this acylation reaction, if R, R 2 and R 5 contain groups which are active towards the reaction, these groups can be protected, as appropriate, by conventional protective groups, previously to the reaction, and these protecting groups can also be removed by a usual method after

the reaction.

  The compounds which are represented by the formula (I) and their salts according to the present invention, obtained by the aforementioned method, can be isolated

by a conventional method.

  (c) Nitrosation Next, to obtain the compound represented by formula (X) or a salt thereof from the compound represented by formula (IX) or a salt thereof, an agent is reacted with nitrosating with the compound represented by the formula (IX) or with a salt thereof. The reaction is usually carried out in a solvent, and a solvent which is inert to the reaction, such as water, acetic acid, benzene, methanol, ethanol, tetrahydrofuran or a similar solvent Preferred examples of the nitrosating agent include nitric acid and its derivatives, for example nitrosyl halides such as chloride nitrosyl, nitrosyl bromide and similar halides; alkali metal nitrites such as sodium nitrite, potassium nitrite and similar nitrites; alkyl nitrites such as butyl nitrite, pentyl nitrite and similar nitrites If a nitrosating salt is used as the nitrosating agent, it is preferable to carry out the reaction in the presence of an inorganic or organic acid. such as hydrochloric acid, sulfuric acid, formic acid, acetic acid or a similar acid If the nitrosating agent used is an alkyl nitrite, it is preferable to carry out the reaction in the presence of a base such as an alkali metal alcoholate or a similar strong base. The reaction is usually carried out at a temperature of 150 ° C to + 300 ° C, and the reaction time is usually 10 minutes to 10 hours. of the compound represented by the formula (X) according to a conventional method, and this salt comprises the same salts as those mentioned above as salts of the compound represented by the formula (I) Although the compound represented by the formula (X) or a salt thereof, thus obtained, can be isolated and purified by a well-known method, it can be used in the reaction

  without isolating it beforehand.

  (d) Etherification and phosphorylation To obtain the compound represented by formula (XI) or a salt thereof from the compound represented by formula (X) or a salt thereof, the compound is subjected to represented by the formula (X) or to a salt thereof an etherification reaction or a reaction

phosphorylation.

  The etherification reaction or the phosphorylation reaction can be carried out by a conventional method such as that described in Japanese Patent Application Nos. Nos. 137,988,78, 105,689 / 80,

  149 295/80, or by a similar method.

  By way of example, the alkylation can be carried out according to a conventional method. The reaction is generally carried out at a temperature of 20 ° C. to + 60 ° C., and

  reaction lasts from 5 minutes to 10 hours.

  As a solvent, it is possible to use a solvent

  inert to the reaction, for example the tetra-

  hydrofuran, dioxane, methanol, ethanol, chloroform, methylene chloride, ethyl acetate,

  butyl acetate, N, N-dimethylformamide, N, N-

  dimethylacetamide, water, or a mixture of the above.

  As the alkylating agent, it is possible to use, for example, a lower alkyl halide such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide or a similar halide. dimethyl sulphate, diethyl sulphate, diazomethane, diazo ethane, methyl para-toluenesulphonate or a similar agent If an alkylating agent other than diazomethane or diazoethane is used, the reaction is carried out in the presence of an alkali metal carbonate such as sodium carbonate, potassium carbonate or a similar carbonate; an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or hydroxide

  similar; or an organic base such as triethyl

  amine, pyridine, N, N-dimethylaniline or a base

similar organic.

  On the other hand, the salt of the compound represented by the formula (XI) can be easily obtained by a usual method, and this salt comprises the same salts as those mentioned above as salts of the compound

represented by formula (I).

  In addition, it is possible to introduce and eliminate a protective group according to a conventional method, which makes it possible to transform a given compound into a compound

corresponding search.

  Although the compounds which are represented by the formula (XI) and their salts thus obtained can be isolated and purified by a usual method, they can be used in the subsequent reaction without first isolating them. (e) Cyclization Reaction The compound represented by the formula (Ia) or (Ib), or a salt thereof, according to the present invention, can be obtained by reacting the compound represented by the formula (IX), ( X) or (XI), or a salt thereof, with the thioformamide or thiourea represented by the formula (XII). This reaction is usually carried out in a solvent. As a solvent, an inert solvent can be used with of the reaction, for example

  water, methanol, ethanol, acetone, tetra-

  hydrofuran, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyridone, alone or in

  mixture of two or more although it is not indis-

  In order to add an acid-removing agent, the reaction is sometimes regular if an acid-removing agent is added in such an amount that the skeleton of the cephalosporin is not influenced. acid removal used in the reaction comprises inorganic and organic bases such as alkali metal hydroxides, bicarbonates of

  alkali metals, triethylamine, pyridine, N, N-

  dimethylaniline and similar bases The reaction is usually carried out at from 0 to 1000 ° C. Thioformamide or thiourea is usually used in an amount of from about 1 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 from 1 to 48 hours, preferably from 1 to hours. Furthermore, in the compound represented by the formula (Ia) or (Ib ), the protection of the carboxyl group and the removal of the protective group, or the conversion of the product to a salt, according to a conventional method, can be carried out to convert the compound obtained into the corresponding desired compound Si i - 2 in the formula (Ia) or (Ib), R, R and R contain reaction-active groups, these groups can be suitably protected by means of a conventional protecting group prior to the reaction. the reaction, and eliminate this groupem The desired compound, represented by the formula (Ia) or (Ib), or its Si, el, thus obtained, can be isolated by a usual method. (f) Oximination The compound represented by formula (Ib) or a salt thereof is obtained by reacting the compound represented by formula (XIV) or a salt thereof with the compound represented by formula (XV) ) or with a salt thereof The salts of the compounds

  represented by the formula (XV) include chlorine

  hydrates, hydrobromides, sulphates and similar salts This reaction is usually carried out

  only in a solvent such as water, alcohol, N, N-

  dimethylacetamide or a similar solvent, but also in other solvents inert to the reaction or in a mixed solvent composed of the preceding -On leads the reaction at a temperature of 0 to 100 ° C, preferably 10 to 10 ° C. at 50 ° C The reaction time is usually 10 minutes to 48 hours The compound represented by formula (XV) or a salt thereof is used in an amount of about 1 mole to several moles per mole of the compound

  represented by the formula (XIV) or a salt thereof.

  Although the salt of the compound represented by the formula (XV) can be used as it is in the reaction, it can also be reacted in the presence of a base, for example a mineral base such as an alkali metal hydroxide. (for example, soda, potash or

  similar hydroxide), an alkali metal hydroxide

  earth (for example, magnesium hydroxide, calcium hydroxide or a similar hydroxide), an alkali metal carbonate (eg sodium carbonate, potassium carbonate or similar carbonate), an alkali metal carbonate earth (eg magnesium carbonate, calcium carbonate or similar carbonate), an alkali metal bicarbonate (eg sodium bicarbonate, potassium bicarbonate or similar bicarbonate), an alkaline earth metal phosphate ( for example magnesium phosphate, calcium phosphate or a phosphate

  similar), an alkali metal hydrogen phosphate (eg

  disodium or dipotassium hydrogen phosphate) or an alkali metal acetate (e.g. sodium acetate or potassium acetate), an organic base such as a trialkylamine (for example trimethylamine, triethylamine or a similar amine), picoline, N-methylpyrrolidine, N-methylmorpholine,

  1,5-diazabicyclol 4 O-5-nonene, 1,4-diazabicyclo

  Loctane, 1,5-diazabicyclol 5,4-l-7-undecene, or a similar compound The compound which is represented by the formula (Ib) or a salt thereof, according to the present invention, thus obtained , can undergo a transformation of R in a conventional manner, and can also be isolated

by a usual method.

  (g) Alkoxylation The compound which is represented by the formula (IV) wherein R 3 is an alkoxy radical can be synthesized from the compound which is represented by the formula (IV) wherein R 3 is a hydrogen atom by a process known per se, for example by the method which is described in Journal of Synthetic Organic

  Chemistry, Japan, 35, (7), 563-574 (1977).

  Moreover, it is possible to synthesize the compounds which are represented by the formulas (I), (Ia), (Ib), (IX), (X), (XI) and (XIV) in which R 3 is an alkoxy radical, from the respective compounds which are represented by the formulas (I), (Ia), (Ib), (IX), (X), (XI) and (XIV) wherein R 3 is a hydrogen atom, d in a manner known per se, for example by the method which is described in the patent applications

  published in Nos. 24 888/79 and 103 889/79.

  The compound which is represented by the formula (I), or a salt thereof, thus obtained, can be administered to humans and animals in the form of a free acid or in the form of a salt. or a pharmaceutically acceptable ester for the purpose of treating bacterial infections and protection against them It is preferable to administer the compound parenterally in the form of a free acid or a pharmaceutically acceptable salt, or to administer the compound orally in the form of a pharmaceutically acceptable ester In this case, it is sufficient that the compound is put into a galenical form usually used in cephalosporin-based medicaments, for example in the form of tablets, capsules, powder, fine granules, granules, syrups, injections (including drip), suppositories, or in a similar form In a dosage form, diluents and / or additives may be used, for example vehicles such as starch, lactose, sugar, calcium phosphate, calcium carbonate or similar compounds; liaison officers

  gum arabic, starch, micro-cellulose

  crystalline, carboxymethylcellulose, hydroxypropyl-

  cellulose or a similar agent; lubricants such as talc, stearate or similar lubricants;

  disintegrating agents such as carboxymethyl-

  calcium, talc or similar agents.

  When the compound which is represented by the formula (I) or a salt thereof is administered, the dosage, and the mode of administration may be varied depending on the symptoms of the patient, and it is generally sufficient to administer the compound orally or parenterally to an adult at a dose of approximately

  at 5000 mg, in one to four doses per day.

  The invention will be explained hereinafter by way of reference examples and preparation examples which are given by way of illustration only and not by way of example.

as a limitation.

  Reference Example N 1 (1) To a solution of 20.0 g of ethyl N- (2,2-diethoxyethyl) oxamate in 60 ml of ethanol was added 6.1 ml of an aqueous solution of 70% by weight of ethylamine, and this mixture was reacted at room temperature for one hour. After completion of the reaction, the precipitated crystals were collected by filtration and recrystallized from ethanol to give

  17.0 g (85.1% yield) of N-ethyl-N '- (2,2-diethoxy)

  ethyl) oxamide having a melting point of 131-132 C.

  -1 IR (K Er) cm 1: C = 01650 In a similar manner, the compounds were obtained

  shown in Table 3 below.

TABLE 3

(CH 3 CH 20) 2 CHCH 2 NHCOCONHR 6

  Compound PF PF Solvent (K Br) cm 1 Compound recrystallized (Oc) R 6 tion = -H Acetate 141-142 1650, 1635 ethyl -CH 3 Ethanol 135-136 1645 - (CH) CH 3 Acetone 84- 1645 CH-CH / 3 Acetone 1516 15.13 NCH n-Hexane 1516 15.13 - (CH 2) 3 CH 3 n -Hexane 111-112 1645 - (CH 2) 4 CH 3 n-Hexane 92-93 1650 - (CH) CH 3 n -Hexane 87-88 1650 - (CH 2) 7 CH 3 n -Hexane 110-111 1645 - (CH 2) 1 CH 3 n -Hexane 83-84 1645 Ethanol 154-155 1640 - CH n- Hexane 113-114 1655

-C 2 Ethanol CO 118-119 -

1 _CH 3

-N Ethanol 157-158 1645

* OCH 3 128-1291655

-CH OCH 3

  (2) To a solution of the 17.0 g of N-ethyl-N '- (2,2-

  diethyloxyethyl) oxamide obtained in paragraph (1) above in 85 ml of acetic acid was added 0.05 ml of concentrated hydrochloric acid The mixture was refluxed for 30 minutes After completion of the reaction, it was removed the solvent by distillation under reduced pressure, and 70 ml of acetone was added to the residue, then the crystals were collected by filtration. These crystals were recrystallized from methanol to obtain

  6.8 g (61.8% yield) of 4-ethyl-2,3-dioxo-1,2,3,4-

  tetrahydropyrazine having a melting point of 173-174 ° C.

-1

IR (K Br) cm 1 VC = 1680-1620.

  In a similar manner, the compounds

  shown in Table 4 below.

TABLE 4

o o

HN N-RO

  COMDOSé Solvent of P F IR (K Br) cm-

recrystalli {c R 6 sation

-H> 2801680-1640

  -CH 3 Ethanol 220-231 1690-1635 - (CH 2) 2 CH 3 Acetone 182-183 1680-1640

CHCH 3

  Acetone 215-219 1680, 1625 (CH 2) 3 CH 3 Actone 149-150 1680, 1640 (CH 2) CH 3 Ac 4 Tone 171-172 1685, 1660,

2 4 3 1620

  - (CH 3) 5 CH 3 Acetone 141-142 1620 160 - (CH 2) 7 CH 3 Ac 6 -one 145-146 1670, 1635 - (CH 2) 1 CH 3 Ethanol 145-146 1660, 1625 Acetone 254-255 1670 1635, 1635 2 __ _ _ _ _ __ _ _ _ _ _acetic acid Mthano 1 1720, 1675, -CH 2 CH 2 OCOCH 3 ehnl 178-180 1625 -N 11 _CH 3 Ethanol 229-230 1700-1625

OCH 3 175-1761740-1620

  -C H O C H __________________________________ ________________________ ____________________________________________

63 2536074

  (3) To a suspension of 5.2 g of 4- (2,4-dimethoxy-

  benzyl) -2,3-dioxo-1,2,3,4-tetrahydropyrazine obtained in

  paragraph (2) above, in 26 ml of N, N-dimethyl-

  formamide, 4.1 g of potassium carbonate was added, and the mixture was stirred at room temperature for

  It was then added 5.8 g of 4-bromine

  methyl-5-methyl-1,3-dioxol-2-one and the mixture was reacted at 50-60 ° C. for three hours. The reaction mixture was introduced into a mixed solvent consisting of 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 distilled off under reduced pressure, and the residue was purified by column chromatography (Wako C-200 silica gel, eluent:

  chloroform) to obtain 4.9 g (66.0% yield) of 1-

  (2,4-Dimethoxybenzyl) -4- (5-methyl-2-oxo-1,3-dioxol)

  4-yl) methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine having

a melting point of 154-156 C.

-1

IR (K Br) cm: CV = 01820, 1675,, 1630.

  In a similar manner, the compounds

  shown in Table 5 below.

TABLE 5

OCH 3 O O

CH 3 O H N-R 6

  compound PlF (OC) IR (K Br> cm -1: v o 188-190 1775, 1700, 1650

  -CH 2 OCOC <CH 3) 3 100-101 1750, 1690, 1660,

  -CH 2 COOC (CH 3> 3 105-106 1740, 1690, 1650

  (4) In a mixed solvent composed of 37 ml of trifluoroacetic acid and 10.8 g of anisole was dissolved 3.7 g

  1- (2,4-dimethoxybenzyl) -4- (5-methyl-2-oxo-1,3-

  dioxol-4-yl) methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine obtained in (3) above, and the mixture was reacted at 50-60 ° C. for two hours. then

  distilled off the solvent under reduced pressure.

  To the residue was added 30 ml of diethyl ether and the crystals 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 225-226C.

  IR (K Br) cm: ν C = O1825, 1805, 1725, 1690, 1670.

  In a similar way, we obtained the

  compounds shown in Table 6 below.

TABLE 6

HN N-R 6

HN N-R 6

  (5) To a solution of 2.6 g of 1-carboxymethyl

  2,3-dioxo-1,2,3,4-tetrahydropyrazine in 13 ml of N, N-

  dimethylacetamide was added 3.9 g of diphenyldiazo-

  methane at room temperature, and the mixture was reacted for ten minutes. The reaction mixture was introduced into a mixed solvent consisting of 25 ml of ethyl acetate and 25 ml of water, and the mixture was stirred. for 15 minutes The precipitated crystals were collected by filtration, and washed with 10 ml of ethyl acetate and then with 10 ml of diethyl ether, to obtain

  2.9 g (80.4% yield) of 1-diphenylmethyloxycarbonyl-

  methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine having a point

melting of 97-98 C.

  compound oF (C) IR (K Br) cm: ν C = O R 6 O

> 270 1790, 1775, 1730,

O 1690

-CH 2 OCO (H)

  -CH 2 COC (CH 3) 3 166-167 1740, 1700, 1660

-CH COOH 282 1730, 1670-1630

2 (decomp)

  IR (K Br) cm: ν C = O 1750, 1675, 1645.

C = O

EXAMPLE 1

  (1) To a solution of 10 ml of ethyl acetate containing 2.71 g of boron trifluoride was added 2.72 g of 7-aminocephalosporanic acid (hereinafter:

  7-ACA) and 1.54 g of 4-ethyl-2,3-dioxo-1,2,3,4-tetrahydro-

  pyrazine, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was added to 50 ml of methanol with cooling, and then 3.16 g of toluene were added dropwise. pyridine The precipitated crystals were collected by filtration, washed sufficiently with 1 ml of methanol, and then dried to give

  3.10 g (88.1% yield) of 7-amino-3- (1- (4-

  ethyl-2,3-dioxo-1,2,3,4-tétrahydropyrazinyl) ylmethyl} -

  3-Cephem-4-carboxylic acid having a melting point of 191-1% OC (dioo

IR (K Br) cm: CH = 1795, 1670, 1620.

  NMR- (CF 3 COOD) 6: 1.44 (3H, t, J = 7Hz, NCH 2 CH 3), 3.69 (2H, 1s, C 2 -H), 4.08 ( 2H, q, J = 7Hz, NCH 2 CH 3), 14, 5.51 (2H, A Bq, J = 15Hz, S),

-CH 2 -

5.48 (2H, s, C 6 -H, C 7 -H), -

  6.74, 7.00 (2H, A Bq, J-6Hz,) HH (2) The transformation reaction at position 3, which was mentioned in (1) above, was carried out in the reaction conditions which are indicated in Table 7 below, to obtain the acid

  7-amino-3- {1- (4-ethyl-2,3-dioxo-11,2,3,4-tetrahydro)

  pyrazinyl) methyl} -A 3-cephem-4-carboxylic acid with the

  yields also shown in Table 7 below.

TABLE 7

  (3) In a manner similar to that of paragraph (1) above, the compounds indicated in

Table 8 below.

  (In this case, the desired compounds were obtained by pouring the reaction mixture into ice water after completion of the 3-position transformation, and adjusting the pH to 3.5 with 28% ammonia. % by weight, in

cooling in the ice).

  NO Starting Material Acid or Conditions Quant.

  Reaction compound (Rend) 7-ACA complex HN 1 N -CH 2 CH 3 acid 1 2.72 g 1.54 g Sulfo trifluoride Temper 2.6 g lane of ambient boron (73.9%) ( 10 ml) (2.71 g) 2 hours 2 2.72 g 1.54 g Nitro Complex Temper 2.85 g Methane Room Trifluo (81.0%) (14 ml) 16 hours boron-diethyl ether. (5.7 g)

1 1 1

  o = O "ZU: (oswa-9 P) NWH GPsjn 9 j LA: luz PEIX) Ili (O), J, d esodwoo ON f 1 1 Nr f 4. CD No M Ln cm H s L

HZ) IL 9 (H O # ZHS = C # P 'HI)

  ## STR1 ## where: ## STR1 ## ## STR1 ## where: ## STR2 ## ST 'HZ) tltleú (E HOP (ZHD) UHDN "UI" M 6 Pe, l-so (i # z H 9 = r "4" Hú) L 8 e O OZ 91 oo 8-l

E S E / C ==

ND (HO) M N-

  e-o 0 (dulooop) HOOD Z k O ZH HO -, te "Z

S H

  8 va CD CD CD CD CD CD,,,,,,,,,,,,,,,,,,,,,,,,,,,, ## EQU1 ## ## STR1 ##

at SL 91

o O 8, l (dulo, jep)

66 T-961

E z / = M

HD (HO) N N-

  ## EQU1 ## where: ## STR1 ## where: ## STR2 ## (S ME 9 (I HZ) (z HD), HZ) N <, 'u,' HE) 9st ú-Zse E "(H-, 7 D They-1 Hz) oseú (E HD 9 (ZHD) E HZ) e, 'UI' HZT) 09 '1- úT and TJ (EHD L (ZHD) N - "" ZH 9 = C il "HE) L 8 (O OZ 91 s

I 008 T

  (dulooop) gez 6 l-sl 6 l E L z F = \

HD (HD) M n

  (Gq Tns) 8 nvaigvi No Cu HOOD AT sup gansaw H Hz) gg L

H (O

(H-LD H-9 D "HZ) Ltlys 009 T

Z O ú 91

  HD issgi ooz <NH YS "ZHSI = C" bg V 'HZ) ZL 9 06 LT Jityg' (H-ZD S Tl 'HZ) ZLU ST

"HZ) 9 L 9

  ## STR2 ## The reaction reaction at the 3-position referred to in (1) above under the reaction conditions shown in Table 9 below to obtain the acid

  7-amino-3- {P- (3,6-dioxo-1,2,3,6-tetrahydropyridazinyl) -1-

  Methyl-A 3-cephem-4-carboxylic acid with yields

  also shown in Table 9 below.

TABLE 9

  N Product of Acid or Conditions Quant.

  starting compound endem reaction) Solvent complex 7-ACA Maleic acid hydrazide 1 2.0 g 0.91 g Trifluo acid Temperature 1.72 g boron trifluoride boron (72.3%) acetic ether 16 hours ml diethyl 4 , 17 g 2.72 g 1.23 g Sulfolane trifluoride Temperature 2.75 g 10 ml of ambient boron (84.9%) 2.71 g 3 hours (5) In a manner similar to that of paragraph (1) ) above, the raw crystals whose

  The formula is shown in Table 10 below.

TABLE 10

2 CH 2

N H 2

COOH No Compound R 2

-N N-H

2 -NN-CH 3

-N N CH 2 CH 2 CH 3

CH 3

-N N-CH CH

C 3

-N N (C

o o O

-N N (CH 2) 1 CH 3

0 O

-N N-CH -

o CH

-N N-N ,, '3

CH 3 CH 3 N il 1 -N CH CH

12 1

-NOT

0 * 2

  13 HN ci -N TABLE 10 (S uite) 0 'O \\

-N N CH 2 CH 2 OCOCH 3

TABLE 10 (continued) CH 3 o HN

+ 1

-N CH 3

0 * 3 N CH ICH 3

16 -N NI

  S-N o O Note: Compounds N 10, 11, 12, 13, 14 and 15 were obtained using sulfolane as the solvent

in the reaction.

  This compound was obtained by the procedure of introducing into methanol, filtering insolubles and

add pyridine to the filtrate.

  * 2: This representation was adopted because it was not confirmed whether the chlorine atom occupied position 4 or position 5, or whether the product consisted of a single compound or a mixture ( such representations in the tables that we will find below have the same meaning). * 3: This representation means that the product consisted of a mixture of a compound substituted in the 4-position and a compound substituted in the 5-position (such representations in the tables that are

  will find further have the same meaning).

EXAMPLE 2

  To a suspension of 3.0 g of the 7-amino acid

  3-S- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) -1-

  Methyl} -A cephem-4-carboxylic acid obtained in Example 1

  (1) in 30 ml of methanol was added 1.62 g of para-toluenesulphonic acid monohydrate to form a solution, then 5.0 g of diphenyldiazomethane was added slowly to this solution, after which the resulting mixture was reacted. at room temperature for 15 minutes After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue thus obtained was dissolved in a mixed solvent.

  composed of 20 ml of ethyl acetate and 20 ml of water.

  The pH of the solution was adjusted to 7.0 with sodium bicarbonate. The organic layer was then separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reflux. Reduced pressure The residue was purified by column chromatography (Wako C-200 silica gel, eluent: 1: 4 by volume benzene: acetate mixture).

  of ethyl) to give 3.1 g (70.3% yield) of 7-amino

  3- {E1- (4-6ethyl-2,3-dioxo-11,2,3,4-tetrahydropyrazinyl) -1-

  diphenylmethyl methyl-3-cephem-4-carboxylate having

  a melting point of 183-186 C (decomposition).

  IR (K Br) cm: C = 1765, 1730, 1680, 1630. In a similar manner, the compounds were obtained.

  which are shown in Table 11 below.

TABLE 11

  ) 2 compounds P F (C) IR (K Br) cm V R 2 o o

2-10 1765, 1725,

  -N NH 12 i 3 <decomp) 1690, 1630 o

N-CH 127-128 1770, 1725,

-NN-C 3 <decomp> 1690, 1640

O, 169-1711765, 1730,

  -N N (CH 2> 2 CH 3 (decomp) 1685, 1635

NCH C 119-180 1760, 1720,

  -N CH 3 <decomp) 1685, 1635 CH 3 o

0 0 1 0-1891760, 1725,

-N (CH 2 3 CH 3 (decomp) 1680, 1630

0 185-1941765, 1730,

  -N N (CH 24 H dcm 1685, 1630 TABLE II (contd.) C On Ip OS P F (a 1> IR (K Br) cm 1:

17.0-174, 1765, 1730,

-N NC) 5H (decomp) 1685, 1635

186-188 1765, 1730,

-N NCH 27 CH dcm 1685, 1635

164-172 1765, 1730,

-N NCH 2) 11 CH 3 (d 4 comp) 18.13

J-4 155-1681765, 1725,

-N <decomp) 1680, 1625 o

-160 1770, 1725,

-N N-CH 2 O (de, comp) 1680, 1630

146-148 1770, 1725,

-N NC COCOCH (decomp) 1678, 1623

0 3

-N N-NN, 1680, 1630

  CH 3 e N 82-85 1775, 1720, -N (decomp) 1650 o TABLE II (Continued) Compound P F (OC) IR (K Br) cm R 2

CH 3 CH 3

108-114 1765, 1725,

(decomp) 1650

132-135 1780, 1730,

-NOT-

H 178-1811780, 1730,

ci (d 4 comp) 1660 o

HN CH HN 137-139 1780, 1730,

HN 3 + (from 1660 o o CH 3

N.X. 90-93 1770, 1720,

<decomp) 1660

CH 2 CH 3

  l 38-143 1770, 1720, (d COMP> 1660 o

EXAMPLE 3

  In a mixed solvent consisting of 25 ml of trifluoroacetic acid and 10 ml of anisole 4.9 g of 7-amino-3-1 1- (2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) were dissolved Diphenylmethyl methyll-3-cephem-4-carboxylate, and the solution was reacted at room temperature for two hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and added. 50 ml of diethyl ether to the residue, after which the crystals were collected by filtration. These crystals were sufficiently washed with 40 ml of diethyl ether and then dried to give 4.25 g (yield 97.0%).

  of 7-amino-3- acid trifluoroacetic acid salt

  {1- (2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl} -

  -A-3-cephem-4-carboxylic acid having a melting point of

-106 C (decomposition).

  -1 IR (K Br) cm: ν C = O 1780, 1700-1630 c = O Values 6 of NMR (CF 3 COOD): 3.72 (2H, ls, C 2 -H),, 14, 5 , 52, (2H, A Bq, J = 15Hz, S, 44 (2H, s, C 6 -H, C 7 -H), -H 2 6, 78, 6.98 (2H, A Bq, J = 6 Hz,

H H

  In a similar manner, the compounds

  which are shown in Table 12 below.

  IR compound (K 13 r) cm-1: Values (dr 6 -DMSO + CF 3 COOD) * 1 MP (Oc) v NMR (C 3 COOD) * 2 R 2 C = O (d 6 -DMSO + D 20) * 109-110 1795, 3; 36 (3H, s,> NCH 3), 350 (2H, Is, C 2 -H), (d 4 comp) 1680, S -N N-CH 3 1635 4) 53 Y 5) 11 (2 H, A Bq, J = 15 Hz, CH 6 (1H, d, J = 5HZ, CH), 5, 17 UH, d, J = 5Hz, C-H), 73 (2HJI is ,

7 am H

* 3

TABLE 12

CF 3 COOH'H:

CH -R 2

Co

-N N (CH 2) 3 CH 3

  1780, 1675, 91 (3H, t, J = 7Hz,> N (CH 2) 2 CH 3) 1 35-28 (2H, m, NCH CH CH).

? 1- 2 2 3

  3) 2 (2H, 1s, C 2 -H) II 3 77 (2H, t, J = 7HZ,

" 'NCHCHCH

/ 4 Z 3 S

4 31.4 (2H, A Bq, J = 15Hz,

86 ICH 2-

152-155

(decomp) r-J Ln LW 0%

* CD 1

  TABLE 12 (continued) 35 (2H, is, C 6 -H, C 7 -H), 6'-73 (2H, 1s, HH * 1146 (6H, d, J = 7) Hz,> NCH _-CH 3),

? 11-1 C H-3

O 'O

\\ Y /

1 CH 3

-N N-C Hl-

k == / '1-1 CH 3

59 5-161 5

, 1 7

decomp) 1780, m

3170 (2H, 1-9, C 2 -H),

  CH 3 4 y 77-5) 60 (3H, M ,, -, N CH 3 f Si) f CH 2? 46 (2H, s, C 6 -H, C 7 -H), 682, 704 (2H, A Bq, J = 6HZ,) H H 1 * 2 rlla tn

LY 1

0% c> 1

-4 1

  J%. TABLE 12 (continued) OH, t, J = 7HZ,> N (CH 2) 3 CH 3), 1 10-190OH, m -NCH (C 1) CH

11 2 2 3

  3> 62 (2H, 1s, C 2 -H), 375 (2H, t, J = 7Hz, INCH 2 (CH 2) 2 CH 3),

56.5 S

18 (2H, A Bq, J = 15Hz,

ICH 2-

  29 (2H, s, C 6 -Hel C 7 -H), 70 (2H, 1s, HH * 1)

158-162

d 4 comp) 1780, 1675, 0 O 1 \

-N N (CH) CH

2 3 3

N ==:>

  Co w he H) il 1 d 15-2? 35 (10H, m, 0> - -N N

1, = O

1780, S

167-169

(decomp) 3) 69 PH, is, C 2 -H),

4147-5) 07 UH, M, 70),

H-. rla Ln w 0% CD, INJ JK% r

1 f 4-

  1 90 NO 1 pn Ln Cu "S'f" HZ) L 9 e 9

# (H-L D H 9 D IST 'HZ) ZEIS

IZH T = c bal 'HZ) Tz (s Ls i V

(E: OT Z

  HD HD) HDNI '' 'ZHL = r' l #HZ) 9 L (ED IST 'HZ) úq E HDOI (EHD) E HDN, ""' read 'Hoz) 58 c T-ZO 1 j (E HDOI ( EHD) z HDN / 1 "ZHL = r '14' HE :) '680 çc 9 T lgLg T

# SLLT

(-Dulooap)

úPT- 8 -E

r - ==

CHZ) TI (ZHD) -N N-

  ho to at (4 i 'ZH 9 = D' bg V 'HE) 86 (9-TB 19 i (HL O IH-9 D Here HZ) c (s -Z YS him' HE) t'si S-Tzes (aq Tns) z L nvsievi TABLE 12 (cont'd) 0 Y

-N NCH CH OCOCH

  k = 2 2 3 2? M, S, -OCOCH 3), 3759 (2Hls, C 2 -H),

86-4, 54 (4H, M, NCH CH O-),

> 11, 2 2

  577, 5, 16 (2H, A Bc1, J = 15Hz, 17CH, 1725, 1675, 86-91 (decomp), 286-81 (2H, Is, C6H, C7H). ), (2 H, lsp ≥) HH CD Ln * 1 3 34 (6H, s, -NI C 5), CH 3 3 72 (2H, Is, C-H) 1 and 50 (2H, A Bq, J = 15 Hz, α-CH (2H, s, C 6 -H, C 7 -H), 7 (2H, Is, CH = 1); NNN

N == CH 3

1780

158-160

  (d1, comp) r%) Ln Lm 1 Cr% c> 1 41 4 H * 2 TABLE 12 (cont'd) 3> 89 (2H, is, C 2 -H) to 26, 62 ( 2H, A Bq, J = 15Hz, S), 52 (2H, s, C -H, CH),

ICH 7

1780

1675 '

119-122

  (d 4 comp) H 7) 93, 8) 69 PH, A Bq, J = 5HZ, x H 588 (1H, S, -H) * 2) It Co 01% 2158 (3H, s, -CH 3), 73 (2H, 1S, C 2 -H), H) and 5150 (2H, 1s, C 2 R 93 (2H, A Bq,

J = 15 HZ, S

  CH 2 H 2 O 52, 7) 79 (2H, A Bq, J = 10HZ, (H) 2, 1800, 1660,

2 -243

  (d) Compound: ## STR1 ## wherein: ## STR1 ## ## STR2 ## ## STR2 ## ## STR2 ## J = 16 Hz, S 47 (2H, s, C 67 H, C 7 -H), 1640,

HN> 200 1600 CH

  1c 2 -N 7; 59 (1He S,> -H) * 2 TABLE 12 (cont.) 1 36 (3H, t, J = 7HZ, -CH CH), 2 2 3, r 9 O (2H, J = 7Hz , -CH 2 CH 3), 3, 69 (2H, 1a, C 2 -H),. 47 (2H, 1 s, C-H, CH), 48, 5 (2H,

6 7>> 90

  A Bq, J = 15 Hz, S 7 48, 766 (2H, A Bq, CH 2 -H J = 10 Hz, 1H

2 9-222

  (d comp) 1800, 1660, Co j * 2 rlo Ln

(A 1

c> c:> ',,

-4 -

9 -

CH CH 3

  N -N TABLE 12 (cont'd) 2 42 (15H s, -CH x O 5), 23 (ly 5H, s, -CH x O 5), 73 (2H, ls, -H ), 3 C 2 J 52 (2H, s CH, CH), 563 (2H, s, S)

6 7 C Hi-

  7 (O 5 H, s,> H x O 5) 760 (O 5 H, S,> H x O) 5) * 2 Ln 1795, 1640,

> 200 '

HN CH 3

-N TABLE 12 (continued)

139-140

  (decomp) 1780, 1710, s 466 (2H, 1s, C 2 -H), 4/47, 5) 07 (2H, A Bq, J = 15Hz, S> CH 2 J = 15Hz, S)

LCH 2-

  ), 504 (1H, d, J = 5 Hz, C 6 -H), 5> 20 (1H, d, J = 5Hz, C 7 -H), 6934, 6) 59 (2H, A) Bq, J = 6Hz, <) HH * 3 ** 3/35 (3H, s,> NCH 3), 3/48 (2H, ss, C 2 -H), OO 152-155 1780, 4 > 50.5; 12 (2H, A Bq, J = 15Hz, S), (decomp) 1690,

-N I N-CH 1660, k CH 2-

-N N CH 1620

  (3H, d, J = 5Hz, C 6 -H), 5> O (1H, d, J = 5Hz, C 7 -H), 6) 70 (2H); , Ls,>) HH * 3 o% O Note * = Free compound; the desired compounds were obtained by reacting in a mixed solvent composed of trifluoroacetic acid and anisole and then removing the solvent, dissolving the residue in water and adjusting the pH to 3.5 to

using ammonia at 28%.

  **, = free compound; obtained by treating the trifluoroacetic acid salt with

pyridine in methanol.

PU Ln o> 1 -4 ** O O \ -N

-N NH

EXAMPLE 4

  To a suspension of 5.0 g of 7-amino-3- acid

  1- (3-Methyl-6-oxo-1,6-dihydropyridazinyl) methyl-A-3-

  Cephem-4-carboxylic acid in 15 ml of acetone was added 2.86 g of 1,8-diazabicyclol 4 O-7-undecene and 4.51 g of pivaloyloxymethyl iodide at 10-15 C, and Reaction of the mixture for 30 minutes After completion of the reaction, the reaction mixture was introduced into a mixed solvent of 50 ml of water and 50 ml of ethyl acetate, and the organic layer was separated off. The mixture was washed with water and dried over anhydrous magnesium sulfate. 10 ml of an ethyl acetate solution containing 1.40 g of oxalic acid was then added and collected by filtration the precipitated crystals and washed with ethyl acetate to obtain 4.59 g

  (yield 56.2%) of 7-amino-3- oxalic acid salt

  {1- (3-methyl-6-oxo-1,6-dihydropyridazinyl) methyl} -

  A pivaloyloxymethyl 3-cephem-4-carboxylate having a point

  melting point 145-147 ° C (decomposition).

  IR (K Br) cm: VC = O 1790, 1750, 1660 c = O NMR values 6 (d 6 -DMSO):

1.21 (9H, s, -CH 3 x 3).

  2.29 (3H, s,> CH 3), 3.52 (2H, es, C 2 -H), 4.94, 5.33 (2H, A Bq, J = 15Hz,); eCH-, 14 (1H, d, J = 5 Hz, C 6 -H), 76-6.23 (3H, m, C 7 -H, -OCH 2 O-), 7.01, 7 , 53 (2H, A Bq, J = 10Hz, 7.44 (3H, es, -NH 3 () H 3.

EXAMPLE 5

  (1) To a solution of 2.69 g of 1- (5-methyl-2-

  oxo-1,3-dioxol-4-yl) 2,3-methyl dioxo-1,2,3,4-tetrahydro-

  pyrazine in 27 ml of N, N-dimethylformamide was added 1.52 g of potassium carbonate, and the resulting mixture was stirred at room temperature for 20 minutes.

  he then added 4.67 g of 7-phenylacetamido-3-bromo-

  tert-butyl methyl-A 2-cephem-4-carboxylate while cooling in ice, and the mixture was reacted with

  resulting at room temperature for two hours.

  The reaction mixture was introduced into a mixed solvent consisting of 200 ml of ethyl acetate and 150 ml of water, then the organic layer was separated, washed with 150 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the resulting residue was dissolved in 100 ml of chloroform. To the resulting solution was added 2.45 g (purity 70%). m-chloroperbenzoic acid, and the mixture was reacted at room temperature for one hour. The solvent was distilled off under reduced pressure, and to the residue was added 100 ml of ethyl acetate and 100 ml. The organic layer was separated, washed with 100 ml of water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and then purified. Resulting residue by column chromatography (Wako C-200 silica gel, eluent = chlorine oforme) to get 2, 70 g

  (yield 43.2%) of 7-phenylacetamido-3- {1-l 4- (5-methyl) -2-

  2-oxo-1,3-dioxol-4-yl) methyl-2,3-dioxo-1,2,3,4-tetra-

  tert-Butyl hydropyrazinylmethyl-L-3-cephem-4-carboxylate-1-oxide having a melting point of 135-136 ° C

(decomposition).

  IR (K Br) cm 1 C = O 1820, 1790, 1720, 1685, 1650.

  (2) In a mixed solvent composed of 12 ml of N, N-

  dimethylformamide and 6 ml of acetonitrile were dissolved

  3.0 g of 7-phenylacetamido-3-yl-4- (5-methyl-2-oxo)

  1,3-dioxol-4-yl) methyl-2,3-dioxo-1,2,3,4-tetrahydro-

  pyrazinylmethyl} -A-3-cephem-4-carboxylate-1-tert-oxide

  Butyl To the resulting solution was added 1.0 g of stannous chloride and 1.58 g of acetyl chloride, in that order, under ice-cooling, and the resulting mixture was reacted at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and to the residue was added 50 ml of ethyl acetate and 50 ml of water, whereupon the resulting mixture was adjusted to pH 6.0. The organic layer was then separated, washed with 50 ml of water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. the residue was purified by column chromatography (Wako silica gel C200, eluent: 3: 2 by volume toluene: acetate

  of ethyl) to give 2.12 g (72.4% yield) of 7-phenyl-

  acetamido-3- {1-1-4- (5-methyl-2-oxo-1,3-dioxol-4-yl) -

  methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinylmethyl) -

  A tert-butyl 3-cephem-4-carboxylate having a

  melting of 120-122 C (decomposition).

  IR (K Br) cm: ν C = O 1820, 1775, 1715, 1685, 1645 c = O NMR values (CD13 C): 1.58 (9H, s, -C (CH 3) 3) , 2.28 (3H, s, -CH 3) 3.17, 3.61 (2H, A Bq, J = 18Hz, C 2 -H), 3.77 (2H, s, CH- ) 4.53, 5.13 (2H, A Bq, J = 15Hz,) 4.71 (2H, s,> NCH 2), -CH, O (1H, d, J = 5Hz) , C 6 -H), 93 (1H, dd, J = 5Hz, J = 8Hz, C 7 -H), 6.53, 6.89 (2H, A Bq, J = 6Hz,)

H H

7.32-7.51 (5H, m, _)

7.57 (1H, d, J = 8 Hz, -CONH-).

  In a manner similar to that of (1) and (2) above, the compounds which are

  represented in Table 13 below.

TABLE 13

CH CONH S Q O

2

CH 2 N N-R 6

0 \ - = d

COOC (CH 3) 3

  NMR 6-DMSO * values: (CDC 13 '' '' '**) 1) 52 (9H, s, -C (CH 3) 3), 357 (4H, C 2 -H, D) CH 2), 4) 30, 5) 12 (2H, A Bq, j = 15HZ, S, CH 5) 12 (1H, d, J = 5 Hz, 6775 (1H, dd, J = 5Hz, J = 8HZ, -H), 7-H), 6d 07, 6754. (2H, A Bq, J = 6Hz, HH

  7 12-7 45 (5H, M, 7) 57-8> 14 (5H,

M, H 0), 9> 14 (1H, d, J = 8HZ,

-CONH-)

  1780, 1710, 1700, 1680, 1645 -183 (eecomp) M VI LM 0% c> TABLE 13 (cont.) 1 21 (9H, S, -C (CH)), 115 OH, S, 3 3 -C (CH 3) 3), 3, 22, 3/61 (2H, A Bq, J = 18Hz, C 2 -H), 37 (2H, S, OE-CH 2 -),, 4 (1H, A Bq, J = 15HZ, S), CH 3 O 3 (1H, 1780, 1740, 1730, -108 (from ecomp)

-CH 2 OCOC (CH 3) 3

d, J = 5HZ,

) 93 (1H,

6) 88 (2H,

  d, J = 9 Hz, C 6 -H), 5 Li 81 (2H, S, -NCH 2), dd, J = 5Hz, J = 9Hz, C 7 -H) OI 6) , A Bq, J = 7 HZ, 'F ='), 7 (1H, HH-CONH), 7) 43 (5H, s, -c D) .c Ln 1 53 OH, s, - C (CH)), 27 (2H, 1H, 3H), C 2 -H), 3'61 (2H, s, & CH -), 4, 54, PH,

1 2

  S, NCH -), 91 (2H, s, S) - CH 1770, 1730, 1685,

-CH 2 COOCI-I (00) 2

124-129

  (dcomp) r%) tn w 0% c>, at 1 CD% Om Ln cm (-HNOD 'z H 8 = ú "P HI) 96 L (E x ul" HST) Li> (L-96 (9 - "" HD "s" Hl) '88 9' ZH 9 = P bvlv HZ) 69 (9 Zi (9 '(H-LD' z H8 = C 'z HS = r "PP' HI) 98% (H-9 D "ZH = r P" H1) 87 A (aq Tns) úL nvsisvi (3) In 30 ml of anhydrous methylene chloride was added

  dissolved, 2.0 g of 7-phenylacetamido-3- (1-l 4- (5-methyl) -2-

  2-oxo-1,3-dioxol-4-yl) methyl-2,3-dioxo-1,2,3,4-tetrahydro-

  Tert-butyl pyrazinylmethyl} -A-3-cephem-4-carboxylate.

  To this solution was added 1.59 g of N, N-dimethyl-

  aniline and 0.57 g of trimethylsilyl chloride, in that order, and the resulting mixture was stirred at room temperature for one hour. The reaction mixture was cooled to 40 ° C., and 0.89 g of pentachloride was added thereto. The reaction mixture was then cooled to 40 ° C, and 5.2 g of anhydrous methanol was added thereto, whereupon the reaction was continued. After cooling to ice for one hour, 20 ml of water were added to the reaction mixture and stirring was continued for a further 30 minutes. The pH of the reaction mixture was then adjusted to 0.5 using 6 ml of ethyl acetate were added to this aqueous layer, and the pH of the mixture was adjusted to 6.5 with sodium bicarbonate. the organic layer was separated, washed with 50 ml of water and then dried over anhydrous magnesium ulfate The solvent was distilled off under reduced pressure, and to the residue was added ml of diethyl ether. The crystals were collected.

  by filtration to obtain 1.05 g (64.8% yield) of 7-

  amino-3- {1-1-4- (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl)

  2,3-dioxo-1,2,3,4-tetrahydropyrazinylmethyl} -A 3-cephem-4-

  tert-butyl carboxylate having a melting point of

-188 C (decomposition).

  IR (K Br) cm-1: VC 1820, 1765, 1705, 1690, 1635 NMR-values 6 (CD C 13 + d 6 -DMSO): 1.52 (9H, s, -C (CH 3) 3 ), 2.24 (3H, s, -CH 3), 3.46 (2H, 1s, C 2 -H), 4.35, 5.08 (2H, A Bq, J = 15Hz SC) )

-CH 2-

  4.76-5.09 (4H, m,> N CH 2, C 6 -H, C 7 -H),

6.74 (2H, s,).

  In a similar manner, the compounds were obtained.

  represented in Table 14 below.

  IR compound (K Br) d DMSO PF (OC) 1 Values 6 6 cm v CDC 1 RC = O NMR 3 1 50 OH, S, -C (CH 3) 3 3 48 (2H, ls, C 2- H),

  0 O 111-113 1780, 4 28, 077 (2H, ABCI, J = 15HZ, S)

(decomp) 1710,

1690, CH 2-

  4) 82 (1H, d, J = 5 Hz, C 6 -H), 5; 03 (1H, d, J = 5HZ, C 7 -H), 6108, 6.15 (2H, A Bq, J = 6Hz, H 7) 58-8112 (5H, m H, 1H); O

TABLE 14

H N; î :: N, S O O

2 CH NM 6

N-R 0 2 Nt == e

COOC (CH 3) 3

132-134

(Eecomp)

17 (9H, S, -C (CH)) 1 1

  1 3 3 f 53 (9H, s, -C (CH 3) 3) 1 3 2 -H), 4, 4p> 67 (2H, 1s, 13 (2H, A Bq, J = 15 Hz , S '; LCH), 1775, 1740, 1715, 1695,

-CH 2 OCOC (CH 3) 3

  (Hydrochloride): embedded image CD, q, AS TABLE 14 (cont'd) -CH COOOCH (e)) 2 -163 (dcomp) 1780, 1760, 1715, 1690, (2H, s,> NCH 2-), 75 (2H; , is, C 6 -H,

C 7 -H), 680 (2H, 3S, H H

  ## STR2 ## H), 40, 4) 99 (2H, A Bq, J = 15Hz, CC 2-4 (2H, S,> NCH-)? 65 (1H, d, J = 5HZ, C 6 -H), 4> 84 <1H, d, J = 5Hz, C 7 -H), 6.09e 6 62 (2H, A Bq, J = 6Hz, t ') 6.85 <1H, s, -CH <), 7 17-7, 31 <10H, M, x 2) Note ** The imino ether was poured into

which is deposited.

  water, and the hydrochloride which was isolated from the CD was isolated.

Example 6

  (1) In 2.29 ml of N, N-dimethylacetamide and 4.58 ml of acetonitrile

  nitrile 2.29 g of 2- (2-formamidothiazol-4-yl) -2-

  (syn) -methoxyiminoacetic acid, and 1.62 g of phosphorus oxychloride are added dropwise to the resulting solution, whereupon

  subject the mixture to reaction for one hour at a temperature

  After 5 to 10 minutes, 5.18 g of 7-amino-3-1 (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl are added.

  Diphenylmethyl cephem-4-carboxylate to the reaction mixture

  The reaction mixture is reacted at -5 ° C. for one hour. After completion of the reaction, the mixture is poured into a mixed solvent of 1 ml of water and 80 ml of ethyl acetate and the pH is adjusted.

  6.5 solution with sodium hydrogencarbonate.

  The organic layer is separated off and dried over anhydrous magnesium sulfate.

  reduced pressure and 60 ml of diethyl ether are added to the residue.

  Then we collect by filtration the crystals and we get

  6.05 g (yield: 83.0%) of 7-1-2- (2-formamidothiazol-4-yl) -2-

  (syn) -methoxyiminoacetamidol-3H- (4-ethyl-2,3-dioxo-1,2,3,4-

  tetrahydropyrazinyl) (methyl) -epephayl-4-carboxylic acid

  methyl having a melting point of 165-168 ° C. -1 IR (K Br) cm -1: C 1780, 1720, 1680, 1640 NMR (d 6 -DMSO) values: 1.18 (3H, t, J); 7 Hz,> N-CH 2 CH), 3.59 (2H, Is, C 2 -H), 3.72 (2H, q, J 7Hz,> N-CH 2 CH 3), 3, 97 (3H, s, -OCH 3), 4.42, 5.04 (2H, A Bq, J = 15Hz, S), CH 2 5130 (1H, d, J = 5Hz, C -) 6.02 (1H, dd, J = 5Hz, J = 8HZ, C 7 -H), 6.50, 6.62 (2H, A Bq, J = 6Hz, = <) H <H 7.04 <1H, s, -CH '-'> 'SH 8.63 <1H, s, HCO), 9.89 (1H, d, J = 8Hz, -CONH-), 12.68 (1H, is, HCONH-> Similarly, the compounds represented are

in Tables 15, 16 and 17.

-2 53607 4

TABLE 15

N C CONH 2

  HCONH-1 <- C H 3 H COO H <1 ((syn-isomer) Compound ___ R (e) c 1: R 2 R 4 P F (O C) IRVUO) c

-125 1780, 1720,

  -N N-CH H (decomp) 16-14, 1515-156 1785, 1720 r O O H (decomp) 1685, 1645

-N N CH CH

1 c24 3

131-136 1783, 1725,

O H (decomp) 1680, 1645

-IS> H CH

3

O 0 H 180-182 1180, 1720,

0 (de'comp) 1680-1640 -

-K (CH 2) 7H

158-166 1780, 1725,

0 H (dec.) 1675, 1640

-N N (H C

Q-H 126-138 1785, 1725,

H, 126-138, 1685, 1650

-N N CH 2 - (- J

TABLE 15 (continued)

-N N-CH CH 3

Br (d 4 comp)

1780, 1720,

1675, 1640

O H 171-173 1780, 1720,

0 H (decomp) 1690-1650 1 HN

H 148-151 1780, 1730,

CH H (decomp) 1690, 1660 C 3

191-195 1775, 1720,

H <decomp> 1670 CH 3

CH 3 -

N -No

TABLE 16

* CH 2 R 2

  (syn-isomer) Compound IR (B) c 1 R 2 R 18 P F OC <R Kr) c

34 176-179 1780, 1720,

-N NH -CH 3 (dcop 1680, 1640

O-CH 3 152-155 1780, 1720,

> _ 3 (decomp) 1680, 1640

-N N- (CH) CH

158-160, 1780, 1720,

OO C -CH 3 (decomp> 1680, 1640

-N NCHX

'"CH 3

166-167, 1780, 1720,

> __ 3 (decomp> 1685, 1645

-N N- <CH) CH

-CH 162-165 1780, 1720,

04 3 (decomnp) 1680, 1640 -N N

CH-145-147 1780, 1720,

P? (decomp) 1682, 1640

-N = N-CH 2 CH 2 OCOCH 3

  2 2 3 _ _ __ _ _ _ __ _ _ __ _ _ __ _ _ _

TABLE 16 (continued)

-N N (CH) 7 CH

-CH 3

138-144

(Decoxnp)

1780, 1715,

1690, 1620

88-90, 1780, 1720,

CH-CH 3 1690-1620

-N N-NCH 3

OCH CH 131 1786, 1723,

O -CH 2 CH 3 (decomp) 1684, 1645

-N N-CH CH

* '2 3

118-120 1780, 1720,

CH 2 CH 3 -CH 3 (decomp) 1660 -k)

0 -CH 190-192 1780, 1720,

-C 3 (decomp) 1665 HN I ci -N

TABLE 16

(after)-

-CH 3

183-185

(Decomp)

1780, 17-20,

128-131, 1780, 1720,

  N -CH 3 (delcomp) 1680, 1660 th NQ. o N o

HN CH 3

-N o + -N o

TABLE 17

CH 3

1 N C CONH -

  CH C 2 -CONH 4- <N Ht C Hun C 3 COOC (CH 3) 3 (syn-isomer) CompoundP OC IR (K Br) cm 1 R 2 P F <Oc

W 141-143 1815, 1775,

  -N N CH -2CH 3 (decomp) 1710, 1680,

3 1640

Y

154-156 1775, 1710,

O O (decomp) 1700, 1680,

0 O 1650

-N

0 85-88 1785, 1730,

id'cm 1715, 1660

-N N-CH OCCH

N = 'Z 2 CCH 3) 3

144-146 1775, 1745,

0 (decomp) 1715, 1690,

4 1650

-N N-CH COOCH <) 2

  (2) To a solution of 6.05 g of 7-l 2- (2-formamidothiazol-4-

  yl) -2- (syn) -methoxyiminoacetamidol-3-1- (4-ethyl-2,3-dioxo)

  Diphenylmethyl 1,2,3,4-tetrahydropyrazinyl) -methyl-3-cephem-4-carboxylate in methanol (31 ml) was added with concentrated hydrochloric acid (0.5 ml) and the mixture was reacted for two hours at 35 ° C. After completion of the reaction, the solvent is distilled off under reduced pressure. 100 ml of ethyl acetate and 100 ml of water are added to the residue and the resulting solution is adjusted to 6.0 with water. Sodium hydrogencarbonate The organic layer is separated and dried over

  anhydrous magnesium sulfate The solvent is distilled off

  under reduced pressure and to the residue 50 ml of diethyl ether. The crystals are collected by filtration and 1 g (yield: 87.7%) of 7-l 2- (2-aminothiazol-4-yl) is obtained. -2- (syn) -

  methoxyiminoacetamidol-3- {1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydrate)

  Diphenyl-3-cephem-4-carboxylic acid hydropyrazinyl) methyl

  methyl having a melting point of 165-167 C. IR (K Br) cm-1: C = O 1780, 1720, 1680, 1640 NMR (d 6 -DMSO) values: 1.18 (3H, t, J) = 7 Hz, N-CH 2 CH 3), 3.55 (2H, 1s, C 2 -H), 3.75 (2H, q, J = 7Hz, N-CH 2 CH 3), 3.90 (3H, s, -OCH 3), 4.41, 5.02 (2H, A Bq, J = 5Hz, SL),

-CH 2-

  , 26 (1H, d, J = 5Hz, C 6 -H), 6.01 (1H, dd, J-5Hz, J = 8Hz, C 7 -H), 6, 52, 6, 65 (2H, A Bq, J = 6Hz,),

H H

NNR

6.68 (1H, s, A),

  SH 7.07 (1H, s, -CH- ") 7.15-7.84 (10H, m, x 2), 9.81 (1H, d, J = 8Hz, -CONH-) Similarly, the indicated compounds are obtained

in table 18.

TABLE 18

H 2 N-S T 4 It CH R 2

0 CH 3 COOCH) 2

(syn-isomer> -

  IR compound (B c-1 R 2 R 4 P F (OC) IR (Br> cm)

W H 158-166 1780, 1720,

N-CH 3 (ecop 1680, 1640

151-156, 1780, 1720,

> 1 (decomp) 1680, 1640

-N N- (CH) CH 3

0H 150-156 1780, 1720,

> 1- (Decline) 1680, 1640

-N N- (CH 2 5 CH 3

168-175 1775, 1723,

m H (decomp) 1685, 1640

-N N- (CH C

O, H 161-166, 1680, 1640,

-N NCH

146, 1780, 1720,

0 Br (decomp) 1680, 1640

-N NCH CH

2 3

TABLE 18 (cont'd) H -178 (decomp>

1780, 1720,

1685 1660

CH I 146-148 1780, 1720,

C 3 Hj (decomp) 1660

NM I

  N o H Nh -N o (3) In a mixed solvent of 25.5 ml of trifluoroacetic acid

  and 7.86 g of anisole, 5.1 g of 7-l 2- (2-aminothiazol-4-

  yl) -2- (syn) -methoxyiminoacetamidol-3-El 1- (4-ethyl-2,3-dioxo)

  Diphenylmethyl 1,2,3,4-tetrahydropyrazinyl) methyl-13-a-3-cephem-4-carboxylate and the solution was reacted at room temperature for two hours. After completion of the reaction, the solvent was removed by distillation. under reduced pressure To the residue is added 40 ml of diethyl ether and

  filter the crystals to obtain 4.3 g (yield

  (91.1%) of the trifluoroacetic acid salt of the acid

  7-1- (2-Aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamidol-3-

  {1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl} A 3-

  Cephem-4-carboxylic acid having a melting point of 155-157 ° C (decomp). 1 IR (K Br) cm: ν C = O 1775, 1710-1630 NMR (d 6 -DMSO) values 1.21 (3H, t, J = 7Hz,> N-CH 2 CH 3), 3, 52 (2H, s, C 2 -H), 3.73 (2H, q, J = 7Hz,> N-CH 2 CH 3), 3.96 (3H, s, -OCH 3), 4.44, 5.12 (2H, A Bq, J = 15Hz, S), CH 2 O, 21 (1H, d, J = 5Hz, C 6 -H),, 83 (1H, dd, J = 5 Hz, J = 8 Hz, C 7 -H), 5.86 (3H, 1s, -NH 3 (), 6.71 (2H, 1s),

H H

  6.95 (1H, s, X 3 T), S H 9.90 (1H, d, J = 8Hz, -CONH-) Similarly, the compounds indicated are obtained

in tables 19 and 20.

  N) ui r-J w w L u w a 1-1 ui FI Ln TAB Lt AU 19 N C -CONH s CF COOH-H N il R 2

2 T ',

3 S R 4 N TN CH 2-

  NMR (d 6 -DMSO) values 9: 3734 (3H-NMR (CH 3) 3), 51 (2H, 1s, C 2 H), 4.100 (3H, m.p. s, -OCH 3), 4.952, 4.90 (2H, A Bq, J = 15Hz, S 1), 5.25 (1H, d, CH = -2Hz = 5Hz, C 6H ), e 9 O (1 H, dd, J = 5 Hz, J = 8 Hz, C -H),

1 7

0 O m

-N, = -CH 3

  1773, 1670, 1660, -102 (decomp) H 1-1 1-1 Ln 6 '6 è (2H, ss, 1H), 699 UH, S, N

1 H H T) 1

  SH 9,, 85 (1H, d, J = 8 Hz, -CONH-) ru A LQ CY% C) -., J, 91. w ul w CD r 1 j (he CD F-ul CD TABLE 19 (after)

  0.86 (3H, t, J = 7Hz,> N- (CH 2) 4 CH 3), 1.05-

  485 (6H, M, N-CH 2 (CH 2) 3 CH 3), 3.53 (2H,

  1s, C 2 -H), 3p 73 (2H, t, J = 7Hz,> N-CH 2 (CH 2) 3 CH 3), 3.93 (3H, se -OCH 3) P 4 , 40, 5.05 (2H, A Bq, J = 15HZ, s

ICH 2-

  , (1H, d, J = 5Hz, C 6 -H),, 86 (1H, dd, J = 5Hz, J = 8Hz C -H), 68

1 7

(2 h, ls 6 f 95 UH, S, NT

H H S H

  9. 85 (1H, d, J = 8 Hz, -CONH-) 1770, 1670, 1660, 1635 O

-N CH

  j N 4 CH 2) 4 3 H -125 (decomp) p F "m ru VI (A (Y% c>, q, & S w ul w CD t 1 o F-1 C) Ln TABLE 19 (cont'd) f - Ln 0 O

-N N (CH) CH H

2 5 p

  0.87 (3H, t, J = 7Hz,> N- (CH 3 CH 3), 1.04-

  1. # 85 (ME ME> NCH 2 (CH 2) 4 CH 3), 3.53 (2H,

1s, C 2 -H), 3.77 (2H, t, J = 7HZ,

  > NCH 2 (CH 2) 4 CH 3), 3.97 OH, S, -OCH 3) JI

  4.r 47, 5113 (2H, A Bq, J = 15Hz, S

ICH 2-

  , 23 (1H, d, J = 5 Hz, C 6 H),? 82 UH, dd, J = 5Hz, J = 8Hz, C-H), 6, 44 (3H, IS, -NH (D) y 6, 70 (2H, 1 SO) c Z 6, 9 UH, S, HHNT), 9 e 85 EU, d, J = 8 HZ, -CONH-) SH 1770, 1670, 1655, -160 (decomp) 1- -1 - J r1) n LY 0% N - il w ui w CD rJ Lri Pli p ui F-1 vi TABLE 19 (cont'd)

  87 (3H, t, J = 7Hz,> N- (CH) CH), 1.04-

  2 μ 18 84 (20 H, M, NCH (CH CH), 3 and 5 (2H,

2 2 10 3

  1s, C 2 -H), 3.72 (2H, t, J = 7HZ,> NCH 2 (CH 2) 10 CH 3), 3.92 (3H, S, -OCH 3). , 45, 5,, 05 (2H, Bq, J = 15Hz, SICH, (1H, d, J = 5Hz, C 6 -H), 5.80 (1H, dd, J = 5Hz, -J = 8Hz, C 7H), 6H (3H, IS, -NH E)), 6, 67 (2H, 1s, ≥), 6, 88 (1H,

3 H H

  s, I), 9.75 UH, d, J = 8 HZ, -CONH-) S H -147 (decomp) 1770, F-1 CD m VI LY 0 CD 1 INJ 1 P%

0 O 1 H

-N N (CH) CH

  2 it 3 it is LTI (i) CD F ui w ui w (1 w TABLE 19 (S uite) 3,52 (2 H, ls, C 2 -H), 3,91 (3 H, S, - OCH 3), 4/41, 4, 98 (2H, A Bq, J = 15Hz, s ICH 4, 95 '(2H, S, -CH, 5, 19 (1H, d, J = 5 Hz, C 5 e 82 (1H, dd, J = 5Hz, J = 8Hz, C-H), 6.15 (3H, 1s, -NH 6.68 (2H,

7 3

  ls, 6 $ 90 (1 H, s, 'N 7 35 (5H, T 1

H H H

  1s, 9e 75 (1H, d, J = 8Hz, CONH-) 1770, 1670, 0M.

-N CH

  _p 2 - <> -135 (decomp) H I-J F-1% D Mi Ln (A CY%

C) 1

  ## STR2 ## 81 (2H, q, J = 7HZ,> NCH 2 CH 3) f 3., 91 (3H, s, -OCH 3), 4 y 42, 5,10 (2H, A Bq, J = HZ, S), 5.19 (1H, d, J = 5 Hz, 1775, 1680,

1 1640

0 1 O

-N NCH CH

  ## EQU1 ## TABLE 1 (S uite) ## EQU1 ## Hz, J = 8 Hz, C 7 H), 6 p 67 (2H, 1 S, c), 9 * 64 (1H, d, J = 8Hz, HH

-CONH-)

  3,, 34 (2H, ss, C 2 -H), 89 (3H, S, -OCH 3), 4.99 (2H, Is, S), S, 12 (1H, d , J = 5Hz, 2-6C), 5.75 (1H, dd, J = 5Hz, J = 8Hz, C 7 -H), N 6184 (1H, s, T) ', 6, 89, 7H (H H, A Bq, HHJ = 10HZ, H H1U, 70 (1H, d, 3 = 8Hz, -CONH-) 1775, 1710, 1-1> JM Ln LY 0% C> -4 41-198 (decomp) H 1 HN -N

1 1 1

  ## EQU1 ## where ## STR1 ## where ## STR1 ## is a compound of the formula ## STR1 ## where 96 '9 HN' gr "HE) Ll" 9 YN J (H-LD ZHS = r IZHS = r "Pp" HI) 88% I (H-9D RDZHS = C #p #HT) úZIG, (s 1 ZHG'l = r 1 bav HZ) Oi> "S" 86 "t, HDO 's HE) 96 41 EJ (HZ" ST Hz) tt, 4, ú HD- "S' HE) -lú z -1 CN f- q o 9 T OIL-1 OLLT (, duioopp)

681-88 T

  H (eq Tns) 61 O Valevi CD N a Ln A 0 ul cn m N - úHD w CD r ') ul w ul rli CD TABLE 19 (cont'd) r- ul r- 2 Y 22 (3 H, S, - CH 3), 3 P 46 (2H, 1s, C 2 -H), 31990 (3H, s, -OCH 3), 4, 4 2, 5, O 5 (2H, A Bq, J = 15 Hz, S 4.78 (2H, S,> NCH

ICH 2-

  UH, d, J = 5 HZ, C 6-11), 5 x 8 O UH, dd, J = 5 Hz, J = 8 Hz, C 1 H), 6, 64 (2H, S, c) f

7 am H

  N 16184 (1H, s, T), 9, 78 (1H, d, J = SHZ, S H

-CONH-)

1820, 1775, 1685, 0 O \ 4

-N N-CH CH

N == / r 3 0 O y

151-154

(decomp) F_ Pli rj the O Ln LY o o 1

at 1

9-

m F-

  TABLE 19 (cont'd) F-1 to Ln w Ln w 3. * 59 (2H, Is, C 2 -H), 3.99 (3H, S, -OCH 3), 4 J 48, 5 , 19 (2H, A Bq, J = 15Hz) ICH'-, 27 (1H, d, J = 5Hz, C6-H), 5.94 UH, dd,

  J = 5Hz, J = 8HZ- C H), 688 (2H, A Bq.

  J-15.6F N J = 6Hz, 6.99, (1H, S,

H H S

H

7.66-8.19 (5H, M, <O

  9792 (1 H, d, J = 8 Hz, -CONH-) 0 O -th OO 1 .d. 1770, -180 (decomp) HP Ni w 1.p 18 (9H, s, -C (CH 3) 3), 3.54 (2H, 1s, C 2 -H), 3.98 (3H 2 SO 3 OCH 3), 4 # 49, 5117 (2H, A Bq, J = 15HZ, 5129 (1H); H, d, J = 5 Hz, CH 2 -C 6 -H), 51 77 (2H, S,> NCH 2), O (1H, dd, J = 5Hz, J = 8Hz , C 7 -H) 1780, 1730, 1690,

108-110

(decompj K) VI

L 4 1

o -

  CD at 19%) C w CD m uul N) CD l- ui F_ CD ul w ul TABLE 19 (cont.) 6/79 (2H, is, ≥), 7702 (1H, SN) 1

H H T

  SH 9199 UH, d, J = 8 Hz, -CONH-) 3.51 (2H, is, C 2 -H), 3.96 (3H, S, -OCH 3), 4., 52, 5 , 15 (2H, 'A Bq, J = 15 HZIS

_CH 2-

  4 e 54 (2H, s,> NCH 2), 5.27 (1H, d, J = HZ, C 6H), 5.88 (1Hfdd, J = 5Hz, J = 8Hz, C 7 -H), N 6, 75 (2H, s, 6.98 UH, at, T) 1

H H S H

  9e 92 (1H, d, J = 8HZ, -CONH-) 1770, 1680, 0O

-N -CH COOH

% == / 2

H

16 I-166

  (de / comp) 1-1 ci 1 a, ru. f.n, w 0% 1 c> 1 Ili 4- NMR (d 6-DMSO) values e: Ln w CD Ni ui m CD FI c> w Ln

TABLE 20

Nj-C CONH 'S CF COOH-H N It 2

3 2 S N 4 VN, CH 2-R

O is COOH (syn-isomer)

J = 7HZ,> N-CH 2 CH 2 CH 3), 1.32-

  ## STR2 ## , 14 (2H, A Bq, G 5.14 UH, d, J = 5HZ, H 2 O, 90 (3H, t, 2, f O 1 (2H, M, C 2 -H)) , 3 rd 73

3,, 96 M, S,

J = 15 Hz, S ic 1770, 1-1 t ') Ln 0 O

-N N (CH) CH

\ ==>, 2 2 3

  -177 (de / comp) ic 6-H), 91 (1H, dd, J = 5Hz, J = 8HZ, C 7 -H), 6.beta. (4H, 1s, - NH (D), 6e, 6 (2H, 1 s,> C: Y),

3 H H

  6.92 (1H, S, NT), 9 P 82 UH, d, J = 8 Hz, S H

-CONH-1

r '.) Ln Lm 1

o -

  CD, + 9% r. 1 CD% O N) Ln CY% .O Il -1

(-HNOD-

  ZH 8 = -C ', p 1 H-1)

1 (H H "IF JHE) EL" 9 HN "IF" Hú)

  9 ú (9 "(H LD l ZH 8 = r l ZHc = f Ipp to HI) 98 s

e (H-9 -1) -lZ "s at (z (E -

  O ZHS = c "PH HD) HD-N <you H HT) IZH I = r lbgv 'HE) is HDO" S' HE) ú 6 'rú "(HZD ls, Hz) H:" HD-N <" ZHL = CP #H 9) Z'T EH D-, the at F = \ 1

HD-N N-

E: HD />

0 O (1 duiooap)

E 9 I-091

0 to 91

  e OUT OLUI EHD- (Gq Tns) oz nvsqgvl 1-4 Ln O r -l N tn CD Ln N ci m i 1 1 1 w ul w CD rl-J ul N) TABLE 20 (cont.) F_ Ln F_ CD ul

  OIF 89 (3H, t, J = 7Hz,> N (CH) CH), 1.03-

* 2 3 3 '

  1.p.93 (4H, m, n-CH 2 (CH 2) 2 CH 3) 3149 (2H, is, C 2 -H) ', 3874 (2H, t, J = 7Hz, > NCH (CH) CH), 92 (3H, e

2 2 2 3 -OCH 3

S

  4.41, 5.11 (2H, A Bq, 15 Hz, ICH 2-

  5.-21 (1H, d, J = 5Hz, C-H), 5.81UH, dd, J = 5Hz, J = 8HZ, C 7 -H), 6.65 (2H, 1s). , HH 6, 87H, S, N 7, P 26 (3H, Is, -NH (D

T 3

  % H, 81 UH, d, J = 8 Hz, -CONH-) 1775, 1710, O

- "(CH) CH

L, 2 3 3

-CH 155-157

3 1 (decomp) for you rlla vi

(A 1

  (X,, "At, 9% w (il w CD Ni ul N) p Ln p a LRI TABLE 20 (cont'd) H H

H H

M,> N) 1

H H

O # 86-21 # 06 (10 AM,

31 45 0 O 1-

_ - (D

  -177 idec O Enp) 1770, -CH 3 (2H, ss, C 2 -H), 3,, 87 (3H, s, -OCH 3),

  4 / 20-4, 71 (1H, M,> N), 4? 36, 5.11

  H (2H, A Bq, J = 15HZ, S-CH), 51.14 (3H, Is, -NH 3), δ p 23 UH, d, J = 5Hz, C 6 11), 5.76 (1H, dd, J 5Hz, J = 8HZ, C 7 -H), 6e 62 (2H, N)

1 S,> C :: Y 1), 6 P 80 (1H, S, T) 1

H H S H

  IP 66 (1H, d, J = 8HZ, -CONH-) r%) Ln L% ècc> 1% to 4%

1 1 1 1

  % e C> NO m Ln r Y úHD- S # ZH T = C 'ba V' HZ) AND "S dl ú 9 E 7 HDO 's' HE) 96 E l (HD (HD)" HDN <"ZHL = f '4 "HZ) úLrú J (HE Ddt" H ?,) E Srú (úHD 9 (ZHD) e HDN <"you" H?: T) 98 EHZ) L (ZHD) N <ZHL = -r 4 "HE) W'O ot, 9 T l 099 T o L T LLT (, duiooap) ET-Túl

ú L 71

HD (HD) men m-

0 O

  (-HNOD 'z H 8 = r' P #Hl) g The 6 'EHN-

1 (H S

  "SI 'HE) 8 ú" L "(O S" HI) 88.19 "(H H

  ## EQU1 ## where ## STR1 ## where ## STR1 ## 'P' HI) S -I They, CE HO-r s ZH T = f Ib UV #HZ) Org 'It, 14 (EHD'o "S" HE)' -16 4 'E (-OZH? HDN <# UI 'Hi "Zi> p (H-ED S 1 HZ) P t,' ú '(E HDODO' S 'HE) L 6' l

0 to 91

YES ozur OLL-1 9 Z

DODO (HD) bf N-

  H 0 O (, diuo oep) L 0-lOl ûHD- (eq Tns) OZ nvaqg Vl a N CD 1 i Ln -ia TABLE 20 (cont'd), (111, d, J = 5 Hz, C 6 -H), 5.88 (111, dd, J = 5HZ, J = 8Hz, C 7 -H), 6, 72 (2H, ss, λ = Y), 6.98 (1H, s, N), 71 (3H, Is, HHT, SH -NH (D) 93 (111, d, J = 8 Hz, -CONH-)

CH 1

  266 (6H, S, -N-, -3), 3.51 (2H, Is' C 2 -H), CH 3 e 93 (3H, s, OCH 3), 4, 42, 5.07 (2H, A Bq, J = 15HZ, S), 5.22 (111, d, J = 5Hz,

ICH 2-

F-1 w CD 0 O cil / il 3

-N N-N

\ _ == 1-1 CH

1770, 1710, -CH 3

179-181

  0, (decomp) C 6 -H), S, 96 (111, dd, J = 5 Hz, J = 8 Hz, C 7 -H), 6, 57, 6 e 72 (2H, A Bq, J = 6 HZ,) =: Y \), 6, 90 (111HH

N (D

  S, T), 7, 44 (3H, 1s, -14119 80 (111, 3 O z SH d = 8HZ, -CONH-) r%) Ln - LY 1 o 1 c>, _Y siii% ## EQU1 ## where: ## STR1 ## where: ## STR1 ## ## STR2 ## ú E s sb (HD & ST 'HE) 9 t, HZ) t, 9 th Z (-Z HDúHD' ZHL = f 11 #HE) Llel

0 to 91

069 T OUT o 8 LT (-duioop) Ip

T-E T

  (-HNOD 'ZH 8 = f' P 'HI) 98 e 6 s H1) 56 "9 HH" SI "HZ) OL' 9 (H LD 'ZH 8 = r' ZH = r EPI ') 06' 9 ## EQU1 ## ## EQU1 ## = P 'b #HZ) Ltl'ru ZD "SI" HZ) ES "' ('HJHDO' ZHL = r" '4 "HE) 6 Z" T # (HZ) ZHDN <"ZHL = f' the HE ) Oz, l E z / = -%

HD 11 D-N N-

0 O St, 91

at SLL-1

  (, dulo Dep) t LI-691 eq Tns) oz nvsqgvl Nt tn -i -1 Ln cli CD m Ln ci tn N-m

úHD HD

E 1 z

H :) HD-

  FIG. 20 (cont.) 1-1 Ln p CD w ul w CD N) μl C 6 -H), 5.88 (1H, dd, J = 5Hz, J = 8Hz, C 7 -H), 6.95, 7 IV 19 (2H, A Bq, J = 1 O Hz, H), 1H

6.P 97 (1H, SN) 1

  T, H, OH (OH), NH (E)), 9.90 (1H, d, J = 8HZ,

"P 3

-CONH-)

  ## STR2 ## (5 H, s, -CH 3 x O, 5), 2.07 (1.5H, s, -CH 3 X 01.5). ), 319 (2H, 1s, C 2 -H), 3H (JH, s, OCH), 4, 97 (2H, 1s, S CH: ux, 09 (1H, d, J); = 5 Hz, C 6 -H), 5.73 (1H, dd, J = 5 Hz, J = B Hz, C 7 -H), 6 IP 77 (0.5H, s, YH x 015) , 6, p BO (1H, s, N: T), 6 # 94 (OJ 5H,

S H 1

> 200 1770, 1710, -CH 3 HN CH

1 3

-NOT

1 1 1 1

% r 1 r 1 CD NO N-) Ln C% to

(-HMOD-

  s "H-1) 86 dr L ZH 8 = ú" P l H-1) 9 9 # S "(" Hi H Hg = V "bg V 'HZ) LS" L "-lud L HT) osf 9 ## EQU1 ## where: ## STR1 ## where: ## STR2 ## "HZ) 99-'S '-lS # tl é (E HDO" S "Hú) L 8 E: to (H ED' ST HZ) út '4 ú mm -1 (' duiooap) LVI-t PT Mi ç

"OLL-E

  ## EQU1 ## -1 CD cn tn ro Ln N- N i

N) F

  TABLE 3 (continued) ## STR2 ## 40 (2H, is, C 2 -H), 3, 90 OH, s, -OCH 3) 4, P 87, 5 P 24 (2H, A Bq, J = 15HZs

icil 2-

  , 06 (1H, d, J = 5 Hz, C 6 -H), 5/78 UH, dd, J = 5Hz, J = 8Hz, C 1H), 6.84 (1H, N, N).

7 T),

  S H 7.44 (1H, s-H), 9.69 UH, d, J = 8HZ,

-CONH-)

  1775, 1710,> 200 -CH 3 F-1 W a. r%) Ln w 1 (X, c>,

4 1

  9% 3, 5 O (2H, 1S, C 2 -H), 3.95 (3H, SI-OCH 3), 41847, 5.15 (2H, A Bq, J = 15Hz, s ICH, 24 (1H, d, J = 5HZ, CH), 85 (1H, dd, J = 5HZ, J = 8Hz, C 7 -H), 6.46, 6.62, (2H, A Bq, J = 6HZ, ≥: Y1,), 6, 94 (1H, INS 7.03

H H T

  ## STR3 ## (1 H, d, J = 8 Hz, -CONH-) O

-IL =, NH

1770, -CH 3

168-170

(decomp) H 1 Nci -N

  (4) In 30 ml of water 6.35 g of trisodium acid salt are dissolved in

  7-l 2- (2-aminothiazol-4-yl) -2- (syn) -methoxy-acid fluoracetic acid

  iminoacetamidol-3- [1- (2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl] -3-cephem-4-carboxylic acid and the resulting solution is adjusted to pH 7.4 with Sodium hydrogencarbonate is then purified by passing it through an "Amberlite XAD-2" column to obtain 4.7 g (86.6% yield) of

  7-1- (2-Aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamidol-3-

  sodium 1- (2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) -1-methyl-3-cefem-4-carboxylate having a melting point of 200 C or higher. IR (K Br) cm-1: CO 1763, 1670, 1650-1620 In a similar manner, the following compounds are obtained: ## STR2 ## 2- (2-Aminothiazol-4-yl) -2- (syn) methoxyiminoacetamidol Sodium 3-1-1- (4-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl) cephem-4-carboxylate, mp: 190-195 ° C (decomp) IR (K Br) cm -1 1: -CO 1760, 1670, 1650, 1630 o 7-1- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamidol

  3- (1- (3,6-dioxo-1,2,3,6-tetrahydropyridazinyl) -methyl) -3-

cephem-4-carboxylate sodium.

  o 7-1 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamidol

  3- (1- (3-methyl-6-oxo-1,6-dihydropyridazinyl) methyl) -3-

cephem-4-carboxylate sodium.

Example 7

  (1) To a solution of 3 g of 2- (2-tritylaminothiazol-4-

  yl) -2- (syn) -t-butoxycarbonylmethoxyiminoacetic acid in 15 ml of

  N, N-dimethylacetamide is added dropwise 0.93 g of oxyhydroxide.

  phosphorus chloride at 10 ° C. and the mixture is subjected to reaction for one hour at 5 ° C. This solution is added dropwise to a solution of 19.4 ml of methylene chloride.

  anhydrous product containing 1.94 g of 7-amino-3-yl 1-l- (4-ethyl-2,3-dioxo)

  1,2,3,4-tetrahydropyrazinyl) N-methyl-3-cephem-4-carboxylic acid and 2.25 g of bis (trimethylsilyl) acetamide at 5 ° C. Once

136 2536074

  the dropwise addition is complete, the mixture is subjected to a reaction at the same temperature for 30 minutes and then to

  a temperature of 0 to 10 C for 30 minutes After the completion

  In the course of the reaction, the methylene chloride is distilled off under reduced pressure and a mixed solvent of 100 ml of saturated aqueous sodium chloride solution and 100 ml of acetonitrile is added to the residue. organic layer and washed twice with 1 ml portions of a saturated aqueous solution of sodium chloride and then the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 50 ml of methanol after which 1 g was added. diphenyl diazomethane to the solution at a temperature of 5 to 10 ° C. and the mixture is reacted at the same temperature for 30 minutes. After completion of the reaction, the solvent is distilled off under reduced pressure and the residue is purified. by column chromatography (Wako C-200 silica gel, eluent: benzene / ethyl acetate

  = 3: 1) to obtain 1.6 g (27.8% yield) of 7-l 2- (2-trityl)

  aminothiazol-4-yl) -2- (syn) -t-butoxycarbonylmethoxyiminoacetamidol -3- {1 (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl) -3-cephem- 4-diphenylmethylcarboxylate having a point of

melting of 98-100 C (decomp).

  -1 IR (K Br) cm: CO 1780, 1720, 1680, 1630 NMR (d 6 -DMSO) values: 1.17 (3H, t, J = 7Hz,> NHC 2 CH 3), 1, 44 (9H, s, -C (CH 3) 3), 3.62 (2H, 1s, C 2 -H), 374 (2H, q, J = 7Hz,> N-CH 2 CH). 3), where 4.55 (2H, s, -OCH 2 C-), 4.51, 5.16 (2H, A Bq, J = 15Hz, S), 2- 1 3 7

519 27

, 87 6, 55 (1 H, (11 i '

(2 E,

  d, J = 5HZ, C 6 -H), dd, J = 5Hz, J = 8Hz, C 7 -H),

1 S, ≥MI \),

H H

S, -CH <),

N S, - STH) (25H, m, _D x 5),

Is, (D) 3 C-NH-) -

d, J = 8 Ez, -CONH-)

6 80 (1H '

6 p 97 UH,

7 E 05-77 67

8, 86 (1H,

9, 54 (1H,

  Similarly, the indicated compounds are obtained

in Tables 21 and 22.

w o Ln t '. o H_ ui H- CD (A

TABLE 21

N -j-CCONH S C-N "/ II N CH-R 2

() 3 H \ Si N O 2-

\ 18 COOCH (D> 2

  OR (syn-isomer) compound P F (OC) IR (K Br) cm-1

R 2 R 18 _ _ _ _ _ _

  O CH 3 118-120 1780, 1720, 1690-1640

  -N N-Ci I CH -C-Cu OC (CH 3) (d 4 comp) C Hi 3 o o

-156 1780, 1720, 1680, 1640

-N N-H 1 -CH 2 COOC (CH)

2 3 3 (Decline) o o

  N-CH 125-127 1785, 1725, 1690, 1645

  3 -C 2 COC 3 3 (decomp> w ua C Da -'J ol TABLE 21 (cont'd) o o

111 CH 3

-N N-Ns

\ - = '/ ", CH 3

-CH 2 COOC (CH 3) 3

151-154

(decomp>

1780, 1725, 1685, 1640

o

-H 126-130 1780, 1725, 1690-1660

-N 2 O <C 3) 3 (decomp)

N 118-1201780, 1720, 1660

  -1 -CH 2 COOC (CH 3) 3 (decomp> Cl o P1) H-ul H-CD Ln 'H w CD c)) -W ul w CD m J Pcl, CD H u L H 1 a Ln'

TABLE 22

N CCONH S

<SQ)) C-N-il: Nr CH R H SN o 2

C OC (CH 3)

OCH 2 COOC (CH 3) 33

p F <oc) IR (K Br> cm

R 2 PF (C =

  0 133-1351820, 1780, 1720, 1690, 1650

  -N N-CH 2 CH 3 (decomp) 0'O o o o -N N 164-167 1785, 1730, 1710, 1690, 1660 (decomp)

-138 1785, 1740, 1730, 1710, 1680,

  -N N-CH 2 COC (CH 3) 3 (decomp) 1660 H 0 a w w w w a N) ul r1) Ln i-1 Ln TABLE 22 (continued)

0 '10

-N N-CH 2 COOCH () 2

D

152-154

(Decomp)

1785, 1750, 1720, 1690, 1655

F-1 J-P r%). t A w 1

0% 1

CD 1

Ili -es

142 2536074

  (2) In a mixed solvent of 8 ml of trifluoroacetic acid and 3 ml of anisole, 1.6 g of 7-l 2- (2-tritylaminothiazol are dissolved in

  -4-yl) -2- (syn) -t-butoxycarbonylmethoxyiminoacetamidol-3-1- (4-

  ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl-3-cephem-

  Diphenylmethyl 4-carboxylate and reacted at room temperature for one hour. After completion of the reaction, the solvent was distilled off under reduced pressure and 10 ml of diethyl ether was added to the residue and the crystals by filtration, they are dissolved in 20 ml of a 50% by weight aqueous solution of formic acid and the solution is reacted at 45-55 ° C. for one hour.

  When the reaction is complete, the precipitated crystals are separated by filtration.

  The residue is distilled off under reduced pressure. 10 ml of ethyl acetate are added to the residue and the crystals are collected by filtration and the crystals are washed.

  enough with 10 ml of ethyl acetate and dry them to obtain

  0.7 g (yield: 80.7%) of 7-1-2- (2-aminothiazol-4-yl) acid.

  2- (syn) -carboxymethoxyiminoacetamidol-3 1- (4-ethyl-2,3-dioxo)

  1,2,3,4-tetrahydropyrazinyl) 1-methyl-3-cephem-4-carboxylic acid

  having a melting point of 139-140 ° C (decomp).

  IR (K Br) cm ν C = O 1775, 1695, 1680, 1635 NMR (d 6 -DMSO) S values: 1.22 (3H, t, J = 7Hz,> NCH 2 CH 3), 3, 53 (2H, 1s, C 2 -H), 3.74 (2H, q, J = 7Hz,> NCH 2 CH 3), 4.70 (2H, s, -OCH 2 CO-), 4.45, 5.10 (2H, A Bq, J = 15Hz, S CH 2, 23 (1H, d, J = 5Hz, C 6 -H),, 90 (1H, dd, J = 5 Hz, J = 8 Hz, C 7 -H), 6.69 (2H, Hs, =), HH

143,253

  6.94 (1H, s, N X S H 9.70 (1H, d, J = 8Hz, -CONH-) Similarly, the compounds indicated are obtained

in Table 23.

  IR compound (K Br) P.P (11c) CM-1: V NMR (d 6 -DMSO) values ce: R 2 1 R 18 C = c w Ln w The i ui Ni CD 1 a F-c> ui

TABLE 23

N C CONH

  H 2 N T il LN ci 2 N 1 i 2 -R 0 COOH (syn-isomer)

OR 1 "

  22 (3H, t, J = 7HZ,> NCH 2 Cl) 1 IP 53 (6H, S, CH 3)

-C-COOH

  CH 3 3 IP 54 (2H, Is, C 2 -H), 3rd 75 (2H, cl, J = 7Hz,> NCH 2 CH 3), 4.49, 5.16 (2H, A) Bq, J = 15 Hz, SI 1),

CH 2-

  5. 27 (1H, d, J = 5HZ, C 6 -H), 6/01 (1H, dd, J = 5Hz, J = 8Hz, C 7 -H), 6.72 ( 2H, ls, '>), 6, 9 6HH * 1O O

-N NCH CH

\: Y, 2 3

  -166 th (decoràp) 1775, 1705, s F-1 P. CH 3 -u-uuun CH rla ui LY 0%

CD 1

  1% j 4% rli m F-1 1-1 ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui ui uu a TABLE 23 (sui-t) (1 H, S, N 9,64

3 IP 44 (2H, IS, C 2 -H), 4, 42,

  0 O 1770, 5 e OO (2H, A Bq, J = 15Hz, S

-CH COOH 182-183 1690,

-N NH 2 ;, CH

(decomp) 1670, 2-

1640 -

  4.60 (2H, 1s, -OCH 2 COOH), Ln, 19 (1H, d, J = 5Hz, C 6 -H),, 84 (1H, dd, J-5Hz, J = 8 Hz, CH), 6.52 (2H, A Bq, J = 6Hz, ≥ = (,), 6.82 (1H, s, NHH S) 1H 9,, 56 (1H, d, J = 8 Hz, -CONH-) c> w ul w O tll) a pu F (TABLE 1 (continued) * 1 3, 34 (3H, s,> NCH), 3 41 (2H, Is, c 2 -H), 4/45, 5.02 (2H, A Bq,

J = 15Hz, S), 4/67 (2H,

CH 2- 0 O m

-N N -CH 3

1770, 1680, 1660,

-CH 2 COOH

  88-91 (dec, comp) Is, -OCH 2 COOH), IP 16 (1H, d, J = 5HZ, C 6 -H), 5.84 (1H, dd, J = 5Hz, J = 8 Hz, C 7 -H), 6 IP 60 (2H, "-), 6.97 (1H, S, N Is, / HH SiHH 9.75 (1H, d, J = 8 HZ, -CONH 7) F-1 ol ru Ln

W 1

&% 1

c>, j, * 1 0 O

> __ / H 3

-N N N

\ == / CH 3

  CH 3 2 85 (6H, s, -N '), 3.49 (ZH, f <CH ls, C 2 -H), 4.43, 4.98 (2H, A Bq, J = 15 Hz , S) # 4 e 65 (2H, S, CH-1770, 1710, 1670, -158 (decomp)

-CH 2 COOH

  m TABLE 23 (cont'd)% u Ln w Ln w Ni ui -OCH CO-), 5.15 UH, d, J = 5 Hz, C 6 -H), 5.79 (1H, dd, J = 5 HZ, J = 8 Hz, C 7 -H), 6.61 (1H, 1s, = =), 6 p 9 (1H, S, Nr), HHSH 9 P 65 (yA, d, J = 8 Hz, -CONH-) 2, 22 (3H, s, -CH 3), 3.50 (2H, Is, C 2 -H), 4.70 (2H, S,> NCH 4 , 85 (4H, 1s, -OCH 2 CO-, S CH 2 - 5.927 (1H, d, J = 5Hz, C 6 -H), 5.794 (1H, ddI, J = 5Hz, J). = 8 Hz,

C H), 65 (2H, S,

7 am H

  N, 6.97 (1H, s, sHII), 9.81 UH, d, J = 8 Hz, -CONH-) 1820, 1770, 1680, I-Ln w (X: CD, IJ 41. 0). O

-N N -CH 2 CH 3

-M 0 y O

-CH 2 COOH

I-154

  (decomp) ## STR1 ## CD 3.75 (2H, Is, C 2H), 41.47, 5, 13 (2H, A Bq, J = 15 Hz, S TABLE 23 (continued) 1 M

-CH COOH 137-140172 (

  ## STR2 ## , J = 5 Hz, C 6 -H), δ p 97 (1H, dd, J = 5Hz, J = 8Hz, C 7 -H), 6e 12, 6X 66 (2H, A Bq , J = 6 Hz, "), 7105 HHN 3 1 (1 H, S, SH) 7.61-8.25 (514, m, H + 8.88, 1H, d, J) = 8 Hz, - CONH-) 1-1b> CO 1790, 1730, 1690, 1.7

* (2 H,

At Bq,

(9H, S, -C (CH 3) 3), 3,, 72

  1s, C 2 -H), 4,, 46, 5.20 (2H, J = 15H 2 O, S J, 4 # 70 (2H, CH 2

178-183

(decomp) r 1 o LA

(A 1

1 O% c>, Ili 1 -es

-CH 2 COOH

0 O H_

-N N CH 20 COC (CH 3) 3

  i 1 1r 'r' O% O 1 M Ln CY "if" HZ) t, L 9 (H LD 1 ZH 8 = r

at ZHS = C 1 PP 1 LO LO "9 '(H-9 D

  "ZHS = L L P HE) 0-l" S l (-ODE HDO_ "S" HZ) E: Read, j (-E HDN <1 S 'HZ) ZHD i> S 4, t ,, (T 9' ZHST = P 'bg'V' HZ) 8 Z 4 '9 8 t, 4' P '(H ZD' 91 'HZ) EL d, EE

HOOD HD-N N-

0 O

9 to 91

1 0891

OUT

'08 LI

("diuo Depy

ZPT- ET

HOO Dz HD-

  m -1 (-HNOD IZH 8 = r ip HT) L 8 "B j (HS, S YN HI) where L j (HH" SI "HZ) EL ,, g, (H_LD z H 8 = r èz HG = ## STR1 ## wherein: ## STR2 ## ## STR1 ## where: ## STR1 ## FIG. 23 (cont'd) ## STR2 ## ) 1

H H S IH

  89 (1H, d, J = 8Hz, -CONH-) II 3.34 (2H, 1s, C 2 -H), 4f 63 (2H, s, -OCH 2 CO-), 4 , 98 (2H, Is, S 5.10 (1H, d, J = 5Hz, U CH 2 -C 6 -H), 5.77 (1H, dd, J = 5Hz, J = 8 Hz, C 7 -H), 6? 83 (1H, s, N 6.85, 7 ill (2H, A Bq,

S TH H

  J = 10 HZ, 9 P 51 (1H, d, J = 8 Hz, -CONH-) * 1770, 1710, 1660,

-CH 2 COOH

  -193 (dcomp) F_Ln a r%) t A LM 01. gc>,

1114 1

  9% HN 1 N TABLE 23 <continued> H-Ln A H -Ac Ln 228 (3H, s,> - c H), 3.43 (2H, is, C 2 -H>, 4.73 ( 2H, s, -OCH 2 CO-), 5.14 (1H, d, J = 5Hz, C 6H, 5.23 (2H, 1s, 1H), CH 2, 88 (1H, dd, J = 5Hz, J = 8Hz, C 7 -H), 6, P 96, 7.46 (2H, A Bq, J = 10Hz, JH), 7.1O (1H, s, ), 7.80 (3H, 1s, -NH (

5311 H 3>

9.76 (1H, d, 7 = 8Hz, -CONH-)

A 1

  Note, * 1 trifluoroacetic acid salt (to purify the product obtained by the process mentioned above, it is converted into a diphenylmethyl ester in the usual manner, then de-esterified with trifluoroacetic acid to obtain a trifluoroacetic acid salt) * 2 Formiate w U 'wo) * 2 CH N -N o

-CH 2 COOH

194-197

(decomp) 1770,

1710 ,.

Ln I H- pu 4-.

Example 8

  (1) To a solution of 1.68 g of diketene in 8.40 ml of

  Anhydrous methylene chloride is added dropwise a solution of

  2.08 g of bromine in 6.25 ml of anhydrous methylene chloride are stirred at 30 ° C. and the mixture is subjected to stirring.

  reaction at a temperature of 30 to 200 C for 30 minutes.

  The reaction mixture thus obtained is added dropwise at a temperature of 30 C or less to a 50 ml solution of

  anhydrous methylene chloride containing 5.20 g of 7-amino-3-

  1- (4-Ethyl-2,3-dioxo-11,2,3,4-tetrahydropyrazinyl) methyl) A 3-

  diphenylmethyl cephem-4-carboxylate and 4.08 g of bis (trimethyl)

  silyl) acetamide. After completion of the dropwise addition, the mixture is reacted at a temperature of 30 to 20 ° C for 30 minutes and then at a temperature of 0 to 10 ° C for one hour. After completion of the reaction, the reaction mixture is removed. distilled off under reduced pressure and the residue thus obtained dissolved in 50 ml of ethyl acetate and 40 ml of water. The organic layer is separated off, washed with 40 ml of water and 40 ml of saturated aqueous solution of water. sodium chloride in this order, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue is added to the residue 50 ml.

  of diisopropyl ether and the crystals are collected by filtration.

  rates thus obtained to obtain 5.85 g (yield: 85.6%)

  7- (4-bromo-3-oxobutylamido) -3-lll- (4-ethyl-2,3-dioxo, 1 12,3,4-

  diphenyl tetrahydropyrazinyl) methyl (3-cephem-4-carboxylate)

  methyl having a melting point of 138-1420 C (decomp).

  IR (K Br) cm-1: ν C = O 1778, 1720, 1680, 1640 NMR (d 6 -DMSO) values: 1.22 (3H, t, J = 7Hz,) NCH 2 CH 3), 3.40 (2H, 1s, C 2 -H), 3.85 (2H, q, J = 7Hz, NCH 2 CH 3), 3.87 (2H, Is, Br CH 2 COCH 2 ), 4.18 (2H, Is, Br CH 2 CO-), 4.47, 4.96 (2H, A Bq, J = 15Hz, YIC 5.04 (1H, d, J = 5); HZ, C-H), 2.90 (1H, dd, J-5Hz, -8HZ, C-) 6, 15, 6, 50 (2H, A Bq, J = 6Hz, ≥D <), HH 6.98 (1H, s, -C <) 7.40 (10H, is, O x 2), 8.55 (1H, d, J = 8Hz, -CONH-) From similarly, the following compound was obtained 4. 09 g (yield 62.6%) of 7- (4-bromo-3-oxo-b-ylamido)

  -3-tl 1 (3,6-dioxo-1,2,3,6-tetrahydropyridazinyl)) methyl) A 3-

  d-iphenylmethyl cephem-4-carboxylate having a melting point of 1241260 ° C (decomp) IR (K Br) cm 1780, 1725, 1660 NMR (d 6 -DMSO) S values: O 3.49 (4H, is , C 2 -H, -CCH 2 C-),

O

  4.52 (2H, s, Br CH 2 C-),, 06 (1H, 1s, S, 26 (1H, d, J = 5Hz, CH), 90 (1H, dd, J = S Hz, J = 8 Hz, C 7 H) 7.01, 7.25 (2H, A Bq, J = 1 O Hz, y) 7.09 (1H, s, -CH), 7.24 -7.91 (10H, m, x 2), 9.34 (1H, d, J = 10Hz, CONH-) (2) To a solution of 5.50 g of 7- (4-bromine) Diphenylmethyl 3-oxobutylamido) -3- [1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) -methyl] -A-cephem-4-carboxylate in 30 ml of acetic acid is added dropwise a solution of 5 ml of water containing 0.74 g of sodium nitrite with ice-cooling in one hour, and then the resulting mixture is subjected to reaction at room temperature for two hours. reaction mixture in 500 ml of water to precipitate crystals The crystals are collected by filtration, washed sufficiently with water and dried. The crystals are then dissolved in 10 ml of chloroform and purified by column chromatography ( Silica gel C- 200 of Wako, eluent: benzene / ethyl acetate = 2: 1 by volume),

  to obtain 3.15 g (yield: 54.9%) of 7- (4-bromo-2-hydroxy)

  imino-3-oxobutylamido) -3- {1 1- (4-ethyl-2,3-dioxo-11,2,3,4-tetrahydrate)

  Diphenyl-3-cephem-4-carboxylic acid hydropyrazinyl) methyl

  methyl having a melting point of 127-132 C (decomp).

  IR (K Br) cm 1 v 1778, 1720, 1680, 1635

C = O

  NMR (CDCl3) values: 1.26 (3H, t, J = 7Hz,> NCH 2 CH), 3.47 (2H, 1s, C 2 -H) 3; 81 (2H, q, J-7Hz,> NCH 2 CH 3), 4.52 (2H, s, Br CH 2 CO-), 4.53, 4.78 (2H, A Bq, J). = 15 Hz, S), CH 2 to 5.11 (1H, d, J = 5 Hz, C 6 -H),

, 80-6.15 (1H, M, C 7H)

  6.13, 6.52 (2H, A Bq, J = 6Hz, H - 7.902 (1H, s, -C) 7, P 41 (10H, 1s, O x 2), 9, (1H, d, J = 8Hz, -CONH-) Similarly, the following compound is obtained

  4.71 g (yield: 75.1%) of 7- (4-bromo-2-hydroxyimixi)

  3-oxobutylamido) -3-ill- (3,6-dioxo-1,2,3,6-tetrahydropyridazinyl) -1-methyl-3-cephem-4-carboxylic acid diphenylmethyl having

  melting point 138-141 ° C (decomp).

  IR (K Br) cm 1780, 1720, 1660 NMR (d 6 -DMSO) values 3.46 (2H, 1s, C 2H), 4.62 (2H, s, Br CH 2 CO-) 4.96 (2 hrs, ls,

, 1 CH 2 -

  5.18 (1H, d, J = 5 Hz, C-), 93 (1H, dd, J = 5Hz, J = 8Hz, C 7 -H), 6.89, 7.13 (2 H, A Bq, J = 1 Hz, 6.96 (1H, s, -CH <), 7.13-7.72 (10H, m, x 2), 9.45 (1H, d, J = 8 Hz, -CONH-), 13.36 (1H, s, = N-OH) (3) In 12 ml of N, N-dimethylacetamide, 3.00 g of

  7- (4-bromo-2-hydroxyimino-3-oxobutylamido) -3-1- (4-ethyl-2,3-

  dioxo-1,2,3,4-tetrahydropyrazinyl) methyl-t-4-carbophenyl

  diphenylmethylate from (2) above and 0.42 g of thiourea and the resulting solution was reacted at room temperature for three hours. After completion of the reaction, the reaction mixture was poured into a mixed solvent. 120 ml of water and 240 ml of ethyl acetate are then adjusted to pH 7.0 with sodium hydrogencarbonate, then the organic layer is separated and washed with 50 ml of water and 50 ml of a saturated aqueous solution of sodium chloride in this order After drying of the organic layer over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure to the residue is added 20 ml of diethyl ether and collected the crystals by filtration to obtain 2.10 g

  (yield: 72.3%) 7-1- 2- (2-aminothiazol-4-yl) -2- (syn) -hydroxy-

  iminoacetamidol-3- {1- (4-ethyl-2,3-dioxo-11,2,3,4-tetrahydropyridine)

  Diphenylmethyl zinyl) -methyl) L 3 cephem-4-carboxylate having

  a melting point of 137-140 ° C (decomp).

  IR (K Br) cm 1 v CO 1778, 1720, 1680, 1640 NMR (d 6 -DMSO) values: 1.19 (3H, t, J = 7Hz,> NCH 2 CH 3), 3.48 ( 2 H, 1 is, C 2 -H), 3.68 (2H, q, J = 7Hz,> NCH 2 CH 3), 4.46, 5.04 (2H, A Bq, J = 15 Hz, SH),

-CH 2

  , 28 (1H, d, J = 5 Hz, C 6 -H),, 97 (1H, dd, J = 5Hz, J = 8Hz, C 7 -H), 6, 57, 6.75 (2H, A Bq, J = 6Hz,>),

H H

  6.79 (1H, s, NT), SH 7.07 (1H, s, -CH <), 7.53 (10H, Is, x 2), 9.70 (1H, d, J). = 8 Hz, -CONH-) (4) In a mixed solvent of 10.0 ml of trifluoroacetic acid

  and 2.0 ml of anisole were dissolved 2.00 g of 7-l 2- (2-aminothiazol-4-

  yl) -2- (syn) -hydroxyiminoacetamidol-3- {1- (4-ethyl-2,3-dioxo-1,2,3,4-

  Diphenyl tetrahydropyrazinyl) methyl S 3 -tephem-4-carboxylate

  methyl obtained in (3) above and the resulting solution is

  aunt to a reaction at room temperature for two hours.

  Once the reaction is complete, the solvent is distilled off

  under reduced pressure and 15 ml of ether are added to the residue.

  diethylic acid after which the crystals are collected by filtration.

  Subsequently, the crystals are sufficiently washed with 10 ml of diethyl ether and dried to give 1.62 g (yield:

  87.6%) of a salt of 7-l, 242-amino acid trifluoroacetic acid

  thiazol-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 112-118 ° C (decomp).

  -1 IR (K Br) cm: VC 1780, 1680, 1620 NMR (d 6 -DMSO) values: 1.19 (3H, t, J = 7Hz,> N-CH 2 CH 3), 3.47 (2 H, 1 s, C 2 -H) 3.72 (2H, q, J = 7Hz,> NCH 2 CH 3), 4.45-6.70 (4H, m, S CH, C 6 -H, C 7 -H), C 2-6.59-6.83 (3H, m ,,)

H H

158-2536074

Example 9

  (1) To a solution of 7.1 g of 7- (4-bromo-2-hydroxyimino-3-

  oxobutylamido) -3- {1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyridine)

3

  diphenylmethyl (1-methyl) -3-cephem-4-carboxylate in 70 ml of anhydrous methylene chloride, a

  diazomethane solution in diethyl ether at a temperature of

  5 to 0 ° C and the resulting solution is subjected to a reaction

  At the same temperature for 30 minutes After confirming the disappearance of the diazomethane, the solvent is distilled off under reduced pressure and the residue is then purified by column chromatography (Wako C-200 silica gel, eluent: benzene / acetate ethyl = 3: 1 by volume) to obtain 2.32 g

  (Yield: 32.0%) 7-1-4-bromo-2- (syn) -methoxyimino-3-oxo

  diphenylmethyl butylamidol-3- {1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl) 3-cephem-4-carboxylate having one point

melting point of 135-140 ° C (decomp).

  -1 IR (K Br) cm: ν C = O 1778, 1720, 1682, 1638 NMR (CDCl3) f values:

3

  1.25 (3H, t, J = 7Hz,> NCH 2 CH 3), 3.48 (2H, Is, C 2 -H), 3.84 (2H, q, J = 7Hz, CH 2 CH 3), 4X00 (3H, s, -OCH 3), 4.10 (2H, s, Br CH 2 CO-), 4.48, 4.67 (2H, A Bq , J = 15Hz, S), CH 2 5.10 (1H, d, J = 5Hz, C 6 -H), 6.05 (1H, dd, J = 5Hz, J = 8Hz, C 7 -H), 6.38, 6.73 (2H, A Bq, J = 6Hz,),

H H

  6.98 (1H, s, -H) 7.32 (10H, s, O x 2), 9.18 (1H, d, J = 8Hz, CONH-) Similarly, we obtain the next compound

  1.70 g (24.5% yield) of 7-l-4-bromo-2 (syn) methoxy-

  imino-3-oxobutylamido D-3-EL- (3,6-dioxo-1,2,3,6-tetrahydropyridine)

  zinyl) 1-methylphenyl-4-phenyl-4-carboxylic acid diphenylmethyl

  a melting point of 145-148 to C (decomp).

  IR (K Br) cm 1780, 1730, 1660 NMR (d-DMSO) values 3, P 49 (2H, ss, C-) 4.03 (3H, s, -OCH 3>), 4.60 ( 2H, s, Br CH 2 CO-),

> 02 (2H, IS, SN-

-H 2-

  , (1H, d, J = 5Hz, C 6H), 6.02 <(1H, dd, J = 5Hz, J = 8Hz, C 7 -H>, H 6.92, 7 , 16 (2H, A Bq, J = 1O Hz, 6.99 (1H, s, -CH <) 7.17-7.78 (10H, m, x 2),, 16 (1H , d, J = 8 Hz, -CONH)

2536074

  (2) In 14 ml of N, N-dimethylacetamide 2.3 g of

  7-1-4-Bromo-2- (syn) -methoxyimino-3-oxobutylamidol 3 1H- (4-ethyl)

  2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl) A-cephem-4-

  diphénylmethyl carboxylate and 0.32 g of thiourea, and the resulting solution is then reacted at room temperature for three hours. After completion of the reaction, the reaction mixture is poured into a mixed solvent of 50 ml of water and

  ml of ethyl acetate is then added hydrogen carbonate.

  The organic layer is extracted twice with 100 ml portions of ethyl acetate. The combined organic layer is washed with water and heated to room temperature. dried over magnesium sulphate

  anhydrous, and then the solvent is distilled off under pressure.

  reduced to 20 ml of diethyl ether, and the crystals were collected by filtration to give 1.92 g.

  (yield: 86.3%) 7-1- 2- (2-aminothiazol-4-yl) -2- (syn) -methoxy-

  iminoacetamidol-3-fluoro-1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyridine;

  diphenylmethyl znyl) -methyl-3-cephem-4-carboxylate having a melting point of 165-167 ° C. IR (K Br) cm 1: C = O 1780, 1720, 1680, 1640 Similarly, the following compound: o 7-1 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamidol

  3- [3- (3,6-dioxo-1,2,3,6-tetrahydropyridazinyl) methyl) Δ3-cephem-

Diphenylmethyl 4-carboxylate.

  Mp: 175-178 ° C (decomp) IR (K Br) cm 1: QC = O 1780, 1720, 1685-1660 The same cyclization reaction is carried out as above and then the reaction mentioned in the example is carried out 6- (3) or Example 7- (2) to obtain the compounds

  shown in tables 24, 25 and 26.

R 2 R 2 R 2

CH O O

3> __ 11

9 \ i

-N-CH 3 -N N-CH COOH

N 'k 2 -N

0 O CH O O

\ 1 e CH 3

  -N N (CH) CH 3 N -N N (CH 2) 2 CH 3

  2 4 3 w Ln w Pl,) ui r%) f- ui 1 l Ln

TABLE 24

N -C CONH S_

  CF COOH H: N-1 II N '3 2 S No. 1-CH 2 R 2

\ OCH COOH

3 (S Yn-i Stern) F-1 0) 1- r 1%)

Ln -

LY O c>, Ili 1 4% lq- E L Z / e ==, \

N HZ) (RD) -M N-

ú H N N-

I + IE 1 E z E / e =, \

NH RD HD HDOD RD HDN n

0 O O

  za EU 1-r 1 N. CD% O m Ln Cu t n o 1 i (P: l Tns) pz flvsrlúlvl CD Ui O N C, 4 m CD r-l Ln 1-1 tn

0 O O O O O

0 O

-N (CH CH -N N -N N (CH CH

0 O O O O

  -N N-CH -N P-CH 2 OCOC (CH 33 -N N (D

  N) a I Ln 1-1 CD ui w ui w a yaa Ln TABLE 24 (cont'd) 0 Y

I 'CH 3

-N -CH

"CH 3

0 O

-N NCH C = C-CH

2 '\ 3

\ == / y 0 O y 0 O

-N N (CH 2) 5 CH 3

  1-1 m w r%) Ln (A 0% c> _, j, 9- NH HD HD z

HN N HD HDN N-

0 Y N -

ID 1 EHD ,,

NH M-N N-

CHD> -

  ## EQU1 ##

TABLE 25

s SJJ 5 NN CORNH y R

OR 18 COOH

(syn isomer)

R 2 R R 18

-N NCH 2 CH 3 NH 2 C 2 COH

0 O CH 3 lm, 1H 2 CH 3 CF 3 COOH NH 2 C-COOH CH 3 O OD

-N NH NH CH COOH

2 2

O O

-N NCH 3 COHNH CH COOH

  HOODERD Z HN c (c HD) DODOERD / -N _e 0 O

0 1

l L., z z O- 'HOOD RD Hm r / e = * \

HZ> -D = DHDN K-

e-40 N-z z 1

HOOD HD HN-HOODH N

RD c oc

N N -

0 O

HOO Dz RD-

-Z HN he

HOOD 2: RD-

_z HN'HOODH s (eq Tns) sz nvsqavl

Z 09 úSZ

TABLE 25 (cont'd) o o

N NCH COOH

\ _ 20 2

H 2-

-C.H 2 COOH

o o

-N NCH CH HOHN HCO

\ - = i 2 3 COHN 2 -C 2 CO-

  CH 2 CH 3 HCOOH-NH 2 CH 2 COO-e

-N T CHCH HCOOHNH HCOCH CH

\ = 2 3 2 d 2 HC 2 3

R R 2

-CHOCOC (CH -N NCH 2 CH 3

1 3) 3

CH 3 O

-CHOCOC (CH 3) 3 -N NCH 3

1 N == / -

CH 3

-CHOCOC (CH 3 3 -14 N- (CH 2) 4 CH 3

1 NC == /

Uli 3 o

CHOCOC (CH-N N- (CH) CH)

1 3 3 2 5 3

Uki 3

TABLE 26

  N-7 C CONH s H It 2 \ s:% m -CHR N -, '/ 1 i, -JN -7-l ",", OCH O e 1 1 -b COOR (syn-isomer) TABLE 26 <continued)

CHOCOC <CH 3) 3

CH 3

-N N <(CE) C

2 7 CH 3

  o -CHOCOC (CH 3) 3 -N N (CH 2) il CH 3 CH 3

-CH OCOOC (CH 3) -N NCH CH

* 2,332 3

-CHOCOC (C 3) 3-N NCH 2 CH 3

0 -NNCH CH

- (CH 2) 3 CH 3 N NC 2 CH 3

2536074

TABLE 26 (continued)

-CH C = C-CH O

2 3 _

y 'NCH CH 3

CH 3

-CH OCOC (CH 3)

C 3 CH 3

-CH 2 OCOC (CH 3) 3 N Ny

O

-CH 2 OCOC (CH 3) 3 H

-

-CH OCOC (CH 3

TABLE 26 (continued)

-CHOCOC (CH 3) 3

CH 3 CH 3 N l 1 -N o

OC O

-CH OCOCC Hc 33 -N N

2 3 3

  Note: * Hydrochloride The physical properties (P F, IR and NMR spectra) of the above compounds are the same as those obtained

in Examples 6, 7, 11 and 12.

Example 10

  (1) To a suspension of 2.2 g of 2- (2-formamidothiazol

  4-yl) glyoxylic acid in 11 ml of N, N-dimethylacetamide, 1.8 g of phosphorus oxychloride are added dropwise at 20 ° C. and the resulting mixture is subjected to a reaction at the same temperature for two hours. reaction mixture, a solution of 26 ml of methylene chloride containing 5.2 g of 7-amino-3-tl 1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) is then added l

  diphenylmethyl methyl 3-cephem-4-carboxylate at a temperature of

  After completion of the dropwise addition, the mixture is reacted at the same temperature for one hour. After this reaction, 70 ml of water and 50 ml of methylene chloride are added to the mixture. Sodium hydrogencarbonate is then added to adjust the pH of the mixture to 6.5 and the insolubles are removed by filtration. The organic layer is then separated off, washed with 100 ml of water and ml of a solution. saturated aqueous sodium chloride, in that order, and dried over anhydrous magnesium sulfate

  then removes the solvent by distillation under reduced pressure.

  The residue is purified by column chromatography (Wako C-200 silica gel, eluent: chloroform / methanol = 20: 1

  volume) to obtain 1.4 g (yield: 20.0%) of 7-l 2- (2-formamide).

  midothiazol-4-yl) glyoxylamidol-3-ll 1- (4-ethyl-2,3-dioxo-1,2,3,4-

  diphenyl-3-cephem-4-carboxylic acid tetrahydropyrazinyl)

  methyl having a melting point of 140-145 C (decomp).

  IR (K Br) cm V 1780, 1720, 1680, 1670, 1640: C = NMR (d 6 -DMSO) values: 1.20 (3H, t, J = 7Hz, NCH 2 CH 3), 3 , 50 (2H, ss, C 2 -H), 3.69 (2H, q, J = 7Hz,> NCH 2 CH 3), 4.40, 5.00 (2H, A Bq, J = 15 Hz, SC),

CH 2-

  -, (1H, d, J = 5Hz, C 6 -H>, 6.00 (1H, dd, J = 5Hz, J = 9Hz, C 7 -H), 6.50, 6 , 62 (2H, A Bq, J = 5Hz,>) c <> 1 HH 7.04 (1H, s, -C 7.30 (10H, Is, x 2), 8.64 (1H, m.p. H, s, N ST H 8.81 (1H, s, HCONH-), 10.20 (1H, d, J = 9HZ, -CONH->, 12.90 (1H, 1s, HCONH-). Similarly, the following compound is obtained: 0.09 g (19.2% yield) of 7-1-2 (2 -formamidothiazol-4-yl) gloyaloyl-36-dodo-1-ethylhexyloyl)

  diphenylmethyl methyl-3-cephem-4-carboxylate.

  Mp: 53-154 ° C (decomp) IR (K Br) cm 1: v 1780, 1725, 1690, 1665 NMR (CDCl + d 6 -DMSO> values 3.42 (2H, 1s, C-) 4, 96-5.40 (3H, m, 6H-SC),) 915 (1H, dd, J = 5Hz, J = 8Hz, C 7 -H), 6.72-7.78 (131H, m.p. H m, -CH () 8, 66 <1H, s, T) SH 8.73 (H, s, HCO-), 9.86 (1H, d, J = S Hz, -CONH-)

  (2) To a solution of 7.0 g of 7-l 2- (2-formamidothiazol-4-

  yl) glyoxylamidol-3-fluoro-1- (4-ethyl-2; 3-dioxo-1,2,3,4-tetrahydropyridine;

  In this case, methoxyamine hydrochloride (1.7 g) was added with ice-cooling to methylene chloride (methylene chloride) in 1 ml of N, N-dimethylacetamide.

  resulting mixture to a reaction at 15-20 C for three hours.

  After completion of the reaction, the reaction mixture is poured into a mixed solvent of 250 ml of water and 250 ml of ethyl acetate and the organic layer is separated, washed with 250 ml of water and 250 ml of water. saturated aqueous solution of sodium chloride in this order and dried over anhydrous magnesium sulfate

  then removes the solvent by distillation under reduced pressure.

  To the residue is added 50 ml of diethyl ether and the resulting crystals are collected by filtration to obtain 6.1 g (yield:

  83.7%) of 7-l 2- (2-formamidothiazol-4-yl) -2- (syn) -methoxyimino-

  diphenylmethyl acetamidol-3- {1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) 1 methyl) to 3-cephem-4-carboxylate having a melting point of C. IR (K Br) cm-1: CO 1780, 1720, 1680, 1640 Similarly, the following compound is obtained:

  7- [2- (2-Formamidothiazol-4-yl) -2- (syn) -methoxyimino]

  acetamidol-3-II 1- (3,6-dioxo-1,2,3,6-tetrahydropyridazinyl) methyl J

  Diphenylmethyl 3-cephem-4-carboxylate.

Mp 171-173 ° C (decomp).

  The same oxidation reaction as above is carried out and then the reaction mentioned in Example 6 (2), (3) and / or Example 7 (2) is carried out to obtain the following compound and the compounds listed in Tables 27, 28 and 29:

  o Trifluoroacetic acid salt of 7-l 2- (2-amino-5-

  bromothiazol-4-yl) -2- (syn) -methoxyiminoacetamidol-1- (4-ethyl)

  2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) 1-methyl) t-ephem-4-

  carboxylic acid, P F: 1470 C (decomp) IR (K Br) cm-1: CO 1775, 1680, 1640

R 2 R 2 R 2

CH O

N N-CH

3 -N N-CH COOH

N 2

-NOT

0 O CH 3 O O

CH

  -N N (CH 2) 4 CH 3 3 N -N N (CH 2) 2 CH 3 '

w a M Ln N) c 1-1 Ln 1-1 CD (n

TABLE 27

Neither C CONH-

CF COOH-H N He

3 2 - <N

  OCH 3 M 2 12 R (Syn isomer) 1-1 the Ln rj

#M -

LY 1

0% CD, Ili 1 -k S

R 2 R 2

0 O O

-i NCH CH OCOCH HN 1 CH HN

\. = 2 2 3 1 3 + 1

-N H 3

0 Y N

-N N- (CH 2) 7 CH 3 re-

  ## EQU2 ## TABLE 27 (cont'd) F.sub.L -M.sub.i, K) Ln w 0%. c> y C%

0 O O O O O

0 O

  -N (CH 2 11 CH 3 -N N N N (CH 2 3 CH 3

0 O O O O O

-N N CH -N P-CH OCOC (CH-N)

  2-e 2 3 3 w CD Ili has ln u Ln w Ln F CD TABLE 27 (cont'd) 0 Y

-N N- (CH 2) 5 CH 3

0 O

-N NCH C = C-CH

2 3

  0 O 0 0 -N-CH I 'Cl' 3 -CH 3 p-1 -J r O Ln

(A 1

CY% c>, Ili 1 t%

0 O O O

-N NCII CH -N NH

\, = 2 3

CH 2 CH 3

  Ili 0 1 w ul w 0,> J Ln r-1) O Ln F- Ln TABLE 27 (cont.)

0> 1- CH 3

-N N N

\ ==, / -'CH 3

  -4 Co Note: '* Hydrochloride M.) Ln (m cy% c> 111-j 4- "I HN 1 ci N

R 2 R 5 R '8

0 * '_ // O

N 7 NCH 2 CH 3 NH 2 CH 2 COOH

0 O CE 3

\\ Z / 1

N N CH CH 'CF 3 COOH-NH -C-COOH

2 3 2 1-

CH 3 O N N% NH NH -CH COOH

2 2

0 O

-N NCH 3 CF 3 COOH-NH -CH COOH

2 2

0 O

\ // ,, C H

N N-N 3 CF COOH-NH -CH COOH

3 2 2

CH 3

TABLE 28

  NI -CONH s R 5, it 2 s N CH 2 R-COOH OR 18 (syn-isomer) is CH

N HCOOHNH -CH

2 2 COOH

-N NCH C = C-C Hi NH LCH COOH-

2/2 2

0 O

> __ NH 2 CH 2 COOR

-N N 0 O

> _CH OCOC (CH NH _CH 2 OOH

-N 2 3) 3 2-

TABLE 28 (continued)

HCOOH-NR 2-

-CH 2 COOR

TABLE 28 (continued) o o

N \ NOM 2 COOH

N 2 -

-CH 2 COOH

o o -N NAME CH HOHN 2 CH 2 COO 4 b

% 2 3 HCOHH 22 -

o o> / <HCOOH-NH 2 C Co-O

N, CH 2 CH 3 2 C O H 2 CO 1

o o

-N, NAME CH HCO-H CH COOHC

\ ./ 23 HOHN 2 2 C 2 CH 3

* 10

R R 2

0 O

-CHOCOC (CH -N NCH 2 CH 3

1 3) 3

CH 3 O

-CHOCOC (CH -N NCH

1 3 3 3

uà 3

-CHOCOC (CE 3) 3 - (CH 2) 4 CH 3

united 3

CHOCOC (CH 3 3 -N N- (CH 2 5 CH 3)

united 3

TABLE 29

N C CONH 'S

R 2

N ,, 2

In 1 he

N CH

2 '<' s I_

OCH 3 O 1 1

  COOR (syn-isomer) TABLE 29 (continued)

-CHOCOC (CH 3) 3

CH 3 o

-N N (CE) C

CHOCOC (CH 3) 3 NNCH 2) ,, CH 3

united 3 3

-CHOCOOC (CH 3> -N NCH C

CH 3 O

-N NCH 2 CH 3

- (CH 2) 3 CH 3 NNC 2 CH 3

r'lN E E z

N ,, (RD) DODO RD-

Lm - 1 E E: z

Na (FID) DODO HD-

rr'l-K ú ú z

N, l (RD) DODO RD-

f E: RD CRD K-

1 E E: HD) :) C) DôHD-

m -

H 0 E 9 T OT 0 / l O E \ z

RD-D = D RD-

E: z F =: \

RD HDN N-

  Oo (e 4 Tns) 6 Z nvausv, t IST i 09 úSZ TABLE 29 (continued)

-CHOCOC (CH 3) 3

CH 3 CH 3

-CH 2 OCOC (CH 3) 3

  CH 3 N -N o Note: * Hydrochloride The physical properties (P F, IR and NMR spectra) of the above compounds are the same as those obtained in the

Examples 6, 7, 1 and 12.

Example 11

  (1) In a mixed solvent of 37 ml of trifluoroacetic acid

  and 10.8 g of anisole, 7.29 g of 7-l 2- (2-formamidothiazol

  4-yl) -2- (syn) -methoxyiminoacetamidol-3 1- (4-ethyl-2,3-dioxo)

  Diphenylmethyl 1,2,3,4-tetrahydropyrazinyl) (methyl) t-p-ephem-4-carboxylate and the resulting solution was reacted at room temperature for two hours. After completion of the reaction, the solvent was distilled off under 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%) 7-1-2- (2-formamidothiazol-4-yl) -2-

  (syn) -methoxyiminoacetamidol-3 1- (4-ethyl-2,3-dioxo-1,2,3,4-

  tetrahydropyrazinyl) 1-methyl-3-cephem-4-carboxylic acid having a melting point of 155-158 ° C (decomp) IR (K Br) cm V 1775, 1710, 1675, 1640

7 C = O

  NMR (d 6 -DMSO) values: 1.20 (3H, t, J = 7Hz,> NCH 2 CH 3), 3.49 (2H, 1s, C 2 -H), 3.73 (2 H, q, J = 7 Hz, NCH 2 CH 3), 3.91 (3H, s, -OCH 3), 4.42, 4; 95 (2H, A Bq, J = 15Hz, S),

AL-CH 2-

  5121 (1H, d, J = 5 Hz, C 6 -H), 89 (1H, dd, J = 5Hz, J = 8Hz, C 7 -H), 6; 65 (2H, ss, H <HHHN 7.46 (1H, s, 8159 (1H, s, HCONH-), 9.77 (1H, d, J = 8Hz, -CONH-), 12 , 58 (1H, 1s, HCONH-) Similarly, the indicated compounds are obtained

in table 30.

TABLE 30

h Nr CF-CONH s HCONH Nl CH R 2

COOH 2

  OCH 3 (syn-isomer) Compound P F <Oc) IR (K Br) R 2 cm - ': Vcç

195-198 1775, 1720,

<decomp) 1680-1640

-N N-CH

\ = / 3 O

-N N- (CH) CH 3 122-125 1775, 1680,

(disappointed) 1640 0-O

-N N- (CH) CH 3 165-170 1775, 1680,

(decomp) 1640

Nos. 195-198, 1775, 1685,

(decertified) 1650 o

-N N (H) CH 155-158 1780, 1720,

(disappointed) 1680-1640

-N N- (CHC 144-147, 1778, 1685,

  -N 1 (C 2) 11 CH 3 <decomp) 1660, 1645 TABLE 30 (continued)

186-188

(Decomp)

1775, 1710,

1690, 1650-

CH 3 CE 3

N 218-221 1775, 1670,

  -N (decomp) 1650 o CH 3 I -N o (2) To a solution of 5.63 g of 7-l 2- (2-fo-n) amidothiazole acid

  4-yl) -2- (syn) -methoxyiminoacetamidol-3-1- (4-ethyl-2,3-dioxo)

  1,2,3,4-tetrahydropyrazinyl) 1-methyl-3-cephem-4-carboxylic acid

  in 25 ml of N, N-dimethylacetamide, 1.52 g of

  diazabicydlol 5.4.0 l-7-undec-ene and 3.84 g of 1-pivaloyloxyethyl iodide with ice-cooling, and the resultant mixture is then subjected to reaction for 30 minutes. After completion of the reaction, The mixture is poured into a mixed solvent of 1 ml of water and 100 ml of ethyl acetate. The organic layer is then separated off, washed with water and dried over anhydrous magnesium sulphate. The solvent is distilled off. under reduced pressure To the residue is added 50 ml of diethyl ether and the crystals are collected by filtration to obtain 5.5 g

  (yield: 79.6%) 7-1-2- (2-formamidothiazol-4-yl) -2- (syn) -

  methoxyiminoacetamidol-3- {1- (4-ethyl-2,3-dioxo-1,2,3,4-tetra)

  1-pivaloyloxyethyl hydropyrazinyl) methyl-3-cephem-4-carboxylate having a melting point of 140-142 C. IR (K Br) cm-1: -C = o 1780, 1740, 1680, 1640 Similarly the compounds listed in Table 31 are obtained. In this case, the compounds listed in Table 31 can also be obtained by the same method as in

  Example 6 (1), except that the diphenylmethyl esters are replaced by

by the corresponding esters.

* w CD o H <J, H. CD

TABLE 31

HCNN <71 C-CONH S

- Ti,;: O N 2 CH-R

1 OCH 3

  COOR- (syn-isoameric) R 1 lops R 2 P F <OC) IR <K Br> cm 1: = o o

-CHOCOC <CH 3) 3 '

  I -N N-CH 3 182-188 1780, 1740, 1680-1640

CH 33 (decomp)

CHOCOC <CH 3) 3O O

1 M 120-1221783, 1740, 1680, 1640

  CH 3 -NN (CH 2) 4 CH 3 (decomp) COCCCH 3100 18-115 1782, 1740, 1680, 1640

CH 3 -N (CH 2) 5 CH 3

  -COO (H 166-168 1780, 1740, 1680-1640

CH -N C Hdecomp) -

  ## STR2 ## TABLE 31 (cont'd)

-CHOCOC (CH 3) 3

CH 3

-N N- (CH) C

117-122

1785, 1745, 1685, 1645

o o

  -C 20 O (C) 158-160 1780, 1742, 1680, 1640

COC (H 3) 3 -N N-CH CH

j 2 3

-CIIOCOOCH 2 CH 3 O O

  1> _ 2 3 _% 150-152 1780, 1760, 1680, 1640

CH 3 -N NCH CH 3

* 1 O O

N 2 C CH 160-162 1780, 1680-1630

2 O

  - (4-CH 2) 3 CH 3 -N NH C 136-141 1780, 1720, 1680, 1640

  N 2 C CH (decomp) H-0%) 1-J 1 es. i 1. w W r MN en F u TABLE 31 (continued)

1 = -CCH O O

165-168 1810, 1775, 1720, 1670,

0 b -N N-CH Cil <decomp) 1640

  12 OCOC <CH 33 -N N 193-195 1775, 1745, 1685, 1650

o wdeom.

CH 3

  2 CCC 3) 3 138-140 1780, 1750, 1690, 1660

  -N (decomp) O r ', I-f w W NHN H U TABLE 31 (continued) ci 3 CH 3

  OCQOC <CH) 158-164 1780, 1740, 1680-1640

  ## STR13 ## To a solution of 5.5 g of 7-1-2- (2-formamidothiazol-4-yl)

  -2- (syn) -methoxyiminoacetamidol-3-1- (4-ethyl-2,3-dioxo-1,2,3,4-

  1-pivaloyl tetrahydropyrazinyl) methyl-3-cephem-4-carboxylate

  oxyethyl obtained in (2) above in 27.5 ml of methanol, 1.13 ml of concentrated hydrochloric acid is added and the resulting mixture is subjected to a reaction at 35 C for two hours. Once the reaction is complete, the solvent is distilled off under reduced pressure. 50 ml of ethyl acetate are added to the residue.

  and 50 ml of water and the mixture is adjusted to pH 6.0 with hydrogen.

  sodium bicarbonate The organic layer is separated off and dried over anhydrous magnesium sulfate, after which the solvent is distilled off under reduced pressure. 45 ml of diethyl ether are added to the residue and the crystals are collected by distillation.

  filtration to obtain 4.65 g (yield: 88.1%) of 7-l 2- (2-amino)

  thiazol-4-yl) -2- (syn) -methoxyiminoacetamidol-3 1- (4-ethyl-2,3-dimethylformamide)

  dioxo-11,2,3,4-tetrahydropyrazinyl) methyl-3-cephem-4-carboxy-

  1-pivaloyloxyethyl late having a melting point of 148-150C. IR (K Br) cm-1: v 1780, 1740, 1680, 1640

: C = O

  NMR (d 6 -DMSO) values: 0.90-139 (12H, m, -C (CH 3) 31> NCH 2 CH 3), 1. 52 (3H, d, J = 5Hz, -OCHO-), CH 3 3.52 (2H, ss, C 2 -H), 3.76 (2H, q, J = 7Hz, NCH 2 CH 3) 3.88 (3H, s). , -OCH 3), 4.38, 5.04 (2H, A Bq, J = 15Hz, S CH 2 - t 21 (1H, d, J = 5Hz, C 6 -H), 5187 ( 1H, dd, J = 5Hz, J = 8Hz, 7-H), 6.61 (2H, 1s, c),

H H

6., 78 (1H,

7.04 (1H,

7, 22 9, 67

(2 hours,

(1 H,

  H, J = 5 Hz, -OCHO-), 1- CH 3 is, -NH 2), d, J = 8 Hz, -CONH-) Similarly, the listed compounds are obtained.

in table 32.

  compound P F (OC) IR 1 (K Br) NMR (d 1 values cm: V 6 -DMSO) R 1 R 2 C = O u (f)) F 1 Ln k-O w Ln w C)

TABLE 32

N) C-CONH S

H 2 N- <Il CH -R 2

S N 2

1 OCH 1

3 coo (syn-isomer) 1780, 1740, S

1.19 OH, S, -C (CH 3) 3),

  1.54 OH, d, J = 5 Hz, -OCHO-), CH 3 31? (3H, s, N-CH 3), 3.54 (2H, Is, C 2 -H), 3H (3H, S, -OCH 3), 4.40, 5.06 (2 H, A Bq, = 15 HZ, SCH 5 P 24 (1H, d, J = 5Hz, C 6 -H), 5.91 (1H, dd, J = 5Hz, J = 8Hz , C-H), 6.46, 6.60 (2H, A Bq, J = 6 Hz, 6 P 80 UH, s, HH '

198-201

(disappointed) O; __

-N N-CH

-1D -J

-CHOCOC (CH 3) 3

  ## EQU1 ## where ## EQU1 ## (ú HDú (ZHD) i HDN <"ZHL = C 1" HZ) Z The rú 'W-ZD "IF" HE) 65 "ú f (ú HDú (Z HD) ZHDN <' ul 'H 9) 98 "TO" -r EHD 1U H1) z Hs = ú 'p úg' Il 1 (E (EHD) D "S 'HO # (ú 111) (EHD) N <" ZIIL = r 4 "HE)

úHD t, (ZHD) -NF == \ N-

/ H

1 O O

Ot? 91 11089 O, LI

"ú 8 LI

EHD

E E 1

(HD) DODUHI) -

" HEY)

8 T 'I

L 8 'O

  ('duloopp) It Ttpl-6 ú 1 (-HNOD IZHS = rp "HI) N 16 (ZHN' sr" HZ) 9 Z "L EH, -) 1 it s (- D #z HS = cb" HI) LO'L '(IN (eq Tns) ze nvalevi C) C'q CD -4 Ln 1 i in N a M Ln w Ln wa cli ul N) F-Ln F-CD TABLE 32 (cont'd) 5128 (l H , d, J = S Hz, C 6 -H), 5.92 (1H, dd, J = 5Hz, J = 8Hz, C 'H), 6., 65 (2H, IS, N) , 6.85 (1H, HHS, NT), 7100 (1H, q, J = 5Hz, SH OCHO), 9182 (1H, -d, J = 8Hz, 1H-CH ': 3

-CONH-)

1-1 lo w

0 1 87 (3H,

1718 OH,

l, 03-1.79

1, 53 (13H,

3.60 (2H,

  t, J = 7 Hz, t, J = 7 Hz,> N (CH 2) 5 CH 3), s, -C (CH 3) 3),

(8H, M,> NCH 2 (CH 2) 4 CH 3) #

  d, J = 5 HZ, -OCHO-), Uri 3 is, C 2 4), 3.72 (2H,

> NCH 2 (CH 2) 4 CH 3),

-150 (from "comp.

-CHOCOC (CH 3) 3

CH 3 1780, 1740, 1685, 0 O

1-N N (CH 2) 5 CH 3

  r%) Ln The 0% c> 1 -4. b. ## EQU1 ## TABLE 32 (cont'd) 1 μl 90 μg (3H, s, -OCH 3), 4.41, 5.09 (2H, A Bq, J 15 Hz, UH, d, J = 5 HZ, C 6 H), 51 # 90 (1 H, dd, J = 5 Hz, J = 8 Hz, C 7 -H),

6; 63 (2H, IS, δ), 6.82 (1H,

  H H 6, 98 UH, q, J = 5HZ, S H -OCHO-), 9.75 (1H, d, J = 8Hz, CH

-CONH-)

Pl) a CD

-CHOCOC (CH 3) 3

  embedded image A 30.88 (3H, t, J = 8HZ,> N (CH 2) 7 CH 3), 1.02-1.43 (21H, m, -C (CH 3) V NCH CH ), 1,, 56 OH, d,

2 (CH 2) 6

-17 2 (déàomp)

17 80,

  1740, 1680, ## EQU1 ##

1 1

F-1 O

J = 5 HZ, -OCHO-), 3.38-31983 OH,

  Uri 3 m, NCH 2 (CH 2) 6 CH 3 C 2 -H), 3 M 90 (3H, s, -OCH 3), 4743, 5, 11 (2H, A Bq 1 J = 15 Hz, S 5.28 ICH (1H, d, J = 5Hz, C 6H), 194 (1H, dd, J = 5Hz, J = 8Hz, C 7 -H), δ 65 (2 H, 1s, = K), 6, 83 (1H, S, HHNT), 7102 (1H, q, J = 5Hz, SH "OCHO-), 7915 (2H, 1s, -NH 2) ## STR1 ## wherein: ## STR1 ## ## EQU1 ## where ## EQU1 ##

P 'SI) O'S S # ZHST = P

bev "HZ) úO'S # Bú 4 HDO-

  "S" HE) L 8 ú E HD O 'l (EHD) -HDN <ZHL = r -4 "HE) OL il E" (HZ D úHD "SI" HZ ú ZHS = flp, Ilú :) gel- l HD HD) ZH Diq <ui 4 1

HOZ) LS T-ZO 1

  EHD) D 's H 6) 8 I l (E "ZHL = r' -4 'Hú) 98' O CD Lr

Ln 1-1 -

  ffli Is Lg T - 'S P LT (duloopp) OBLT 85 T-úSl (el-Tns) ZE ri Vsqsvjj N EHD

E ú 1

(HD) DO Duti) -

CD m L e c TT TT Z 'e

HD (HD) N N-

0 O

1 1 1

  1 c (((((((((((((((((((

-H i-

  HI OL o 9 'sr (HL yes D -Oi H -L 9' r S o (HD EZHS = r op HD-c S z HST = il To "S ouri> o (E HDO os HD z HDN <'z HL = r 'b If (il-Z D os-l "HZ) Lt ,, C uj E (EHD) D' ul HZT) it) 6 HS It (_ym # sj Hz) ggg on) 90,19 li H1) vi 19 It bqv, Hz) o HO 8 L dú

HZ) OL'ú

  f (E HDZ HDN <çc'I-To t 1 Ot, 91 S Lq-1 O Pl 1 08 LI cn a cm

E (EHD) DOD Oz HD-

ú z

HD HD-M N-

  0 O Ltpl-Stl (-HNOD 'ZH 8 = r' P EHD j (-l -o HDO # ZHS = r 'b HI) 99 i 6 o HI) 1041 L (e 4 Tns) Zu nvaqgvl in O 1- ## STR2 ## (6H, t, J = 7Hz,> CH 2 CH 31 -OCH 2 CH 3), 1.55 (3H, m.p. d, J = 5 HZ, -OCHO-), 3.53 (2H, Is, C 2 H), UH 3 N) CD F-1 Ln w CD m Ln w ui TABLE 32 (continued

1 1

-157

17 80,

1760, 1680, 0 O 1

-N -CH CH

N_ / 2 3

-CHOCOOCH 2 CH 3

  Uki 3.76 (2H, q, J = 7Hz,> NCH 2 CH 3), 3e 86 (3H, s, -OCH 3 4.19 (21i, q, J = 7Hz, - OCH 2 CH 3 4.40,, 05 (2H, A Bq, J = 15Hz, S) -CH 5121 (1H, d, J = 5HZ, C 6 -H), 5,, 86 (1H); H, dd, J = 5 Hz, J = 8 HZ, C 7 -H), 6, 52, 6, 65 (2 H, A Bq, J = 6 Hz, X), 6 P 74 UH, s, NV)

H H S H

  6.87 (1 H, q, J = 5 Hz, -OCHO-), i-CH 3 m CD ru fn LM 0% CD 4% Nr 1 r 1 qc>% O wire> Ln Cu

H H

H 0 -'ul'HS) H s

HS'O) 001 L

  ## EQU1 ## ## EQU1 ## where ## EQU1 ##

(H D lz Hg = E 'P' HI) ZE S, "YIN-

  19-Z HI-f S "U 'HG) s' HE) 66" ú HD HDN <' ZHL = f 'q HZ) 18' ú (HZ D "sr" HZ) L 9 "E i (C HDZHDN < 'HL = f' the HE) TZ'I U'i CD N 0 O EHDEHDN F = s N-0 O OP 91 1 o 89-1

08 L-1

  ooz <(-HMOD IZH 8 = r ip "11-1) 99 '16 10 (Z HM 'sf" HE) ZO "L (q Tns) Zu nva 9 evi Ln CD

-1 CN

  CD 1-1) (FIG. 32 (continued) 1-1 LQ 1-1 to 9187 (1H, d, J = 8 Hz, -CONH-) 0163-lx 85 (10H, m,

  -COOCH 2 CH 2 CH 2 CH 3 '> NCH 2 CH 3) 01

  3, p 55 (2H, Is, C 2 H), 3.76 (2H, q, J = 7Hz,> NCH 2 CH 3), 3p 89 (3H, S, -OCH 3), 4.30 (2H, t, J = 7HZ,

  -COOCH 2 CH 2 CH 2 CH 3), 4139, 5.12

  (2H, A Bq, J = 15Hz, S CH 2 - J (1H, d, J = 5Hz, C 6 -H), 5.92 (1H, dd, J = 5Hz, J = 8 Hz, C 7 -H), 6 IP 68 (2 H +, -> <), 6 p 82 (1H, H 'HNS, Z), 7, 28 (2H, 1s, -NH 2 ), SH 9.79 UH, d, J = 8 Hz, -CONH-) 0 O 1 \

-N NCH CH

% C == / 2 3

13.9-144

(decomp) 1780, 1720, 1680,

- (CH 2) 3 CH 3

  Neither CD m ria A (A 0% c> qe% (-HNOD 'ZH 8 = r' P 'HT) Z 9 i 6 (Z i S S H HH 1 HZ) LI e LS HH) t, Lr 9 ## EQU1 ## = r

bg'V #HZ) 9 O'S # (ú HDO-

  s HE) P 8 4 'ú (EHJHDN -e- "' ZHL = C b 'HZ) úL'E' (H ZD" S-1 'HZ)

"HE) Z'Z

  Es "O O O (ú HDZHDN- <# ZHL = r 'the HE) 61' l -r N. CD% O ro Ln cmr- CD C'q il / 11 \ 0 O 1 i

EHDD DZHD-

Ot, 91 oag-l Where LI

OZ 8-1

E Z

HD HD-N N-

  0 O (duo Dep) LI-úLl (p 4 Tns)?: E nvagevi N a -1 m ui I.-I Ln m ul w ul w CD L Ili ul Ni CD F ul l CD TABLE 32 (cont.) 24 (9H, s, -C (CH)), 2, 31 (311, 33, -CH 3), 3.40 (2H, 1s, C 2 11), 3.99 (3H). , s, -OCH 3), 5.01, 5.33 (2H, A Bq, J = 1511, S, CH = 09 (Di, d, J = 511, C, 6-11) 5. p 61-614 (3H, m, -OCH 2 o-, C 7 H), 6, 71 (2H, 1S, -Nll 2), 6H (111, S, N Ir), 6 , 86, S he 7.24 (2H ,, A Bq, j = 10 liz, he 9.34 (111, d, J = 8 Hz, -CONII-)

-CH 2 OCOC (CH 3) 3

14 1-14 2 1

  (decomp) 1775, 1740, and in the following table: ## EQU1 ## ## STR1 ## ## STR2 ## 9H, s, -C (CH 3) 3), 2, 27 (6H, SO CH 3), 3H (3H, Is, C 2H), CH 3

31.86 OH,

(2 H, A Bq,

156-159

  (decomp) -CH 2 ococ (CH 3) 3 1775, 1740, s, -OCH 3), 511? 02, 5140

J = 15 HZ, S.

1 CH 2-

d, J = 5 Hz, C 6 H), 5.70

M, C 7 H, -OCH 2 O-),

  s, N), 7.26 (2H, T s H, 7.98 (1H, s, -H) 51 20 6 d 14 6.p 81

(1 H,

  OH, (1H, Fold CD%, O m, -NH 2), where n is 0% c> j 4-

CH CH 3

  ## STR2 ## TABLE 32 (follow: CD ## 17 (9H, s, -c (cH 3) 3, 31, 4 (4H, 1s, C) 2H, -NH 2), 3 Y 55

  (3H, S, -OCH 3), 4.75, 5.01 (2H,

A Bq, J = 15 Hz, s, CH 2? 16

J = 5HZ, C 6 -H), 5.60-6.08

(3H, m, C 7 -H 2 -OCH 2 -) #, 6 Y 77

UH, S, N, JI 89, 7.12 (211,

  S H A Bq, J = 10 Hz, H), 9.62 UH, 1H d, J = B Hz, -CONH-) * 3

-CH 2 OCOC (CH 3) 3

151-153

  (decomp 1780, 1745, F-1 ro Ln L 0 0% c> -t- HN 1 -N 1-1 ui S) Ni a TABLE Au 32 (follow p Ln w rl ui w ui 1 24 (9 H, s, -C (CH)), 3.53 (2H, 3H is, C 2 -H), 4.06 (3H, S, -OCH 3), 4 IP 70, 5.35 ( 2H, A Bq, J = 15HZ, S IP 25 (1H, d, J = 5Hz, CH)

C 6 -H), 5, 98-6.48 (5H, M,

-OCH 0-, C H, -NH), 6.88

2 7 2

  (1 H, S, N n 7.5 4, 7.70 (2H, SHA Bq, J = 5Hz, H), 8.33 (1H, s H 8.59 (1H, d, J = 8) Hz,

-CONH-)

measured in CDC 13) * 3

-CH 2 OCOC (CH 3) 3

134-137

(Decomp)

17 80,

  1750, ## EQU1 ## ## EQU1 ## ## STR2 ## FIG. 18 (9H, s, -C (CH 3 Y, 1.53 (311, d, J = 6 Hz, -OCHO-), 2 x 28 OH, S, CH 3 one 3 OEOC (CH N 143-145 1780, CH 3), 3.47 (4H, 1s, C 2 -H 3 3 1 (decomp) 1740,

  -N 1655 -NH 2), 3.89 (3H, s, -OCH 3), 4.91,

e 29 (2H, A Bq J = 15 fiz, S

ICH 2-

  , 22 (1H, d, J = 5 Hz, C 6 -H), 51? 88 (1 H, dd, J = S Hz, J = S Hz, C 7 -H), 6192 (1H, NSH 6,, 93, 7 X 41 (2H, A Bq, J = 10 Hz, H), 6) 96 (1H, q, J = 6Hz, -OCHO-),

IH 1-

  CH 3 91974 (1H, d, J = B Hz, -CONH-) Ln LM c> -cii Uli TABLE 32 (cont.) -C 12 OCOC (CH 3) 3 o o

-N_O

154-160

  (decomp) 1775, 1750, 1700, 1, M 21 <9H, s, -C (CH 3) 3 3.65 (2H, Is, C 2H), 3, P 93 <3H, s, - OCH 3), 4, p 44, 5.14 (2H, A Bq, J = 15Hz, S CH 2 5, 28 (1H, d, J = 5H 1z, C 6H), 5, 78-6, p 76 (5H, mx, C 7H)

-OCH 201,

  r <) 6, P 89 (1H, S, N -a A), 7.36 (2H, is, NH 2),

S H H

7.72-8.27 (5H, M, -O)

  9, $ 81 (1H, d, J = 8 Hz, -CONH-) Note: * 1 Diastereoisomer * 2 Hydrochloride (the salt is prepared in the usual way)

  The desired compound is obtained by reacting the trifluoroacetic acid salt with

  with a halide in the presence of 1,8-diazabicyclol 5,4, 7-7undecene at a temperature of from 5 to 5 ° C. Ho> Ln 'Pl) FI. (4) To a solution of 1.05 g of 7-l 2- (2-formamidothiazol) acid

  4-yl) -2- (syn) -methoxyiminoacetamidol-3- {1- (2,3-dimethyl-6-oxo) -2-yl) -2-

  1,6-dihydropyrazinyl) -methyl} -3-cephem-4-carboxylic acid obtained in (1) above in 10 ml of methanol, 0.38 ml of concentrated hydrochloric acid is added and the resultant mixture is subjected to a reaction. at 35 ° C. for two hours. After the reaction is complete, the solvent is distilled off under reduced pressure and 10 ml of diethyl ether are added to the residue and the crystals are then collected by filtration to give 0.43 g (yield: 84.8%) of 7-l 2- (2-aminothiazol) hydrochloride

  -4-yl) -2- (syn) -methoxyiminoacetamidol-3- {1- (2,3-dimethyl-6-oxo) -2-

  1,6-dihydropyrazinyl) methyl-3-cephem-4-carboxylic acid having a

melting point of 250 C or more.

  IR (K Br) cm-1: C = O 1765, 1660, 1620 NMR (d 6 -DMSO) values: 2.20 (6H, ss, -CH 3 x 2), 3.18 (2H, ss). , C 2 -H), 3.90 (3H, s, -OCH 3), 4.94, 5, 24 (2H, A Bq, J = 15Hz, SC, 10 (1H, d, j = 5HZ, C 6 -H), 5178 (1H, dd, J = 5Hz, J = 8Hz, C 7 -H), N, 6.89 (1H, s, SiH) 7, 82 (1H, s, H), 9.79 (1H, dd, J = 8Hz, -CONH-)

215-2536074

Example 12

  (1) In a manner similar to that of Example 7- (1), the compounds listed in Table 33 are obtained from

  starting materials indicated below.

N C-COOH

(9_c-N-4T 1

3 H 'S-T N

* OCH 2 COOR

  (starting material, syn-isomer) s o oo

7 "> N, CHNN-CH CH

COOCH (Q)) 2

2 3

N-C-CONH O O

3 CN-I II II SN CH 2 No N-CH CH

1 COOCH "() 2

OCH 2 COOR 1

(desired compound, syn-isomer)

TABLE 33Approved IR Compound (K Br)

R (O) P F (OC 1

IR cm-: VC = O

127-130 1780, 1720,

(Dé'comp)

1685, 1645

127-130 1780, 1720,

(decomp) | GD <decomp) 1685, 1635

-152 1780, 1720,

  -CH 2 CH 3 (decomp) 1680, 1645 2 '- (cm 1680, 1645 (2) The compounds of Table 34 are obtained by reacting the aforementioned compounds in a similar manner as in Example 7- (2) IR compound (K Br)

  R1 P F ('C) cm-1: VC = 0 NMR (d 6 -DMSO) values 1.

w ui w CD rj

TABLE 34

1-1 Ln F Ln

N C CONH S Q O

HCOOH-H N> __

2 _sr Nu CH 2 N N-CH 2 CH 3 \ == f

1 COOH

OCH 2 COOR 1 _ -

i have F_ -J i i M Ln LY

0% 1

c> 1

114 1

  a-% 1 ,? (3H, t, J = 7Hz, NCH CH 2 3 3 y 50 (2H, Is, C 2 -H), 3.76 (2H, J = 7Hz,> NCH CH), , 03 (2H, 23 -OCH 2 CO-), 4, 50-5. O (2H, e 2 O (1H, d, J = 5Hz,

S) _CH 2-

  c 6 -H), 5190 (1H, dd, J = 5Hz, J = 9Hz, C 7 -H), 6P 70 (2H, s, ≥ <), 6, 98HH NT), UH , s, 7 p 30 (5 H, 1 s, SH

123-125

  (decomp) 1770, 1680, 1670, N) Ln Ni TABLE 34 (cont'd) W Ln F Ln F CD ul 81927 UH, s, -HCOOH), 9.80 (1H, d, J = 9 Hz, - CONH-) i) 25 (3H, t, J = 7Hz,> NCH 2 CH 3),

2.00 (2H, H -), 21980 4H,

  ## STR5 ## (H, 1s, C 2 -H), HH 3,, 75 (2H, q, J = 7Hz,> NCH CH 2)

  / 00 (2H, S, -OCH 2 CO-), 4.50-5.00

  (2H, m, 51? 25H, d, S: k CH J = 5Hz, C 6 -H), 5e 95UH, dd, J = 5Hz, J = 9Hz, C 7 -H) , 61970 (2H, s,

6, 96 HU, S, N

H H STH

-129 (decomp)

-00 ID

  1770, 1680, 1670, r 1) f- CD rla Ln Lw 1

O, 1

  ## EQU1 ## TABLE A 34 (cont'd) Ln F-1

M, H) O

  H, J, HCOOH), d, J = 9 Hz, -CONH-)

7 30 (3H,

O 'l

8.P 27

911 80

  UH, UH, 22 (6H, t, J = 7HZ, CH 2 CHV -OCH 2 CH 3), 3.51 (2H, 1s, C 2 -H) 3.76 (2H, q, J = 7Hz, NCH CH 2 3 4.18 (2H, q, J = 7Hz, -OCH CH 2 3 41.77 (2H, s, -OCH 2 CO-), 4.50-5. , 00 (2H, M, S 5.24 (1H d, CH 2 J = 5Hz, C 6 -H), 5.91- (1H, dd, J = 5Hz, J = 9Hz , C 7 -H), 6.69 (2H, s, r 1, F-1 D r%) Ln

L% & 1

0% c> - * to

122-123

f (decomp) 1770, 1720, 1670,

-CH 2 CH 3

w W N) F F-

  ui TABLE 34 (continued) -), 6, 96 (1H, s, N

H H S TH

  27 (1 H, s, HCOOH), 9 p 84 (1H, d, J = 9 Hz, -CONH-) Ln Lm 1 CN C>

Example 13

  (1) To a solution of 2.72 g of 2- (2-t-amyloxycarboxylic acid)

  Midothiazol-4-yl) acetic acid in 40 ml of anhydrous methylene chloride, 1.06 g of N-methylmorpholine is added, and the mixture is cooled to 35 ° C. 1.12 g of ethyl chlorocarbonate are then added and the mixture is subjected to stirring. the mixture was reacted at 35 ° C to 25 ° C for 1.5 hours, after which 5.18 g was added.

  7-amino-3 - {(1H- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) -1-

  diphenylmethyl methyl] -3-cephem-4-carboxylate, and the reaction mixture is subjected for one hour at a temperature of 20 ° C and then for one hour at a temperature of

  at + 10 C After the reaction is complete, the soil is removed

  The residue is dissolved in 40 ml of ethyl acetate and 30 ml of water. The organic layer is separated and 30 ml of water are added again.

  at pH 7.0 with sodium hydrogencarbonate with cooling

  The organic layer is separated off, washed with 30 ml of water and 30 ml of a saturated aqueous solution of sodium chloride.

  in that order, then dry it over anhydrous magnesium sulfate.

  The solvent is distilled off under reduced pressure and 35 ml of diethyl ether are added to the residue and the crystals are collected by filtration to give 3.62 g (yield: 90.5%).

  1- (2- (2-t-amyloxycarboxamidothiazol-4-yl) acetamidol-3- (1- (4-

  ethyl-2,3-dioxo-11,2,3,4-tetrahydropyrazinylmethyl) A 3-cephem-4-

  diphenylmethyl carboxylate having a melting point of

152-154 C (decomp).

  IR (K Br) cm-1 1780, 1720, 1685, 1640 Similarly, the following compound was obtained: 6.15 g (yield: 82.7%) of 7-l 2- (2-tamyloxycarboxamidothiazol-4- yl) acetamidol-3- {1- (3,6-dioxo-1,2,3,6-tetrahydropyridazinyl) methyl)

  Diphenylmethyl 3-cephem-4-carboxylate.

  Mp: 136-139 ° C (decomp) IR (K Br) cm-1: ν C 1780, 1720, 1665 c = 0 The compounds of Table 35 are obtained by subjecting the compounds obtained above (1) to a reaction of the same way

than in Example 6- (3).

  compound P F (OC) IR (K Br) NMR (d DMSO) values

-1 6-

  R 2 cm C = O 1 (3H, t, J = 7 Hz, NCH CH), 350 (2H, 2 0 109-115 1775, 1s, C-H), 3 e 6 1-3 81 (4H, m, -NCH1Cl (decomp) 1690, 2 2 3 P -N 2 CH 3 CH 3 1630 N CH 2 4 47 47, 5317 (2H, A Bq, J = 15Hz, δ 21 (1H, d, J = 5Hz, CH),

S) -: - CH

  Y 6 O-6.02 (3H, m, C 6 81 (11,

7 am H

  s, N 9.24 (111, d, J = 8 Hz, -CONH-) S -TH w ui w a c'a Ln

N) F 01

THIS TABLE 35

CF 3 COOH-11 2 NN -CH 2 CONH S 2

S CH 2 R

  COOH ui t \ r%. M M Ln LY 0% e c> & N% r r-. 1 c>% O r 4 l) Ln cm m CN CN ii 671 c 6 "(1 ZHOI = r Hmf (-HNOD" Z'Hq = r, p, RT) H s bg V "HZ) t T'L ## EQU1 ## where ## STR2 ## where ## STR2 ## is a compound of the formula ## STR2 ## Sir "HZ) 80" S

0 to 91

"OL 91

1 Oi L, l

"O LLT

z Hs = -V "P" HE) 9-lds, (ooz <

4 (H :).

  "SI 'HE) L 9 g E # (H-Z D" s HZ) úpi E (Pq Tns) GE nvausvi 1-i n Ln 11 Ln O ul C, 4 Mm N-MH

Example 14

  In 48 ml of N, N-dimethylacetamide, 6.82 g are dissolved

  7- (4-Bromo-3-oxobutylamido) -3-1- (4-ethyl-2,3-1,2,3,4-dioxo)

  tetrapydropyrazinyl) l-methyl) cephem-4-carboxylate diphenyl

  The mixture is reacted at room temperature for two hours. After the reaction is complete, the mixture is poured into a mixed solvent of 500 ml of water and 500 ml of ethyl acetate. and the mixture is adjusted to pH 6.7 with sodium hydrogencarbonate. The organic layer is separated and dried over anhydrous magnesium sulfate.

  then the solvent is distilled off under reduced pressure.

  Subsequently, the residue is dissolved in 33 ml of trifluorinated

  and 8 ml of anisole and the mixture is reacted with

  room temperature for one hour. Once the reaction is complete

  The solvent is distilled off under reduced pressure and 40 ml of diethyl ether are added to the residue.

  collects the crystals by filtration to obtain 4.50 g (yield

  74.1%) of trifluoroacetic acid salt of 7-l 242-

  aminothiazol-4-yl) acetamidol-3- {1- (4-ethyl-2,3-dioxo) -11,2,3,4-

  tetrahydropyrazinyl) methyl)? -ephem-4-carboxylic acid having a

  melting point 109-115 ° C (dec).

  Similarly, the following compound is obtained: 7-1- [2- (2-aminothiazol-4-yl) acetamido] -3-yl] 3,6-dioxo-1,2-trifluoroacetic acid salt, 3,6-Tetrahydropyridazinyl Methyl

  3-Cephem-4-carboxylic acid, mp: 200 ° C or more.

  The physical properties (IR values, NMR) of this

  compound are identical to those of Example 13- (2).

225-2536074

  Preparation Example 1 An aqueous solution of sodium salt of acid is treated

  7-1- (2-Aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamidol-3-

  El 1- (2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl} -3-cephem-4-carboxylic acid, conventionally to obtain a freeze-dried and sterilized sodium salt is dissolved 1 gram (active amount) of sodium salt in 20 ml of physiological saline

  to obtain a solution for injection.

Preparation Example 2

  1 gram (active amount) of the lyophilic product is dissolved

  obtained in Preparation Example 1 in 4 ml of a solution

  0.5% (w / v) aqueous solution of lidocaine hydrochloride

  to obtain a solution for dilutable injection.

Preparation Example 3

  1 gram (active amount) of the lyophilic product is dissolved

  obtained in Preparation Example 1 in 20 ml of a solution of

  5% glucose to obtain a solution for injection.

  In addition, the other compounds of formula (I) can also be converted into corresponding freeze-dried products (sodium salts) or solutions for injection by treating them with

  in the same way as in Preparation Examples 1 to 3.

226 2536074

Claims (87)

  A cephalosporin derivative represented by the formula below, or a salt thereof: ## STR1 ## wherein R 1 represents a hydrogen atom or a protecting group of the carboxyl function; R 2 represents a group of formula R 7 R 8 : O R> R N-R 6 -N 9 -N N-R R R 13 II 14 R 10 _N 4 N R 10-N 253 12 or -N R 15 -N R   R 6 represents a hydrogen atom, a hydroxyl, nitro, carbamoyl or thiocarbamoyl group, an alkyl, alkenyl, alkynyl, alkadienyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl, aralkyl or acyl radical,   alkoxy, alkylthio, acyloxy, cycloalkyloxy, aryloxy, alkoxy-   carbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyl   oxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocycle-sulfonyl, alkylcarbamoyl,   dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthio- 227 2536074   carbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkyl   sulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulphonyl-   thiocarbamoyl, arylsulfonylthiocarbamoyl, sulfamoyl, alkylsulphamoyl, dialkylsulphamoyl, alkoxythiocarbonyl,   alkylideneamino, cycloalkylmethyleneamino, arylmethylene-   amino, optionally substituted heterocycle-methyleneamino or heterocyclic, or a group of formula R 16 16 17   Each of the substituents R 6 and R 17 which R 7 may be identical or different, represents a hydrogen atom or an alkyl radical, or R 16 and R 17 form a ring with the nitrogen atom which is adjacent, each of the substituents R 7, R 8 R 9, R, R 1 R 14 and R 15 which may be the same or different, represents a hydrogen or halogen atom or a optionally substituted alkyl, aralkyl or aryl radical, R 13 represents a hydrogen or halogen atom, a carboxyl, sulfo, carbamoyl or thiocarbamoyl group, or an alkyl, aralkyl, aryl, alkoxy or alkylthio radical,   acyl, alkoxycarbonyl, cycloalkyloxycarbonyl, acyl-   oxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkyl   alkylsulfonyl, arylsulfonyl, heterocycle-sulfonyl, alkyl-   carbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, acylcarbamoyl, acylthiocarbamoyl,   alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyl-   sulfonylthiocarbamoyl or arylsulfonylthiocarbamoyl, optionally substituted R 3; R represents a hydrogen atom or an alkoxy radical; R represents a hydrogen or halogen atom; R 5 represents a hydrogen atom or an optionally protected amino group O; A represents a group of formula -CH 2, or a group of formula C-   OR in which R 18 represents a hydrogen atom, a   alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl,   alkenyl, aralkyl, aryl or heterocyclic, optionally substituted, or a protecting group of the function 0 R 19   hydroxyl, or a group of formula -P / \ _ R 20   each of the substituents R 19 and R 20, which may be identical or different, represents a hydroxyl group   or an alkyl, aralkyl, aryl, alkoxy or aralkyl radical   oxy or aryloxy, and the β bond means that the compound may be a syn isomer or an anti isomer or a mixture both.   Cephalosporin derivative or salt thereof according to claim 1, wherein R 3 is a formula hydrogen atom.   Cephalosporin derivative or salt thereof according to claim 1 or 2, in whose formula R 4 is a hydrogen atom.   4 Cephalosporin derivative or salt thereof   according to any one of claims 1 to 3, in the   formula of which R 5 is an amino group Derived from cephalosporin or salt thereof   according to any one of claims 1 to 4, in the   formula of which A is a group of formula -_ 18   N in which R and the bond have the ORs 18   same definitions as in claim 1.   A cephalosporin derivative or salt thereof according to claim 5, wherein R 18 is   an optionally substituted alkyl radical.   7 Cephalosporin derivative or salt thereof   according to any one of claims 1 to 6, in the 229 2536074   -c- formula of which A is a group of formula \ O CH 3   (syn isomer). 8 Cephalosporin derivative or salt thereof   according to any one of claims 1 to 6, in   -C It has the formula of which A is a group of formula N OCH 2 COOR   (syn isomer) in which R has the same definition as 2 in claim 1.   9 Cephalosporin derivative or salt thereof   according to any one of claims 1 to 6, in   the formula of which A is a group of formula -c- N CH 3 O-C -COOR   CH 3 (syn isomer) in which R 1 has the same definition as in claim 1.   Cephalosporin derivative or salt thereof   according to any one of claims 1 to 9, in the   2 O formula of which R 2 is a group of formula -N N-R 6 in 6 N = 21 R   which R has the same definition as in claim 1. A cephalosporin derivative or salt thereof according to claim 10, wherein R 6 is a hydrogen atom, a heterocyclic radical, an alkyl, aralkyl or cycloalkyl / substituted, or R 16 a group of formula -N / wherein R 16 \ RR 17 and R 17 have the same definitions as in claim 1. 230-2536074   12 Cephalosporin derivative or salt thereof according to claim 10, wherein R 6 is a formula   hydrogen atom, an alkyl, aralkyl or cycloalkyl radical   optionally substituted alkyl, or a group R 16 of formula N in which R 16 and R 17 have the \ "R 17   same definitions as in claim 1.   13 Cephalosporin derivative or salt thereof   according to any one of claims 1 to 9, in   the formula of which R 2 is a group of formula 7 Re 8 -NWRJ 9 7 8 9   in which R, R and R have the same definitions that in claim 1.   A cephalosporin derivative or salt thereof according to claim 13, wherein each of the substituents R, R and R, which may be the same or different, is a hydrogen atom or an alkyl radical. Cephalosporin derivative or salt thereof   according to any one of claims 1 to 9, in   the formula of which R is a group of formula o R 11 R -N -N R 12   where R, Ri 1 and R have the same definitions that in claim 1.   A cephalosporin derivative or salt thereof according to claim 15, wherein each of the substituents R, R and R, which may be the same or different, is a hydrogen atom or 231 2536074 halogen or an alkyl radical.   17 Cephalosporin derivative or salt thereof   according to any one of claims 1 to 9, in the   formula of which R 2 is a group of formula R 13 R 14 N N 15   13 14 15 o where R, R and R have the same definitions that in claim 1.   18 Cephalosporin derivative or salt thereof according to claim 17, in the formula of which each 13 14 15   substituents R 13 R 4 and R 5, which may be identical or different, is a hydrogen atom or a radical alkyl.   19 7-1- 2- (2-Aminothiazol-4-yl) -2- (syn) - acid   methoxyiminoacetamidol-3- {1- (2,3-dioxo-1,2,3,4-tetrahydrate)   hydropyrazinyl) methyl} 3-cephem-4-carboxylic acid, ester of it or salt of it.   7-I-2- (2-Aminothiazol-4-yl) -2- (syn) - acid   carboxymethoxyiminoacetamidol-3- {1- (2,3-1,2,3-dioxo)   tetrahydropyrazinyl) methyl} -A 3 -cephem-4-carboxylic ester of it or salt of it.   Acid 7-1 2- (2-aminothiazol-4-yl) -2- (syn) -   Methoxyiminoacetamidol-3- {1- (4-methyl-2,3-1,2,3,4-dioxo)   tetrahydropyrazinyl) methyl 3-A 3 -cephem-4-carboxylic acid,   ester thereof or salt thereof.   22 7-I-2- (2-Aminothiazol-4-yl) -2- (syn) - acid   carboxymethoxyiminoacetamidol-3- {1- (4-methyl-2,3-dioxo)   1,2,3,4-tetrahydropyrazinyl) lmethyl} -A 3-cephem-4-   carboxylic acid, ester thereof or salt thereof.   Acid 7-1- (2-aminothiazol-4-yl) -2- (syn) -   methoxyiminoacetamidol-3- {1- (4-ethyl-2,3-dioxo-11,2,3,4-   tetrahydropyrazinyl) -methyl} -A 3 -cephem-4-carboxylic acid,   ester thereof or salt thereof.   24 7-1- 2- (2-Aminothiazol-4-yl) -2- (syn) - acid 232 2536074   carboxymethoxyiminoacetamidol 1-3 {1 - (4-ethyl-2,3-dioxo)   1,2,3,4-Tetrahydropyrazinyl) -methyl-3H-cephem-4-   carboxylic acid, ester thereof or salt thereof.   7-I 2- (2-Aminothiazol-4-yl) 2- (syn) -acid   methoxyiminoacetamidol 1-3 {1 (4-isopropyl-2,3-dioxo)   1,2,3,4-tetrahydropyrazinyl) methyl} -A-cephem-4-   carboxylic acid, ester thereof or salt thereof.   26 7-1- 2- (2-Aminothiazol-4-yl) -2- (syn) - acid   Methoxyiminoacetaxnido 1-3 (4-dimethylamino-2,3-dimethylamino)   1,2,3,4-dioxo, tetrahydropyrazinyl) methyl] -A 3-cephem-4-   carboxylic acid, ester thereof or salt thereof -   7-1- [2- (2-Amino-thiazol-4-yl) -2- (syn)] acid   carboxymethoxyiminoacetamido 1-3 {1 (4-dimethylamino)   2,3-dioxo-1,2,3,4-tetrahydropyrazinylmethyl-A-3-cephem-4-   carboxylic acid, ester thereof or salt thereof.   Acid 7-1-12- (2-aminothiazol-4-yl) -2- (syn) -   Methoxyiminoacetamido 1-3 {1 (2-oxo-1,2-dihydropyrazinyl) 11-   Methyl-3-phenre-4-carboxylic acid, ester thereof or salt of it.   Acid 7-1 [2- (2-aminothiazol-4-yl) -2 (syn)]   methoxyiminoacetamido 1-3 {1 - (3,6-dioxo-1,2,3,6-tetrahydro)   pyridazinyl) Imethyll} -3-cephem-4-carboxylic acid ester this one or salt of it.   7-I-2- (2-Aminothiazol-4-yl) -2- (syn) -acid   carboxymethoxyiminoacetamidol-3- {11- (3,6-dioxo-1,2,3,6-   tetrahydropyridazinyl) ethyl-3-cephem-4-carboxylic acid,   ester thereof or salt thereof.   31 7-1-2- (2-Aminothiazol-4-yl) -2- (syn) - acid   methoxyimninoacetamido 1-3- {1- (3-methyl-6-oxo-1,6-dihydro)   pyridazinyl) 1-methyl-3-cephein-4-carboxylic acid ester this one or salt of it.   32 7-I-2- (2-Aminothiazol-4-yl) -2- (syn) - acid   carboxymethoxyiminoacetamido 1-3 {1 - (3-methyl-6-oxo-1,6-)   dihydropyridazinyl) methyl] -3-phenf-4-carboxylic acid,   ester thereof or salt thereof. 233 2536074   Process for preparing a cephalosporin represented by the following formula, or a salt thereof: R 3: s N A-CONH C R 2 s x 4 o t__ R COOR   wherein R 1 represents a hydrogen atom or a protecting group of the carboxyl function; R 2 represents a group of formula: R 8   _m 6 R R 10 ONR 3 (-N__N-R, N or -r \ R 9 -N R 12 O R 13 R 14 -N R 15   or R 6 represents a hydrogen atom, a hydroxyl, nitro, carbamoyl, thiocarbamoyl or sulphamoyl group, or an alkyl, alkenyl or alkynyl radical,   alkadienyl, cycloalkyl, cycloalkenyl, cycloalkyl   dienyl, aryl, aralkyl, acyl, alkoxy, alkylthio, acyloxy,   cycloalkylacy, aryloxy, alkoxycarbonyl, cycloalkyl   oxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkyl   sulfonyl, cycloalkylsulfonyl, arylsulfonyl, 234 25364   heterocycle-sulfonyl, alkylcarbamoyl, dialkylcarbamoyl.   alkylthiocarbamoyl, dialkylthiocarbamoyl, acylcarbamoyl,   acylthiocarbamoyl, alkylsulfonylcarbamoyl, arylsulfonyl-   carbamoyl, alkylsulfonylthiocarbamoyl, arylsulfonyl-   thiocarbamoyl, alkylsulfamoyl, dialkylsulphamoyl, alkoxy-   thiocarbonyl, alkylideneamino, cycloalkylmethyleneamino,   arylmethyleneamino, heterocycle-methyleneamino or heterocycle   optionally substituted, or a group of R 16   formula -N O each of the substituents R 16 and R 17 17 R   R 17, which may be the same or different, represents a hydrogen atom or an alkyl radical, or R 16 and R 17 may form a ring with the nitrogen atom which 7 S   is adjacent to them; each of the substituents R 7, R 8, 9, R 9, R 10, R 11, R 12, R 14 and R 15, which may be identical or different, represents a hydrogen or halogen atom; or an optionally substituted alkyl, aralkyl or aryl radical; R 13 represents a hydrogen or halogen atom, a carboxyl, sulfo, carbamoyl or thiocarbamoyl group, or an alkyl radical,   aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxy-   carbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl,   arylsulfonyl, heterocycle-sulphonyl, alkylcarbamoyl.   dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthio-   carbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkyl   sulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyl   sulfonylthiocarbamoyl or arylsulfonylthiocarbamoyl.   optionally substituted; R 3 represents a hydrogen atom or an alkoxy radical; R 4 represents a hydrogen atom; psar in atname of hyise to ix guana amdi possibly protected; A represents a group of formula -CH 2, or a group of formula = To 235 2536074   in which R 18 represents a hydrogen atom, OR 18 or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl or heterocyclic radical, or a group protecting the hydroxyl function, or a group of formula R c 9 -O each of the substituents R 19 and R 20 which R 20 R may be identical or different, represents a hydroxyl group or an alkyl, aralkyl, aryl, alkoxy, aralkyloxy or aryloxy radical; and the -5 bond means that the compound may be a syn isomer or an anti isomer or a mixture of both, characterized in that it consists of reacting a compound of the following formula, or a salt thereof, this: R 3 R 28 S I JA <CH 2 R   COOR formula in which R 28 represents a grouping friends   or a group of formula R 31. C = C-NH- 32 J I R 32 / R 33 R 31 32 33   in which each of the substituents R 31, R 32 and R 33, which may be identical or different, represents a hydrogen atom or an organic residue not participating in the reaction, or a group of formula R 34 C = N-R 35 236-2536074   wherein each of the substituents R 34 and R 35, which may be the same or different, represents a hydrogen atom or an organic residue not participating in the reaction, and R, R and R have the same definitions as above, with a compound represented by the following formula, or with a reactive derivative thereof at the carboxyl group: A-COOH SR   R 4 wherein R 4, R and A have the same definitions as above, or 1B to react a compound of the following formula, or a salt thereof: R 3 s 0 XCH 2 CO-A-CONH NH 2 C 2 R   In which X represents a halogen atom and R 1 R 2 3 and A have the same definitions as above, with a compound represented by the formula: ## STR3 ## wherein R 5 has the same definition as above; above, or 1Cl to react a compound of the following formula, or a salt thereof: R 3 N 'C to   N-w COCONH 2 R 5 _ST _ oeJN CH 2 R 2 S R R O 237 2536074 1 2 3 4 5   wherein R, R, R and R have the same definitions as above, with a compound represented by the following formula, or one with a salt thereof H 2 NOR 18   formula in which R 18 has the same definition as above   above, and, if appropriate, after step IA1, IB1 or IC1, to eliminate the protective group, to protect the grouping   carboxyl or to convert the product into a salt of this   this. 34 Process according to claim 33, characterized in that it consists in reacting a compound corresponding to the following formula, or a salt thereof R 3 R 28 S   And wherein R, R, R, and R have the same definitions as in claim 33, with a compound represented by the following formula, or with a reactive derivative of the present invention. carboxyl * A-COOH Nt R S R 4   formula in which R 4, R and A have the same definitions as in claim 33, then, if appropriate, to eliminate the protecting group, to protect the carboxyl group or to transform the product into a salt of it.   Process according to Claim 34, 41 Process according to Claim 40, characterized in that the reaction is carried out at a temperature from 0 to 100 C -   7- (optionally substituted amino) -3,3-methyl substituted -A-cephem-4-carboxylic acid represented by the following formula, or salt thereof: R 3 R R 28 S 1 Y N C H 2 R 2 COOR 1   wherein R 1 represents a hydrogen atom or a protecting group of the carboxyl function; R 2 represents a group of formula: R 13   R 6 represents a hydrogen atom, a hydroxyl, nitro, carbamoyl, thiocarbamoyl or sulphamoyl group, or an alkyl, alkenyl or alkynyl radical,   alkadienyl, cycloalkyl, cycloalkenyl, cycloalkyl   dienyl, aryl, aralkyl, acyl, alkoxy, alkylthio, acyloxy,   cycloalkyloxy, aryloxy, alkoxycarbonyl, cycloalkyloxy-   carbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkyl   sulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocycle-sulfonyl, alkylcarbamoyl, dialkylcarbamoyl,   alkylthiocarbamoyl, dialkylthiocarbamoyl, acyl-   carbamoyl, acylthiocarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulphonylthiocarbamoyl, arylsulphonylthiocarbamoyl, sulfamoyl, alkylsulphamoyl, dialkylsulphamoyl, alkoxythiocarbonyl, alkylideneamino,   cycloalkylmethyleneamino, arylmethyleneamino, heterocycle-   methyleneamino or heterocyclic, optionally 241 2536074   R 16 R substituted, or a group of formula -N o R 17 16 17   each of the substituents R 16 and R 17 which may be the same or different, represents a hydrogen atom or an alkyl radical or else R 16 and R 17 may form a ring with the nitrogen atom adjacent thereto; R 7 8 9 10 each of the substituents R 7 R, R 9, R 10 R 12 14 16   R and R 16 which may be the same or different, represents a hydrogen or halogen atom or an optionally substituted alkyl, aralkyl or aryl radical; R 13 represents a hydrogen or halogen atom, a carboxyl, sulfo, carbamoyl or thiocarbamoyl group, or an alkyl, aralkyl, aryl, alkoxy, alkylthio or acyl radical,   alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxy-   carbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkyl   alkylsulfonyl, arylsulfonyl, heterocycle-sulfonyl, alkyl-   carbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, di-   alkylthiocarbamoyl, acylcarbamoyl, acylthiocarbamoyl,   alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkyl-   sulfonylthiocarbamoyl or arylsulfonylthiocarbamoyl, optionally substituted; R 3 represents a hydrogen atom or an alkoxy radical; R 28 represents an amino group, a group of formula 31 3 R 2 CC-NH- R 133 R 31 32 33   in which each of the substituents R, R 32 and R 33 which may be the same or different, represents a hydrogen atom or an organic residue, or a group of R 34 formula R 3 -C = N in which each of the substituents R   characterized in that A is a group of -N- wherein N and R 18 and the bond in which R and the bond   have the same definition as in claim 33.   The method of claim 34 or 35, characterized in that the reaction to a reaction temperature of 50 C to + 40 C.   37 Process according to claim 33, characterized in that it consists in reacting a compound   represented by the following formula, or a salt thereof ci 3 R XCH 2 CO-A-CONH- COOR R 1 2 3   wherein R, R 2, R, A and X have the same definitions as in claim 33, with a compound represented by the formula: H NCR 5 2 i S   in which R 5 has the same definition as in claim 33, then, if necessary, to eliminate the protective group, to protect the carboxyl group   or to turn the product into a salt of it.   38. Process according to claim 37, characterized in that A represents a group of -C-II OR 18   have the same definitions as in claim 33. 239 2536074   Process according to claim 37 or 38, characterized in that the reaction is carried out at a temperature of from 0 to 1000 ° C. The process according to claim 33 for the preparation of a compound represented by the following formula, or salt of it 3 R N CCONHN RS <4 N N> C 2 R OR COOR 1 1 2 3 4 5 18   wherein R 1, R 2, R 3 and the bond - a have the same definitions as in claim 33, characterized in that it consists in reacting a compound represented by the following formula, or a salt thereof R 3 N C R 5 __ <2 S T 4 t CCH R R 2   Wherein R, R, R, R and R have the same definitions as in claim 33, with a compound represented by the following formula, or with a salt thereof H 2 NR 18   formula in which R has the same definition as in claim 33, then, if necessary, to eliminate the protective group, to protect the grouping   carboxyl or to convert the product into a salt thereof. 242 2536074   R and R 'which are identical or different,   represents a hydrogen atom or an organic residue.   7- (optionally substituted amino) acid -   A substituted 3-methyl-3-ketohem-4-carboxylic acid or a salt thereof according to claim 42 in the formula   of which R 3 is a hydrogen atom.   44- (optionally substituted amino) -3-   substituted methyl-A-cephem-4-carboxylic acid or salt thereof   ci according to claim 43, in the formula of which R 28 is an amino group.   7- (optionally substituted amino) -3-   methyl substituted -A 3-cephem-4-carboxylic acid or salt thereof   ci according to claim 44, in the formula of which R 2 is a group of formula O O -N N-R   in which R 6 has the same definition as in the claim 42.   46- (optionally substituted amino) -3-   methyl substituted -A 3-cephem-4-carboxylic acid or salt thereof   ci according to claim 45, in the formula of which R 6 is a hydrogen atom, a heterocyclic radical or an alkyl, aralkyl or cycloalkyl radical) R 16   substituted, or a group of formula -N I R 17   R in which R 16 and R 17 have the same definitions as in claim 42.   47- (optionally substituted amino) -3-   substituted methyl-A-cephem-4-carboxylic acid or salt thereof   ci according to claim 46, in the formula of which R 6 is a dialkylamino radical or a hydrogen atom, or an alkyl, aralkyl or cycloalkyl radical, optionally substituted with an alkanoyloxy group or 243 2536074   -C This carboxyl R 24 or a group of formula I \ oy O R 24 O-   in which R 24 represents a lower alkyl radical   7- (optionally substituted amino) -3-   substituted methyl-A-cephem-4-carboxylic acid or salt thereof   ci according to claim 45, in the formula of which R 6 is a hydrogen atom or an optionally substituted alkyl, aralkyl or cycloalkyl radical, or a R 16 group of formula -N R 17 R   wherein R 16 and R 17 have the same definitions as in claim 42.   7- (optionally substituted amino) -3-   methyl substituted -A 3-cephem-4-carboxylic acid or salt thereof   ci according to claim 48, in the formula of which R 6 is a dialkylamino group or a hydrogen atom, or an alkyl, aralkyl or cycloalkyl radical,   optionally substituted with an acyloxy radical.   (7-amino optionally substituted S-3-   methyl substituted -A 3-cephem-4-carboxylic acid or salt thereof   ci according to claim 44, in the formula of which R 2 is R 7 R 8   a group of formula N in which R 7, R 8 and o No R 9   R have the same definitions as in claim 42.   51- (optionally substituted amino) -3-   methyl substituted -A 3-cephem-4-carboxylic acid or salt thereof   The compound according to claim 50, wherein each of the substituents R, R and R, which may be the same or different, is a hydrogen atom or an alkyl radical.   7- (optionally substituted amino) -3-   methyl substituted -A 3-cephem-4-carboxylic acid or salt thereof   2 ci according to claim 44, in the formula of which R 2 ci according to claim 44, in the formula of which R 244 2536074 O is a group of formula O) R 10-N R   in which R 10, R 11 and R 12 have the same definitions as in claim 42.   7- (optionally substituted amino) -3-   methyl substituted -A 3-cephem-4-carboxylic acid or salt thereof   ci according to claim 52, in the formula of which each of the substituents R 10, R and R 12, which may be identical or different, is a hydrogen atom or halogen or an alkyl radical.   Acid 7- (optionally substituted amino) -3-   methyl substituted -A 3-cephem-4-carboxylic acid or salt thereof   ci according to claim 44, in the formula of which R 2 is a group of formula R 13 N R 14 O   in which R 13, R 14 and R 15 have the same definitions that in claim 42.   7- (optionally substituted amino) -3-   methyl substituted -A 3-cephem-4-carboxylic acid or salt thereof   ci according to claim 54, in the formula of which each of the substituents R 13, R 14 and R 15, which may be identical or different, is a hydrogen atom or a alkyl radical.   56 Process for preparing a 7- (amino acid   optionally substituted) -3-methyl substituted-A 3-cephem-4-   carboxylic acid represented by the following formula, or a salt thereof: 245-2536074 R 3 R 28 2 R 2 8 N CH 2 R   Wherein R 1 represents a hydrogen atom or a protecting group of the carboxyl function; R 2 represents a group of formula: ## STR2 ## R 1 -NN-N 9 R 1 1 O O 12 or R 1 -N 1 R 8 R 6 represents a hydrogen atom, a hydroxyl group,   nitro, carbamoyl, thiocarbamoyl or sulphamoyl, or an alkyl, alkenyl or alkynyl radical,   alkadienyl, cycloalkyl, cycloalkenyl, cycloalkyl   dienyl, aryl, aralkyl, acyl, alkoxy, alkylthio, acyl-   oxy, cycloalkyloxy, aryloxy, alkoxycarbonyl, cycloalkyl   oxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocycle-sulfonyl, alkylcarbamoyl, dialkylcarbamoyl,   alkylthiocarbamoyl, dialkylthiocarbamoyl, acyl-   carbamoyl, acylthiocarbamoyl, alkylsulphonylcarbamoyl,   arylsulfonylcarbamoyl, alkylsulfonylthiocarbamoyl, aryl-   sulfonylthiocarbamoyl, alkylsulfamoyl, dialkylsulphamoyl,   alkoxythiocarbonyl, alkylideneamino, cycloalkylmethylene-   optionally substituted amino, arylmethyleneamino, heterocycle-methyleneamino or heterocyclic, or a R 16   group of formula -N o each of the substituents \ R 17   R 16 and R 17, which may be the same or different, represents a hydrogen atom or an alkyl radical, or R 16 and R 17 may form a ring with the nitrogen atom which is acent; each of the substituents F 7, Rb, R 9 R 0, R 2, R 1 R 14 and R 15 which may be identical or different, represents a hydrogen or halogen atom or an alkyl, aralkyl or aryl radical; eventually substituted; R 13 represents a hydrogen or halogen atom, a carboxyl, sulfo, carbamoyl or thiocarbamoyl group, or an alkyl radical,   aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxy-   carbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulionyl, arylsulfonyl, heterocycle-sulfonyl, alkylcarbamoyl,   dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthio-   carbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkyl   sulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulphonyl-   thiocarbamoyl or arylsulfonylthiocarbamoyl, optionally substituted; R 3 represents a hydrogen atom or an alkoxy radical; R 28 represents an amino group, a group of formula R 31 32-C = C-NH- R 133   in which each of the substituents R 31, R 32 and R 33, which may be identical or different, represents a hydrogen atom or an organic residue not participating in the reaction, or a group of formula R 34 C = N in wherein each of the substituents R 34 and R 35 R 35, which may be the same or different, represents a hydrogen atom or an organic residue not participating in the reaction, characterized in that it consists in reacting a cephalosporanic acid represented by the following formula, or a salt thereof: 247 2536074 R 3 28 Z o AN H 2 29 CH 2 R   Wherein R 3 and R 28 have the same definitions as above; R 29 represents an optionally substituted acyloxy or carbamoyloxy radical; and Z is I / S or S-O, with a compound of formula: HI O 'R 7 R 8 O 13   HNN 1 IL 12 Cu 15 6 HN 6 7 Se 9 Oil 12 $ 13 14 R 15 o R 6, R 7, R 8, R 9, R 10, R 1, R 1, RR 13 R 14 and R 5 have the same same definitions as above, or with a salt thereof, in the presence of an acid or an acid complex compound, then, if appropriate, to eliminate the protective group, to protect the carboxyl group or to   turn the product into a salt of it.   Process for preparing a 7- (amino acid   optionally substituted) -3-methyl substituted-A 3-cephem-4-   carboxylic acid or salt thereof according to claim   56, characterized in that R 3 is a hydrogen atom.   58 Process for preparing an acid 7-   (optionally substituted amino) -3-methyl substituted-A 3-   cephem-4-carboxylic acid or a salt thereof according to claim 57, characterized in that said acid or said acid complex compound is a Lewis acid or   a complex compound of a Lewis acid.   59 Process for preparing an acid 7-   (optionally substituted minium) -3-substituted methyl   A 3-cephem-4-carboxylic acid or a salt thereof according to claim 58, characterized in that said Lewis acid or said complex compound of the Lewis acid is boron trifluoride or a complex compound of this 248 2536074   latest. Process for preparing a 7- (amino acid   optionally substituted) -3-methyl substituted-A 3-   cephem-4-carboxylic acid or a salt thereof according to one of   any of claims 56 to 59, characterized in that   the reaction is carried out in the presence of an organic solvent. 61 Process for preparing a 7- (amino acid   optionally substituted) -3-methyl substituted-A 3-cephem-4-   carboxylic acid or a salt thereof according to claim 1, characterized in that said organic solvent is an organic carboxylic acid, an ester, a nitroalkane or a sulfolane.   62 Process for preparing an acid 7-   (optionally substituted amino) -3-substituted methyl   3-Cephem-4-carboxylic acid or a salt thereof   any of claims 56 to 61, characterized   in that R 29 is an acetoxy radical.   63 Process for preparing an acid 7-   (optionally substituted amino) -3-substituted methyl   3-Cephem-4-carboxylic acid or a salt thereof   any of claims 56 to 62, characterized   in that the reaction is carried out at a temperature of O C at 800 C.   Pharmaceutical composition for use in the treatment of bacterial infections in humans and animals, characterized in that it comprises an antibacterially effective amount of a cephalosporin or a pharmaceutically acceptable salt   of it according to any one of claims 1   at 32, in combination with an inert diluent or a vehicle pharmaceutically acceptable.