BE898249A - New cephalosporins, processes for their preparation, antibacterial agents containing them, intermediates for their preparation, and process for the preparation of intermediates - Google Patents

Abstract

New cephalosporins in formula (I) of which R2 is 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, -A- represents a group -CH2- or a group C = NmOR18, in which R18 represents a hydrogen atom or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl radical , aralkyl, aryl or heterocyclic, optionally substituted, a group protecting the hydroxyl function, or else a group of formula (II) and the bond means that the compound may be a syn isomer or an anti isomer or a mixture of the two.

Description

       

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  The so-called Company: TOYAMA CHEMICAL CO., LTD in Tokyo
 EMI1.1
 (Japan) -: -: -: -: -: -: -: -: -: -: -: -: -: -: -: -: - "New to prepare them, antibacterial agents containing them, intermediates for their preparation , and process for preparing intermediates "
 EMI1.2
 ¯8¯8¯8¯8¯8¯8¯8¯8¯8¯8¯8¯8¯8¯8¯8¯8¯8- ............... ..



  C. I.: Japanese patent applications no 200382/82 filed on November 17, 1982, no 67871/83 filed on April 19, 1983 and no 199945/8 filed on October 27, 1983.

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   New cephalosporins, processes for their preparation, antibacterial agents containing them, intermediates for their preparation, and process for the preparation of intermediates
The present invention relates to new cephalosporins, methods for preparing them, antibacterial agents containing said new cephalosporins, intermediates allowing the preparation of said cephalosporins, and a process for preparing said intermediates.



   The authors of the present invention have carried out research with the aim of discovering compounds having a broad antibacterial spectrum, demonstrating an excellent antibacterial action against gram-positive and gram-negative bacteria, stable with respect to ss-lactamase produced by bacteria, having a low toxicity, and which can at the same time be well absorbed by oral or parenteral administration and having an excellent therapeutic action on diseases of human beings and animals.

   As a result of this research, it was discovered that new cephalosporins, characterized in that a radical 2,3-dioxo-1,2, 3,4-tetrahydropyrazinyl, 2-oxo-1,2-dihydropyrazinyl, 3 , 6-dioxo-1, 2,3, 6-tetrahydropyridazinyl or 6-oxo 1,6-dihydropyridazinyle, optionally substituted, is attached to the exomethylene group in position 3 of the cephem ring via a carbon-nitrogen bond , and in that the following radical is attached to the amino group in position 7, had the excellent properties mentioned above:
 EMI2.1
 

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 formula in which A, R4 and R meet the definitions below.



   It is an objective of the present invention to provide new cephalosporins having the characteristic features of chemical constitution mentioned above and having a broad antibacterial spectrum, stable with respect to the s-lactamase produced by bacteria, having a low toxicity, which can be well absorbed by oral or parenteral administration, and having an excellent therapeutic action on diseases of human beings and animals.



   It is another object of the present invention to provide a process for the preparation of said new cephalosporins.



   It is another object of the present invention to provide an antibacterial agent containing one of said cephalosporins.



   It is yet another object of the present invention to provide intermediates for the preparation of said new cephalosporins, and to provide a process for the preparation of said intermediates.



   Other objectives and advantages of the present invention will emerge on reading the description which follows.



   According to the present invention, there is provided a new cephalosporin, in particular a cephalosporin represented by the following formula, or a salt thereof:
 EMI3.1
 

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 EMI4.1
 formula in which a hydrogen atom or a protecting group for the carboxyl function R2 represents a radical of formula:

   
 EMI4.2
 
 EMI4.3
 R13? i - N R 6 'i O. in which R represents an atom
 EMI4.4
 hydrogen, a hydroxyl, nitro, carbamoyl, thiocarbamoyl, or sulfamoyl group, or an alkyl, alkenyl, alkynyl, alkadienyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl, aralkyl, acyl, alkoxy, alkylthio, acyloxy, cycloalkyl radical alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclic sulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, acylcarbamoyle, acylthiocarbamoyle, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonylthiocarbamoyle, arylsulfonylthiocarbamoyle, alkylsulfamoyl, dialkylsulfamoyl, alkoxythiocarbonyl, alkylideneamino, cycloalkylméthylèneamino, arylméthylèneamino,

   heterocycle-methyleneamino, or heterocyclic, optionally substituted, or else a group of formula
 EMI4.5
 

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 EMI5.1
 (hd b. 16 17. ^ (each RR, may be the same or different, represents a hydrogen atom or an alkyl radical, or else can form a ring with the nitrogen atom adjacent to them) 7 8 9 15. each of R, R,,,,, R and R, which may be the same or different, represents a hydrogen or halogen atom or an optionally substituted alkyl, aralkyl 13 or aryl radical;

   R represents a hydrogen or halogen atom, a carboxyl, sulfo, carbamoyl or thiocarbamoyl group, or else an alkyl, aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl radical arylsulfonyl, heterocycle-sulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkylsulfonylcarbamoyle, arylsulfonylcarbamoyonyl arylsulfonyl R3 represents a hydrogen atom or an alkoxy radical; R4 represents a hydrogen or halogen atom;

   R5 represents a hydrogen atom or an optionally protected amino group; and A represents
 EMI5.2
 a group of formula-cabbage a group of
 EMI5.3
 - j) -j0 formulates an atom formula N in which R OR
 EMI5.4
 hydrogen, an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, or heterocyclic radical, optionally substituted, or a protective group
 EMI5.5
 of the hydroxyl function: or a group of
 EMI5.6
 0 0 formula (each who can X 20

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 be the same or different, represents a hydroxyl group or an alkyl, aralkyl, aryl, alkoxy, aralkyloxy or aryloxy radical); and linkage means that the compound can be a syn isomer or an anti isomer or a mixture of the two.



   The present invention also provides a process for the preparation of said cephalosporins and their salts, antibacterial agents containing said cephalosporins, intermediates for the preparation of said cephalosporins, and a process for the preparation of said intermediates.



   The invention will be described in more detail below.



   Throughout the present description, unless otherwise specified, the term "alkyl" denotes a C1-C4 alkyl radical with a straight or branched chain and includes, for example, the methyl, ethyl, npropyl, isopropyl, n-butyl radicals , isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, dodecyl, lauryl, and the like; the term "alkoxy" denotes an O-alkyl radical in which the alkyl radical is defined as above; the term "alkyl
 EMI6.1
 lower "denotes a straight or branched C1-CS l-c5 alkyl radical and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl radicals , pentyl, and the like;

   the term "lower alkoxy" denotes an O-lower alkyl radical in which the lower alkyl radical is defined as above; the term "acyl" denotes a formyl radical; a C 1 -C 6 alkanoyl radical comprising, for example, acetyl, propionyl, isovaleryl, pivaloyl, pentane-

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 carbonyl and the like; a C-C8 carbonyl cycloalkane radical comprising, for example, cyclopentylcarbonyl, cyclohexylcarbonyl and the like; an aroyl radical comprising, for example, the benzoyl, toluoyl, 2-naphthoyl radicals and the like radicals; or a heterocycle-carbonyl radical comprising, for example, thenoyl, 3-furoyl, nicotinoyl and similar radicals;

   the term "acyloxy" denotes an O-acyl radical in which the acyl radical is defined as above; the term "alkylthio" denotes an S-alkyl radical in which the alkyl radical is defined as above; the term "alkenyl" denotes a C2-C10 alkenyl radical and includes, for example, vinyl, allyl, isopropenyl, 2-pentenyl, butenyl and the like; the term "alkynyl" denotes a C2-C10 alkynyl radical and includes, for example, ethynyl, 2-propynyl and the like; the term "cycloalkyl" denotes a C3-C7 cycloalkyl radical and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like;

   the term "alkadienyl" means an alkadienyl radical in C.-C. and includes, for example, 1,3-butadienyl, 1,4-hexadienyl and the like; the term "cycloalkenyl" denotes a C-C-cycloalkenyl radical and includes, for example, cyclopentenyl, cyclohexenyl and the like; the term "cycloalkadienyl" denotes a C-C cycloalkadienyl radical. y and includes, for example, cyclopentadienyl, cyclohexadienyl and the like; the term "aryl" includes, for example, phenyl, naphthyl, indanyl and the like; the term "aralkyl" includes, for example, benzyl radicals,

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 phenethyl, 4-methylbenzyl, naphthylmethyl and the like;

   the term "heterocyclic radical" denotes a heterocyclic radical containing at least one heteroatom chosen from oxygen, nitrogen and sulfur and includes, for example, the furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl radicals , isoxazolyl, thiadiazolyl, oxadiazolyl, thiatriazolyl, oxatriazolyl, triazolyl, tetrazolyl, pyridyl, 4- (5-methyl-2-pyrrolinyl), 4- (2-pyrrolinyl), N-methylpiperidinyl, quinoleyl, phenazinyl, 1,3-benzodiox , benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, phthalidyl, coumarinyl and the like; 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 the present description, the symbol R1 represents a hydrogen atom or a protective group for the carboxyl function, and the protective group for the carboxyl function includes those which are conventionally used in the fields of penicillins and cephalosporins, for example an ester-forming group which can be eliminated by catalytic hydrogenation, by chemical reduction, or by treatment under other mild conditions; an ester-forming group which can be easily eliminated 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

  <Desc / Clms Page number 9>

 following: (a) alkyl radicals, for example a C1-C4 '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 radical, alkoxy, oxo, cyano, hydroxyl, cycloalkyl, aryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, 5-alkyl-2-oxo-1, 3dioxol-4-yl, 1-indanyl, 2-indanyl, furyl, pyridyl, 4- imidazolyle, phthalimido, succinimido, azétidino, aziridino, pyrrolidino, pipéridino, morpholino, thiomorpholino, N-lower alkyl-pipérazino, pyrrolyle, pyrazolyle, thiazolyle, isothiazolyle, oxazolyle, isoxazolyle, thiadiazolyle, thiadiazolyle, thiadiazolyle, thiadiazolyle , phenazinyl, benzofuryl, benzothienyl,

   benzoxazolyle, benzothiazolyle, coumarinyle, 2,5diméthylpyrrolidino, 1,4, 5, 6-tétrahydropyrimidinyle, 4-
 EMI9.1
 methylpiperidino, 2, 6-dimethylpiperidino, 4- 2-pyrrolinyl), 4- N-methylpiperidinyl, 1,3-benzodioxolanyl, alkylamino, dialkylamino, acyloxy, acylthio, acylamino, dialkylaminocarbonyl, alkoxycarbonylamino, alkyoxyoxyalkoxyalkyloxyalkoxyalkyloxyalkoxyalkyloxyalkoxyalkyloxyalkoxyalkyloxyalkoxyalkyloxyalkoxyalkyloxyalkoxyalkyloxyalkoxyalkyloxyoxyalkyloxyalkoxyalkyloxyalkoxyalkyloxyoxyalkyloxyoxyalkyloxyalkyloxyalkyloxyoxyalkyloxyoxyalkyloxyoxyalkyloxyoxyalkyloxyalkyloxyoxyalkyloxyalkyloxyalkyloxyalkyloxyalkyloxyalkyloxyalkyloxyalkyloxyalkyloxyalkyloxyalkyloxyalkyloxyalkyloxyalkyloxyalkyl,, , heterocycle-oxy, alkoxycarbonyloxy, alkenyloxycarbonyloxy, aryloxycarbonyloxy, aralkyloxycarbonyloxy, heterocycle-oxycarbonyloxy, alkenyloxycarbonyl, aralkyloxycarbonyl a cycloalkyloxycarbonylalkyloxycarbonylalkylcarbonyloxycarbonyloxycarbonyloxy lower or by 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,

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 (f) the phenyl radical; a substituted phenyl radical of which at least one of the substituents is chosen from those which have been expressly listed in paragraph (b) above; or else aryl radicals such as those represented by the formula:
 EMI10.1
 where-Y-is-CH = CH-O -, - CH = CH-S-, -CH2CH2S -, - CH = N-CH = N -, - CH = CH-CH = CH -, - CO-CH = CH-CO-, or-CO-CO-CH = CH-, or a substituted derivative of these radicals, the substituents of which are chosen from those which have been expressly listed in paragraph (b) above, or else aryl radicals represented by the formula:

   
 EMI10.2
 
 EMI10.3
 1 in a lower alkylene group such as- (CH) -.- or- (CH) ,, or a substituted derivative of these radicals, the substituents of which are chosen from those which have been expressly listed in paragraph (b) above- above, (g) aralkyl radicals such as optionally substituted benzyl radicals, the substituents of which are chosen from those which have been expressly listed in paragraph (b) above, (h) optionally substituted heterocyclic radicals of which at least one substituents is chosen from those which have been expressly listed in paragraph (b) above, (i) optionally substituted indanyl or phthalidyl radicals, the substituents of which are methyl radicals or halogen atoms;

   tetrahydronaphthyl radicals

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 optionally substituted, the substituents of which are methyl radicals or halogen atoms; the trityl, cholesteryl, bicyclo radicals [4. 4. 0] decyl and similar radicals, (j) optionally substituted phthalidylidene-lower alkyl radicals, the substituents of which are halogen atoms or lower alkyl radicals.



   The protective radicals of the carboxyl function which have been mentioned above are typical examples, and the protective radical of the carboxyl function can also be chosen from the other protective groups which are described in the patents of United States of America Nos. 3,499. 909.3. 573.296 and 3.641. 018, and in German patent applications published under Nos. 2.301. 014, 2.253. 287 and 2.337. 105.



   Among these protective groups for the carboxyl function, the radicals diphenylmethyl, 5-lower alkyl-2-oxo-1, 3-dioxol-4-yl-lower alkyl, acyloxyalkyl, acylthioalkyl, phthalidyl, indanyl, phenyl, phthalidylidene-lower alkyl are preferably preferred. substituted, or radicals which can be easily eliminated in a living body, such as the radicals represented by the formulas:
 EMI11.1
 -)) 1 R "" R "" R ""
 EMI11.2
 which represents an optionally known substituted alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic radical;

   R represents a hydrogen atom or an alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic radical, optionally substituted known; 2 R represents a hydrogen or halogen atom or an alkyl, cycloalkyl, aryl or heterocyclic radical, optionally substituted known, or else a radical 22 22 of formula- (CH) COOR (R has the same meaning as

  <Desc / Clms Page number 12>

 
 EMI12.1
 above and n is 0, 1 or 2); and m is 0, 1 or 2.



  More specifically, it is possible to use 5-lower alkyl-2-oxo-1,3-dioxol-4-yl-methyl radicals such as 5-methyl-2-oxo-1, 3-dioxol-4-yl- methyl, 5-ethyl-2-oxo-1, 3-dioxol-4-yl-methyl, 5-propyl-2-oxo-1, 3-dioxol-4-yl-methyl and the like; acyloxyalkyl radicals such as acetoxymethyl, pivaloyloxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, valeryloxymethyl, 1acetoxyethyl, 1-acetoxy-n-propyl, 1-pivaloyloxy-ethyl, l-pivaloyloxy-radicals; acylthioalkyl radicals such as acetylthiomethyl, pivaloylthiomethyl, benzoylthiomethyl, para-chlorobenzoylthiomethyl, 1-acetylthioethyl, 1-pivaloylthioethyl, 1-benzoylthioethyl, 1-ethyl and the like radicals;

   alkoxymethyl radicals such as methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, n-butyloxymethyl and the like; the alkoxycarbonyloxyalkyl groups such as methoxycarbonyloxymethyl radicals, ethoxycarbonyloxymethyl, propoxycarbonyloxyméthyle, isopropoxycarbonyloxymethyl, n-butoxycarbonyloxyméthyle, tertbutoxycarbonyloxyméthyle, 1-methoxycarbonyloxyethyl, 1- ethoxycarbonyloxyethyl, 1-propoxycarbonyloxyethyl, l-isopropoxycarbonyloxyethyl, 1-tert-butoxycarbonyloxyethyl, ln-butoxycarbonyloxyethyl and similar radicals ; alkoxycarbonylmethyl radicals such as methoxycarbonylmethyl, ethoxycarbonylmethyl and the like; the phthalidyl radical; the indanyl radical; the phenyl radical;

   phthalidylidenealkyl radicals such as 2-ethyl, 2-ethyl, 2-ethyl, 2-

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 EMI13.1
 (phthalidylidene) ethyl and the like; etc.



  2 R2 represents a radical of formula:
 EMI13.2
 in which R6 represents a hydrogen atom, a hydroxyl, nitro, carbamoyl, thiocarbamoyl or sulfamoyl group, or else an alkyl, alkenyl, alkynyl, alkadienyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl, aralkyl, acyl, alkoxy radical acyloxy, cycloalkyloxy, aryloxy, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclic sulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, acylcarbamoyle, acylthiocarbamoyle, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonylthiocarbamoyle, arylsulfonylthiocarbamoyle, alkylsulfamoyl, dialkylsulfamoyl, alkoxythiocarbonyl, alkylideneamino, cycloalkylmethyleneamino, arylmethyleneamino,

   heterocyclic-methyleneamino or heterocyclic, optionally substituted; a grouping of formula
 EMI13.3
   1 1 * 7 (each of R and R, which may be the same or different, represents a hydrogen atom or an alkyl radical, or else R and R form a ring with the nitrogen atom which is adjacent to them);

   each of the substituents

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 EMI14.1
 7 8 9 lU 11 12 14 15. ^ R, R, R, R, R, R and R, which may be identical or different, represents a hydrogen or halogen atom or an alkyl, aralkyl or aryl radical, 10 a hydrogen or halogen atom, a carboxyl, sulfo, carbamoyl or thiocarbamoyl group, or an alkyl, aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, arylsulfonyl, alkylsulfonyl radical heterocycle-sulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, cycloalkyl and arylsulfonylthiocarbamoyl

   the term "aryloxy" denotes an Oaryl radical, the term "alkoxycarbonyl" denotes a radical
 EMI14.2
 -CO-alkyl, the term "cycloalkyloxycarbonyl" denotes a C-O-cycloalkyl radical, the term "acyloxycarbonyl" 8 denotes a C-O-acyl radical, the term "aralkyloxy-carbonyl" denotes a radical C-0-aralkyl, the term 0
 EMI14.3
 "alkylsulfonyl" denotes an SO-radical the term "cycloalkylsulfonyl" denotes an SO-cycloalkyl radical, the term "arylsulfonyl" denotes an SO 2 aryl radical, the term "heterocycle-sulfonyl" denotes - -heterocycle, the term "alkylcarbamoyl" denotes a
 EMI14.4
 radical-C-NH-alkyl, the term "dialkylcarbamoyl" means it 0
 EMI14.5
 a radical of formula

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 EMI15.1
 alkyl - \ 0 alkyl
 EMI15.2
 the term "alkylthiocarbamoyl" denotes a radical of
 EMI15.3
 formula-C-NH-alkyl,

   the term "dialkylthiocarbamoyl" il S alkyl denotes a radical of formula-C-N, the term 11 S alkyl "acylcarbamoyl" denotes a radical of formula-C-NH-acyl, ss
 EMI15.4
 the term "acylthiocarbamoyl" denotes a radical of formula
 EMI15.5
 - The term "alkylsulfonylcarbamoyl" denotes an Il S radical of formula-C-NH-SO-alkyl, the term "arylg 8 sulfonylcarbamoyl" denotes a radical of formula-C-NH-SOll o
 EMI15.6
 aryl, the term "alkylsulfonylthiocarbamoyl" denotes a
 EMI15.7
 radical of formula the term "arylIl 2 S
 EMI15.8
 sulfonylthiocarbamoyl "denotes a radical of formula
 EMI15.9
 - -aryl, the term "alkylsulfamoyl" designates an S
 EMI15.10
 radical of formula -SO-NH-alkyl, the term "dialkylsulfamoyl" designates a radical of formula
 EMI15.11
 alkyl SO SO, -N alkyl
 EMI15.12
 the term "alkoxythiocarbonyl" denotes a radical of formula-C-O-alkyl,

   the term "alkylideneamino" denotes an S S radical of formula-N = CH-alkyl, the term "cycloalkylmethyleneamino" denotes a radical of formula-N = CH-cyclo-

  <Desc / Clms Page number 16>

 
 EMI16.1
 alkyl, the term "arylmethyleneamino" denotes a radical of formula -N = CH-aryl, and the term "heterocyclemethvleneamino" desicin-N = CH-heterocvcl, ---
 EMI16.2
 R The radicals of formula * N \
 EMI16.3
 wherein R and the same definitions as above include the amino radical, the alkylamino radicals represented by the formula -NH-alkyl, the radicals
 EMI16.4
 alkyl dialkylamino represented by the formula -N alkyl and the radicals represented by the formulas -N, -N - Nb, -N).

   alkyl, -N] IN-N / N = N or '- .. /' - 1 '- 1 -N - N 0, -N S02'-N or - N = N - \ = N
 EMI16.5
 The substituents of the various radicals mentioned above include the halogen atoms, the alkyl, aralkyl, aryl or alkenyl radicals, the hydroxyl group, the oxo group, the alkoxy radicals.

   alkylthio, nitro, cyano or amino groups, acyl radicals, carboxyl, carbamoyl, sulfo groups or alkylamino radicals represented by the formula -NH-alkyl, dialkylamino radicals
 EMI16.6
 alkyl represented by formula-N, alkyl radicals

  <Desc / Clms Page number 17>

 
 EMI17.1
 acylamino represented by the formula -NH-acyl, the alkoxvcarbonvle radicals represented by the formula
 EMI17.2
 -C-O-alkyl, acylalkyl radicals, such as Il 0
 EMI17.3
 acetylmethyl, propionylmethyl and similar radicals, aminoalkyl radicals such as aminomethyl, aminoethyl and similar radicals, N-alkylaminoalkyl radicals such as Nmethylaminomethyl, N-methylaminoethyl radicals and similar radicals, N, N-dialkylaminoalkyl radicals such as N radicals,

   N-dimethylaminomethyl, N, N-dimethylaminoethyl and similar radicals, hydroxyalkyl radicals such as hydroxymethyl, hydroxyethyl and similar radicals, hydroxyiminoalkyl radicals such as hydroxyiminomethyl, hydroxyiminoethyl and similar radicals, radicals alkoxyalkyl radicals such as methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl and similar radicals, carboxyalkyl radicals such as carboxymethyl, carboxyethyl and similar radicals, alkoxycarbonylalkyl radicals such as methoxycarbonylmethylcarbonethylmethylcarbonoxyethylcarbonoxy similar radicals, aralkyloxycarbonylalkyl radicals such as benzyloxycarbonylmethyl radicals,

   benzyloxycarbonylethyl and similar radicals, sulfoalkyl radicals such as sulfomethyl, sulfoethyl and similar radicals, sulfamoylalkyl radicals such as sulfamoylmethyl, sulfamoylethyl radicals and the like, carbamoylalkyl radicals such as carbamoylmethyl radicals, carbamoylmethyl radicals, carbamoylmethyl radicals, carbamoylmethyl radicals, carbamoylmethyl radicals, carbamoylmethyl radicals, carbamoylmethyl radicals, carbamoylmethyl radicals, carbamoylmethyl radicals, carbamoylmethyl radicals, , carbamoylalkenyl radicals such as the carbamoylallyl radical and similar radicals, the N-hydroxycarbamoyl- radicals

  <Desc / Clms Page number 18>

 
 EMI18.1
 allyle such as j.



  N-hydroxycarbamoylethyl and similar radicals,
 EMI18.2
 a radical of formula -c = c i zo 0
 EMI18.3
 represents a lower alkyl radical, etc. The various groups mentioned above in the definitions of R6, R7, R8, R9, R10, R11, R12, R13, R14 15 R &commat; R R, R, R, R, R &commat; R &commat; R and R are optionally substituted with at least one of the aforementioned substituents. Among the above substituents, the hydroxyl, amino and carboxyl groups are optionally protected by a suitable protective group ordinarily known in the art.

   Protective groups for the hydroxyl function include all those which can be used usually, such as easily removable acyl radicals, for example benzyloxycarbonyl radicals,
4-nitrobenzyloxycarbonyle, 4-bromobenzyloxycarbonyle, 4-methoxybenzyloxycarbonyle, 3,4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl, 4- (4-methoxyphenylazo) benzyloxycarbonyl, tert-butoxycarbonyl,
1, 1-dimethylpropoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2, 2-trichlorethoxycarbonyl, 2,2, 2-
 EMI18.4
 tribromethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyl-5-oxycarbonyl, 1-cyclopropylethoxycarbonyl, 8 quinol-eiloxycarbonyl, formyl, acetyl, chloroacetyl, benzoyl, trifluoroacetyl and the like;

   alkylsulfonyl radicals, for example methanesulfonyl, ethanesulfonyl radicals and similar radicals; arylsulfonyl radicals, for example phenylsulfonyl, toluenesulfonyl radicals and the like; the benzyl radical; the diphenylmethyl radical; the trityl radical; the methoxy-methyl radical; the tetrahydropyranyl radical; the tetrahydrofuranyl radical; the 2-nitrophenylthio radical; the

  <Desc / Clms Page number 19>

 2,4-dinitrophenylthio radical; and similar radicals.



   In addition, the protective groups for the amino function include all those which are usually usable, such as the easily removable acyl radicals, for example the 2,2, 2-trichlorethoxycarbonyl, 2,2, 2-tribromethoxycarbonyl, benzyloxycarbonyl, para-radicals. toluenesulfonyl, 4-nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, acetyl, (mono-, di-, tri) chloracetyl, tri fluorine acetyl, formyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl phenylazo) benzyloxycarbonyl, 4- (4-methoxyphenylazo) benzyloxycarbonyl, pyridine-1-oxide-2-yl-methoxycarbonyl, 2-furyloxycarbonyl, diphenylmethoxycarbonyl, 1, 1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 1cyclopropylethoxy

   phthaloyl, succinyl, adamantyloxycarbonyl, 8-quinoleyloxycarbonyl and the like; other easily removable radicals, e.g. trityl, orthonitrophenylsulfonyl, 2,4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-
 EMI19.1
 1-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, 1methoxycarbonyl-2-propylidene, l-ethoxycarbonyl-2propylidene, 3-ethoxycarbonyl-2-butylidene, 1-acetyl- 2-propylidene, 1-benzoyl-2-propylidene, 1- phenyl) carbamoyl] -2-propylidene, 1- carbamoyl] -2-propylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3, 3-dimethyl-5-oxo-cyclohexylidyl, 4-nitrofur similar; a di- or tri-alkylsilyl radical; and similar radicals.



   Finally, the protecting groups for the carboxyl function include all the protecting groups for

  <Desc / Clms Page number 20>

 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, n-propyl, isopropyl, tert-butyl, n-butyl, benzyl, diphenylmethyl, trityl radical. , 4-nitrobenzyl, 4-methoxybenzyl, benzoylmethyl, acetylmethyl, 4-nitrobenzoylmethyl, para-bromobenzoylmethyl, 4-methanesulfonylbenzoylmethyl, phthalimidomethyl, 2,2, 2-trichlorethyl, 1,1-dimethyl-2-propenyl , acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, 3-methyl-3-butynyl, succinimidomethyl, 1-cyclopropylethyl, methylthiomethyl, phenylthiomethyl, dimethylaminomethyl,
 EMI20.1
 quinoline-1-oxide-2-yl-methyl,

   pyridine-1-oxide-2y-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 dimethylchlorosilane, as described in the patent application
 EMI20.2
 Japanese published under the NO and in the Dutch patent application published under the NO
7073/71 R5 represents a hydrogen atom or an optionally protected amino group, and the protective groups of the amino group include many radicals usually used in the field of penicillins and cephalosporins, in particular all
 EMI20.3
 amino protecting groups which have been mentioned above in the definition of A represents a group of formula -CH.

   
 EMI20.4
 



  - "indeed a group of formula N in which R e 18 OR18
 EMI20.5
 represents a hydrogen atom; an alkyl, alkenyl alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl radical or

  <Desc / Clms Page number 21>

 
 EMI21.1
 heterocyclic, optionally substituted, or a group protecting the hydroxyl function, or a group
 EMI21.2
 0 20)) of formula-P \ (each of R and R, which can "
 EMI21.3
 be the same or different, represents a hydroxyl group or an alkyl, aralkyl, aryl, alkoxy, aralkyloxy or aryloxy radical), and the ovo bond means that the compound can be a syn isomer or an anti isomer or a mixture of the two. Said hydroxyl functional group includes the hydroxyl functional groups which have been mentioned in the definition of R2.

   In addition, the various radicals that have been
 EMI21.4
 1 mentioned above in the definition of are optionally substituted with at least one substituent chosen from halogen atoms, oxo, cyano and hydroxyl groups, alkoxy radicals, amino, alkylamino and dialkylamino groups, hetero radicals
 EMI21.5
 cyclic, and the radicals of formula:
 EMI21.6
 R25 - -N 6 "" "OR26
 EMI21.7
 which have the same definition as above and each of the substituents and R27, which may be the same 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 groups protecting the hydroxyl function and of the groups protecting the amino function which have
 EMI21.8
 n were mentioned above in the definition of and by the protective group for the carboxyl function which was 1 mentioned above in the definition of R1.
 EMI21.9
 



  - It The oximes of formula N include the * 18 OR18

  <Desc / Clms Page number 22>

 
 EMI22.1
 syn and anti isomers and mixtures thereof.
 EMI22.2
 



  51 In the grouping of formula RS
 EMI22.3
 as it appears in all the formulas of the present description, there are tautomers represented by the following equilibrium formulas, R5 being an optionally protected amino group, and these tautomers form part of the present invention:
 EMI22.4
 formulas in which R and RD have the same definitions as above and R5a represents an optionally protected imino group.

   In the preceding formulas, the protective group for the imino function which is designated by R comprises the groups used in the field of penicillins and cephalosporins, and in particular the monovalent groups forming part of the protective groups for the amino function which have been mentioned above in the definition of R2.
 EMI22.5
 



  2 When the group of formula-CHR the formula (I) is a group of formula:
 EMI22.6
 o 0) cRll 6 R 2 CH.-NN-R R in which R, 1 R10, 12 1 ^ d'f '". d R, R have the same definitions as above, there are tautomers represented by the following equilibrium formulas when each of the substituents R6 and R10 is a hydrogen atom, and these tautomers make

  <Desc / Clms Page number 23>

 also part of the present invention:
 EMI23.1
 
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.

   Salts at the basic group include salts formed with mineral acids such as hydrochloric acid, nitric acid, sulfuric acid and the like; salts formed with organic carboxylic acids such as oxalic acid, succinic acid, formic acid, trichloracetic acid, trifluoroacetic acid and the like;

   and the salts formed with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluene-2-sulfonic acid ,. toluene-4-sulfonic acid, mesitylenesulfonic acid (2,4,6-trimethylbenzenesulfonic acid), naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, phenylmethanesulfonic acid, acid benzene-1, 3disulfonic, toluene-3,5-disulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6disulfonic acid, naphthalene-2,7-disulfonic acid, benzene-1,3,5-trisulfonic acid, benzene-1,2,4-

  <Desc / Clms Page number 24>

 trisulfonic, naphthalene-1,3,5-trisulfonic acid and the like.

   Salts at the acid group level include salts formed with alkali metals such as sodium, potassium and the like. salts formed with alkaline earth metals such as calcium, magnesium and similar alkaline earth metals; ammonium salts; and the salts formed with nitrogenous organic bases such as procaine, dibenzylamine, N-benzyl-ss-phenethylamine, 1-epheneamine, N, N-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridyne, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine and the like.



   The present invention also encompasses all the optical isomers and all the racemic compounds of the cephalosporins of formula (I) and their salts, as well as all the crystalline forms and all the hydrates of said compounds. More specifically, the preferred examples of the compounds represented by formula (I) are the oximes in
 EMI24.1
 the formula of which A is a group of formula
 EMI24.2
 - it N, in particular their being of OR18 OR
 EMI24.3
 preferably an alkyl radical, in particular a methyl or ethyl radical, or else a substituted alkyl radical, in particular a radical of formula -CHCOOR
 EMI24.4
 CH3 1 1 1 has the same definition as above).



  ) CH3 n Preferred examples of R2 consist of U the radicals of formula N-R in which R 1 "=: /",
 EMI24.5
 is an optionally substituted ome, or a radical of formula

  <Desc / Clms Page number 25>

 
 EMI25.1
 Rl -N (R the same definitions as cirJ7 R above) of the radicals of i o
 EMI25.2
 Which each of the substituents R7, R and R, which may be the same or different, represents a hydrogen atom or an alkyl radical; radicals of formula
 EMI25.3
 Rit \ il in which each of the substituents - N 12 il R, R which may be the same or different, R e
 EMI25.4
 represents a hydrogen or halogen atom or a radical; and radicals of formula
 EMI25.5
 R.



  R r which each of the substituents - "Y.



  150 and identical or different,
 EMI25.6
 represents a hydrogen atom or an alkyl radical.



  We will now describe the pharmacological effects manifested by certain standard compounds represented by formula (I).



  1) Antibacterial activity (Table 1) According to the standard method of the Japan Society of Chemotherapy ["CHEMOTHERAPY", Vol. 23, pp. 1-2 (1975)], a bacterial solution was obtained, obtained by cultivating a heart infusion broth (manufactured by Eiken Kagaku) at 37 ° C. for 20 hours, in a heart infusion agar containing a drug, and it was grown at 37 ° C for 20 hours, after which the growth of bacteria was observed to determine the minimum inhibitory concentration (MIC) (eng / ml) at which the growth of bacteria was inhibited. The number of bacteria inoculated was 104 cells per plate (106 cells per ml).

   The

  <Desc / Clms Page number 26>

 
 EMI26.1
 ICD values for the following test compounds are shown in Table 1 below: (A) Salt of trifluoroacetic acid of 7- [2- 3- 2, 3, 4-tetrahydropyrazinyl) methyl} --cephem-4-carboxylic.



  (B) Trifluoroacetic acid salt of 7- [2- 3- 3-dioxo-1, 2, 3, 4-tetrahydropyrazinyl)] - -cephem-4-carboxylic acid, (C) Trifluoroacetic acid salt 7- [2- 3- 3-dioxo-1, 2, 3, 4-tetrahydropyrazinyl)] - - (D) 7- [2- 3- 2, 3, 3-trifluoroacetic acid salt, 4-tetrahydropyrazinyl)] - (E) Trifluoroacetic acid salt of 7- [2- 3- 2, 3, 4-tetrahydropyrazinyl) methyl} -A-cephem-4-carboxylic acid, (F) Acid 7- carboxymethoxyiminoacetamido] -3- 3-dioxo-1, 2, 3, 4- (G) Salt of trifluoroacetic acid 7- [2- acetamido] -3- 3-dioxo-1, 2, 3, 4 -tetrahydropyrazinyl) methyl} -A3-cephem-4-carboxylic acid (H) Salt of trifluoroacetic acid 7- [2- acetamido] -3- 3-dioxo-1, 2, 3, 4-tetrahydropyrazinyl) methyl} -A3-cephem-4-carboxylic acid, (I)

   7- acid trifluoroacetic acid salt

  <Desc / Clms Page number 27>

 
 EMI27.1
 [2- acetamido] -3- 3-dioxo-1, 2, 3, 4tetrahydropyrazinyl) methyl} -A3-cephem-4-carboxylic, (J) 7-Aminothiazol-4-yl acid trifluoroacetic acid salt ) carboxylic, (K) Trifluoroacetic acid salt of 7-aminothiazol-4-yl) {6-dioxo-1, 2, 3, 6-tetrahydropyridazinyl) methyl} A-cephem-4-carboxylic, (L ) Formic acid salt of 7-thiazol-4-yl) -2- 3- 6-dioxo-1, 2, 3, 6-tetrahydropyridazinyl)] methyl} - 3-cephem-4-carboxylic acid, ( M) Salt of trifluoroacetic acid of 7- [2- 3- 6-dihydropyridazinyl) methyl} A-cephem-4-carboxylic acid, and (N) Salt of formic acid of 7-thiazol-4 acid -yl) 3- 3-cephem-4-carboxylic.

   

  <Desc / Clms Page number 28>

 c-TALBEAU 1
CIM antibacterial activity (pg / ml)
 EMI28.1
 
 <tb>
 <tb> Compound <SEP> A <SEP> B <SEP> C <SEP> D <SEP> E <SEP> F <SEP> G <SEP> H <SEP> I <SEP> J
 <tb> Organization
 <tb> E. <SEP> coli <SEP> NIHJ <SEP>; <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1
 <tb> E. <SEP> coli <SEP> TK-3 * <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> 0.2 <SEP> # 0.1 <SEP> # 0.1 <SEP> 0.2
 <tb> Kl. <SEP> pneumoniae <SEP> Y-50 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> 0.2 <SEP> 0.2 <SEP> 0.2 <SEP> # 0.1
 <tb> Kl. <SEP> pneumoniae <SEP> Y-41 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> 0.39 <SEP> # 0.1 <SEP> # 0, <SEP> 1 <SEP> 0, <SEP> 2
 <tb> Kl.

    <SEP> pneumoniae <SEP> Y-4 * <SEP> # 0, <SEP> 1 <SEP> 0.2 <SEP> # 0.1 <SEP> 0.39 <SEP> # 0.1 <SEP> 0.2 <SEP> 0.2 <SEP> 0.2 <SEP> 0.39
 <tb> Ser. <SEP> marcescens <SEP> W-134 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0, <SEP> 1 <SEP> 0, <SEP> 39 <SEP>
 <tb> Ser. <SEP> marcescens <SEP> IID620 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1
 <tb> Pro. <SEP> morganii <SEP> T-216 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1
 <tb> Pro. <SEP> mirabilis <SEP> T-lll <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0, <SEP> 1 <SEP> 0, <SEP> 2 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> 0.2
 <tb> Pro.

    <SEP> vulgaris <SEP> GN76 ** <SEP> # 0.1 <SEP> 0, <SEP> 2 <SEP> 1, <SEP> 56 <SEP> 0, <SEP> 39 <SEP> 1, <SEP> 56 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> 0.78
 <tb> Cit. <SEP> freundii <SEP> N-7 <SEP> 039 <SEP> 1, <SEP> 56 <SEP> 0.78 <SEP> 1.56 <SEP> 0.78 <SEP> 0, <SEP> 78 <SEP> 1, <SEP> 56 <SEP> 1.56 <SEP> 1.56 <SEP> 0.78
 <tb> Ps.

    <SEP> aeruginosa <SEP> GN918 ** <SEP> 12, <SEP> 5 <SEP> 25 <SEP> 6.25 <SEP> - <SEP> - <SEP> - <SEP> - <SEP> 6.25 <SEP> 12.5 <SEP> -
 <tb>
 

  <Desc / Clms Page number 29>

 TABLE 1 (continued)
 EMI29.1
 
 <tb>
 <tb> K <SEP> L <SEP> M <SEP> N
 <tb> # 0.1 <SEP> # 0.1 <SEP> # 0.1 <SEP> # 0.1
 <tb> 0.2 <SEP> 0.78 <SEP> 0.2 <SEP> 0.2
 <tb> # 0.1 <SEP> 0.78 <SEP> 0.2 <SEP> 0.39
 <tb> - <SEP> - <SEP> - <SEP> -
 <tb> - <SEP> - <SEP> - <SEP> -
 <tb> # 0.1 <SEP> # 0.1 <SEP> 0.78 <SEP> # 0.1
 <tb> # 0.1 <SEP> 1.56 <SEP> 0.2 <SEP> # 0.1
 <tb> # 0.1 <SEP> # 0.1 <SEP> 0.2 <SEP> # 0.1
 <tb> # 0.1 <SEP> # 0.1 <SEP> 0.2 <SEP> # 0.1
 <tb> # 0.1 <SEP> # 0.1 <SEP> 0.2 <SEP> # 0.1
 <tb> 0.78 <SEP> 3.13 <SEP> 0.78 <SEP> 0.78
 <tb> - <SEP> - <SEP> - <SEP> -
 <tb>
 Note:

   * Penicillinase producing strain ** Cephalosporinase producing strain

  <Desc / Clms Page number 30>

 2) Urinary recovery
A test compound was administered orally to mice (ICR, males, 4 weeks old) at a dose of 1 mg / mouse, and urinary recovery was determined. The results obtained are given in Table 2 below.



   In the test compounds NO 1 and NO 2, the ester group is easily eliminated in a living body, so that the compounds are transformed into the corresponding free carboxylic acids. Therefore, urinary recovery was determined by quantitatively measuring the free carboxylic acids excreted in the urine.



   Method of administration: A test compound suspended in 0.5% carboxymethylcellulose (CMC) was administered orally.



   Quantitative measurement method: the amount of free carboxylic acid was measured by bioassay (paper disc method) using the test organism mentioned in Table 2 below.

  <Desc / Clms Page number 31>

 TABLE 2
 EMI31.1
 NTi-C-CONH-j-r "\ sJi CH mother-syn) S ORl8 COOR Compound Organism Test recovery No. R15 RI R2 (%) jN pneumoniae 159 6 1-CH-CH2OCOC.



  "" 0 0 N 2-CH-CH2OCOC 4 7 3 0 CH 3-CH COOH-H H,, 2 N lof4 1, 1 N -N 0 Note: * 0 to 6 hours, a group of 5 mice (statistical mean ¯ standard deviation)

  <Desc / Clms Page number 32>

 3) Acute toxicity
The mean lethal doses (DLcn) of the following test compounds were 3 g / kg or more when the compounds were administered to mice intravenously (ICR breed mice, males, body weight 20-24 g).



  Test compounds: o 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxy-
 EMI32.1
 iminoacetamido] -3- 3-dioxo-1, 2, 3, 4-tetrahydropyrazinyl) methyl} -A3-cephem-4-sodium carboxylate, {[1- (2, o 7- [2- (2-aminothiazol- 4-yl) -2- (syn) -methoxyiminoacetamido] -3 - {[1- (4-methyl-2, 3-dioxo-1,2, 3,4-tetrahydropyrazinyl) methyl} -A3-cephem-4- sodium carboxylate, o 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxy-
 EMI32.2
 iminoacetamido] -3- 2, 3, 6-tetrahydropyridazinyJj} methyl} -A-cephem-4-carboxylate, and {[1- (3, 6-dioxo-1, o 7- [2- (2-aminothiazol -4-yl) -2- (syn) -methoxyiminoacetamido] -3 - {[1- (3-methyl-6-oxo-1, 6-dihydropyridazinyl) methyl} -A3-cephem-4-carboxylate.



   We will now explain and describe the processes for preparing the compounds according to the invention.



   The compounds according to the present invention can be prepared by the following methods:

  <Desc / Clms Page number 33>

 
 EMI33.1
 Route of preparation R 'p28Z!' A-COOH OY-CHR COOR 'All <"Y or salt or reactive derivative S R 0 2 or salt thereof '.



  [III-a] [III-c] or salt thereof. ci (transformation on position 3) XCH2COCH2COOH XCH2COCH2COOH 2 or derivative redact, of XCH R3.



  ") C pr'Tl [IV] r -N-CHR tion) or salt thereof derived amino group thereof 1 or follow)

  <Desc / Clms Page number 34>

 
 EMI34.1
 * Route of preparation NO, 1 XCH 2 y --r'H XCHCOCCOOH zei Il (acylation) H COOR-L N / 011 salt thereof OH HC SO salt, or derivative (etherification (cyclization) s (cyclisatioll) reactive i reagent XCH2COCCOOH R3 R3. 3 "l8 z? CCONH-jOR ± N XCH N salt, or derivative). (cyclization) S 0 T CH O thereof N COOR-L - 'Q.



  (acylation) 18a COCOOH '' this R)) salt thereof ox. or R4 oximinationt C1, or derivative oximination) l salt, or derivative R groupeg) thereof H 5 thereof R 5 p R (p4 CH, e (acylation), COOL [XIV] or salt thereof

  <Desc / Clms Page number 35>

 
 EMI35.1
  .



  HN HN N-R Note: The formula [III-a] R7 '".



  2) The formula [III-b] HN0R9 T 0 10 0 \ 0 Ril N 10 3) The formula [III-cl is 1 HN R12 0 ''.



  R12 R14 N N 4) The formula [III-d] is HN ho o

  <Desc / Clms Page number 36>

 
 EMI36.1
 Route of preparation NO 2
 EMI36.2
 
 EMI36.3
 or salt of it
 EMI36.4
 V6 t mation position 3) - ,,. or salt thereof R3 R30¯CONH O N COOR + R3 R30¯CONH V N 0 '== d COOR
 EMI36.5
 or salt of it
 EMI36.6
 (transformation into A-cephem), s Q 0 RcoNH-r- R30-CoNH N o '== 1 0 COORi or salt thereof (deacylation) (to follow)

  <Desc / Clms Page number 37>

 Route of preparation N 2 (continued)
 EMI37.1
 or salt of it
 EMI37.2
 1

  <Desc / Clms Page number 38>

 
 EMI38.1
 1 In the above formulas, R, R, R, i \, f \, i \, i \, R, R, R, i \, i \, i \, 1 R, A and the bond the same definitions that 10- above R has that R except that it cannot represent a hydrogen atom;

   represents an amino group, or a group of
 EMI38.2
 R31 "formula each of R32 R33
 EMI38.3
 b'31 R32 R33. ^ t'd t, may be the same or different, represents a hydrogen atom or an organic residue not participating in the reaction, or a
 EMI38.4
 R34 grouping of formula. which each R "
 EMI38.5
 substituentsRetR, can be or different represents a hydrogen atom or an organic residue not participating in the reaction; represents an acyloxy or carbamoyloxy radical, a benzyl, phenoxymethyl radical or a radical of formula
 EMI38.6
 R-'4 in which R, R and A have the same R4
 EMI38.7
 definitions as above; X represents a halogen atom> Z represents> S or SO; and the broken line in 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 represents an amino group, a
 EMI38.8
 \ grouping of formula. C-NH- a group of R32 R33

  <Desc / Clms Page number 39>

 
 EMI39.1
 R "formulates the group of formula R R31 C = C-NH-comprising the group of formula R32 / 33 R R R 31 R31 R3 CH-C = N-which is its isomer. The residues 3 2 .- '1 33 R
 EMI39.2
 non-participating organic compounds which are denoted by R, R, R, R and include those which are well known in the art, including aliphatic residues, alicyclic residues, aromatic residues, aromatic-aliphatic residues, residues heterocyclic, acyl and similar residues, optionally substituted.

   More specifically, they include the following radicals: (1) aliphatic radicals: 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, (6) acyl radicals:

   acyl radicals which can be derived from organic carboxylic acids including aliphatic carboxylic acids, alicyclic carboxylic acids and alicycloaliphatic carboxylic acids; they also include aromatic-aliphatic carboxylic acids, aromatic-oxyaliphatic carboxylic acids, aromatic-thioaliphatic carboxylic acids, acids

  <Desc / Clms Page number 40>

 heterocyclic aliphatic carboxylic, heterocyclic oxyaliphatic carboxylic acids, and heterocyclic thioaliphatic carboxylic acids, in which an aromatic residue or a heterocyclic radical is linked, directly or through an oxygen or sulfur atom, to a carboxylic acid aliphatic;

   organic carboxylic acids in which an aromatic residue, an aliphatic radical or an alicyclic radical is linked 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, acid acrylic, crotonic acid and the like; the above alicyclic carboxylic acids include cyclohexanoic acid and the like; and the above alicycloaliphatic carboxylic acids include cyclopentaneacetic acid, cyclohexaneacetic acid, cyclohexanepropionic acid, cyclohexadieneacetic acid, and the like.



   On the other hand, the aromatic residues forming part of the abovementioned organic carboxylic acids include the phenyl, naphthyl and similar radicals.



   Each of the groups constituting these organic carboxylic acids may also be substituted by a substituent such as a halogen atom, an optionally protected hydroxyl group, or an alkyl, alkoxy or acyl radical, by a nitro group or by an optionally amino group. protected, or by a

  <Desc / Clms Page number 41>

 an optionally protected carboxyl group.



   On the other hand, the optionally substituted acyloxy and carbamoyloxy radicals which are designated
 EMI41.1
 29 include alkanoyloxy radicals such as acetoxy, propionyloxy, butyryloxy and the like; alkenoyloxy radicals such as acryloyloxy radicals and the like; aroyloxy radicals such as benzoyloxy, naphthoyloxy and the like; and the carbamoyloxy radical. These groups can be substituted by one or more substituents such as halogen atoms, nitro and amino groups, alkyl, alkoxy, alkylthio, acyloxy, acylamino radicals, hydroxyl groups, carboxyl, sulfamoyl, carbamoyl, alkoxycarbonylcarbamoyl radicals, aroylcarbamoyl, alkoxycarbonylsulfamoyl, aryl, carbamoyloxy, etc.
 EMI41.2
 



  In the substituents for R, the hydroxyl, amino and carboxyl groups and the like groups can be protected by protecting groups which are usually used, and these protecting groups include in particular the groups protecting the hydroxyl function, the groups protecting from the amino function and the protective groups for the carboxyl function which have been mentioned above in the definition of R2.



  (a) Transformation reaction on position 3
An optionally substituted 7-amino-substituted-3-methyl cephem carboxylic acid of formula (IV) or a salt of this acid can be prepared, in high yield and high purity, using an easy-to-carry out procedure. on an industrial scale, by reacting a 2, 3-dioxo-1, 2,3, 4tetrahydropyrazine of formula (III-a), a 2-oxo-1,2dihydropyrazine of formula (III-b), a 3, 6-dioxo-

  <Desc / Clms Page number 42>

 
 EMI42.1
 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 of a complex compound of an acid, then,

   where appropriate, by eliminating the protective group, by protecting the carboxyl group or by transforming the compound obtained into a salt thereof. Furthermore, the above-mentioned 2, 3-dioxo-1,2,3,4-tetrahydropyrazine can be prepared by the method described in Journal of Chemical Society, Perkin I, pp. 1888-1890 (1975).



   Furthermore, if necessary, the substituent can be removed from the amino group at position 7, in a conventional manner, to form an unsubstituted 7-amino compound. According to this procedure, we can
 EMI42.2
 use as starting compounds not only of the 3 A-cephem compounds and in the case where it is the cephem compounds which are used as starting compounds, the-cephem compounds produced by the reaction are subjected to a new 3 transformation into A-cephem compounds.



  On the other hand, one can use as starting materials not only compounds in which> Z is> S, but also compounds in which> Z is> SO, and in the latter case one can transform> SO into> S during the reaction or in a post-processing step.



   If 2,3-dioxo-1,2,3,4-tetrahydropyrazine from
 EMI42.3
 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, 6-dihydropyridazine of formula (III-d) which are used as reactants in the reaction are substituted by basic or acidic groups, it is possible, if necessary, to use these

  <Desc / Clms Page number 43>

 
 EMI43.1
 compounds in the reaction in the form of the corresponding salt.



  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 used, or else they can be prepared in situ.



  As acids or as complex compounds of acids used in the reaction, there may be mentioned, by way of example, protonic acids, Lewis acids or complex compounds of Lewis acids. Protonic acids include sulfuric acids, sulfonic acids and super acids (super acids refer to acids that are stronger than 100% sulfuric acid, including some of the sulfuric and sulfonic acids mentioned above).

   More specifically, protonic acids include sulfuric acids such as sulfuric acid proper, chlorosulfuric acid, fluorosulfuric acid and the like, sulfonic acids such as alkyl (mono- or di-) sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and similar acids, aryl (mono-, di- or tri) sulfonic acids such as para-toluenesulfonic acid and similar acids, as perchloric acid, magic acid (FSOH-SbF), H-AsF, SOH-SbF, HF-BF, SO.-SO, similar acids.



  Lewis acids include, for example, boron trifluoride, and complex compounds of Lewis acids include complex compounds of boron trifluoride with dialkyl ethers such as

  <Desc / Clms Page number 44>

 diethyl ether, di-n-propyl ether, di-n-butyl ether and the like ethers; with amines such as ethylamine, n-propylamine, nbutylamine, triethanolamine and the like; with carboxylates such as ethyl formate, ethyl acetate and the like; with aliphatic acids such as acetic acid, propionic acid and the like; and with nitriles such as acetonitrile, propionitrile and the like.



   The reaction is preferably carried out in the presence of an organic solvent. The organic solvents used include all of the organic solvents inert to the reaction, for example nitroalkanes such as nitromethane, nitro ethane, nitropropane and similar nitroalkanes; organic carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, dichloracetic acid, propionic acid and similar carboxylic acids; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like ketones; ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, anisole, dimethyl cellosolve and the like ethers;

   esters such as ethyl formate, diethyl carbonate, methyl acetate, ethyl acetate, ethyl chloroacetate, butyl acetate and the like; nitriles such as acetonitrile, butyronitrile and similar nitriles; and sulfolanes such as the sulfolane itself and the like sulfolanes. These solvents can be used as a mixture of two or more. In addition, a complex compound formed from these can be used as solvents.

  <Desc / Clms Page number 45>

 organic solvents and Lewis acids. It suffices that the quantity of the acid or of the complex compound of the acid used is at least equimolar with respect to the quantity of the compound represented by the formula (II) or of a salt thereof, and one can do vary this amount depending on the situation.

   In particular, it is preferred to use a proportion of 2 to 10 moles per mole of the compound of formula (II) or of a salt thereof. In the case where a complex compound of the acid is used, it can be used as it is as a solvent, and two or more of the complex compounds can be used as a mixture.



   It is sufficient that the amount of 2,3-dioxo-
 EMI45.1
 1, 2, 3, 4-tetrahydropyrazine of formula (III-a), of 2oxo-1, 2-dihydropyrazine of formula (III-b), of 3, 6dioxo-1, 2, 3, 6-tetrahydropyridazine of formula (III-c) or of 6-oxo-1, 6-dihydropyridazine of formula (III-d), or of a salt of the preceding ones, ie at least equimolar to the amount of the compound represented by formula (II) or a salt thereof, and it is particularly preferred to use an amount of 1.0 to 5.0 moles per mole.



   This reaction is usually carried out at a temperature of 0 to 80 ° C, and it ends in ten minutes to thirty hours. The presence of water in the reaction system may cause undesirable side reactions such as lactonization of the product or of the starting products, and that a breakdown of the ss-lactam cycle, so that it is desirable to maintain the system under anhydrous conditions.

   In order to fulfill this condition, it suffices to add to the reaction system an appropriate dehydrating agent, for example a phosphorus compound such as phosphorus pentoxide, polyphosphoric acid, phosphorus pentachloride, phosphorus trichloride, oxychloride. phosphorus or a similar compound; an organic silylating agent such as

  <Desc / Clms Page number 46>

 N, O-bis (trimethylsilyl) acetamide, trimethylsilylacetamide, trimethylchlorosilane, dimethyldichlorosilane or the like; an organic acid chloride such as acetyl chloride, para-toluenesulfonyl chloride or the like; an acid anhydride such as acetic anhydride, trifluoroacetic anhydride or the like;

   a mineral desiccant such as anhydrous magnesium sulfate, anhydrous calcium chloride, a molecular sieve, calcium carbide or the like.



   If a compound represented by formula (II) in which R1 represents a protective 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 formula (IV) in which R1 represents a hydrogen atom, or else this compound can be obtained by eliminating the protective group in a conventional manner.



   We will now describe the transformation reaction at position 3 which is described in the preparation route NO 2.



   The halogenated compound represented by formula (XVI) can be prepared according to the method described in Tetrahedron Letters, NO 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 a 2,3-dioxo-1 , 2,3, 4-tetrahydropyrazine of formula (III-a) or with a salt thereof, in the presence of a base. This base can be an alkali metal carbonate (for example sodium carbonate or a similar carbonate); a metal bicarbonate

  <Desc / Clms Page number 47>

 alkaline (e.g. sodium bicarbonate, potassium bicarbonate or similar bicarbonate); an alkali metal hydroxide (e.g. soda, potash or the like); an organic nitrogen base, for example triethylamine, pyridine, N, N-dimethylaniline or the like.



   The transformation is generally carried out at position 3 in an appropriate solvent. This solvent can be a halogenated hydrocarbon such as chloroform, methylene chloride or a similar compound; an ether such as tetrahydrofuran, dioxane or the like; N, N-dimethylformamide; N, N-dimethylacetamide; acetone; the water ; or a mixture of the previous ones.



   In this case, the compound represented by 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 formula (XVI) or a salt thereof. The reaction is generally carried out at a temperature of 0 to 50 ° C. for 30 minutes to 10 hours.
 EMI47.1
 



  1 3 The mixture of compounds T- and A-cephem thus obtained, that is to say a compound represented by formula (XVII) or a salt thereof, can easily be transformed into compound A- cephem, to prepare the compound of formula (XVIII), or a salt thereof, which is then transformed 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" (from Flynn, Academic Press), pages 56-64.



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

  <Desc / Clms Page number 48>

 
 EMI48.1
 tetrahydropyrazine of formula (III-a), of 2-oxo- 1, 2-dihydropyrazine of formula (III-b), of 3, 6-dioxo- 1, 2, 3, 6-tetrahydropyridazine of formula (III- c), or of 6-oxo-1, 6-dihydropyridazine of formula (III-d), or of a salt of the preceding ones, which are used as reactants in the reaction, are themselves substituted by a hydroxyl group , amino, carboxyl or the like, these groups can optionally be protected using the above-mentioned protecting groups, prior to the reaction, then subjecting them to a conventional elimination reaction after completion of the reaction to obtain the desired compound.



   On the other hand, the carboxyl group of the compound represented by formula (IV) or (XIX) can, if necessary, be protected or be transformed into a salt according to a conventional process, to give the desired compound. Else
 EMI48.2
 On the other hand, the compound represented by the formula (IV) in which R represents an amino group can be transformed into a reactive derivative at the level of the amino group or into the compound represented by the formula (XIX), as mentioned below, by a classic process.



  (b) Acylation
When the compound represented by formula (V), (VI), (VII), (VIII) or (XIII), or a salt thereof, or a reactive derivative thereof, is reacted with a compound represented by formula (IV) or with a salt thereof or with a reactive derivative at the amino group level, a compound is obtained by 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 have been mentioned for the salts of the compound represented by formula (I).

  <Desc / Clms Page number 49>

 



   Reactive derivatives at the amino group level of the compound represented by formula (IV) include all derivatives which are often used in acylation, for example: an isocyanate; a Schiff base produced by the reaction of the compound represented by the formula (IV) or a salt thereof with a carbonyl compound such as an aldehyde, a ketone, or a similar compound (ketimine type 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 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,
 EMI49.1
 or a similar compound, or a tin compound such as (C4H9) 3SnCl or a similar compound.



   Reactive derivatives of the compounds represented by formulas (V), (VI), (VII), (VIII) and (XIII) specifically include acid halides, acid anhydrides, mixed acid anhydrides, active acid amides, active esters, reactive derivatives obtained by reacting the compounds represented by formulas (V), (VI), (VII), (VIII) and (IX) with a Vilsmeier reagent. The mixed acid anhydride can be a mixed acid anhydride formed with a monoalkyl carbonate such as monoethyl carbonate, monoisobutyl carbonate and the like carbonates, a mixed acid anhydride formed with an optionally lower alkanoic acid substituted with a halogen, such as pivalic acid, trichloroacetic acid or a similar acid.

   The active acid amide includes N-acylsaccharin, N-acylimidazole, N-acyl-

  <Desc / Clms Page number 50>

 benzoylamido, N, N'-dicyclohexyl-N-acylurea, N-acylsulfonamide and the like. The active ester includes the cyanomethyl ester, substituted phenyl esters, substituted benzyl esters, 1 substituted thienyl esters and the like.



   Reactive derivatives obtained by reaction with a Vilsmeier reagent include those obtained by reaction with a Vilsmeier reagent itself obtained by reacting an acid amide such as N, N-dimethylformamide, N, N - dimethylacetamide or a similar amide with a halogenating agent such as phosgene, thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, phosphorus pentachloride, trichloromethyl chloroformate, chloride oxalyl 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 condensation. This condensing agent comprises N, N'-disubstituted carbodiimides such as N, N'-dicyclohexylcarbodiimide; azolides such as N, N'-thionyldiimidazole; dehydrating agents such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, alkoxy acetylenes, and the like; 2-halopyridinium salts such as 2-chloropyridinium-methyl iodide 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 inert to the reaction, for example a halogenated hydrocarbon such as chloroform, methylene chloride or the like, can be used as the solvent; such an ether

  <Desc / Clms Page number 51>

 as tetrahydrofuran, dioxane or a similar ether; N, N-dimethylformamide; N, N-dimethylacetamide; acetone; the water ; or a mixture of the previous ones.

   A mineral base such as an alkali metal hydroxide, an alkali metal bicarbonate, an alkali metal carbonate, an alkali metal acetate or the like may be used as the base; a tertiary amine such as trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine, Nmethylmorpholine, lutidine, collidine or the like; or a secondary amine such as dicyclohexylamine, diethylamine or the like.



   The compounds represented by formula (IX), or their salts, which can be transformed into the compounds represented by 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, it is possible to react a halide of 4- halo-3-oxobutyryl, which is formed by reacting a diketene with a halogen such as chlorine or bromine [Journal of the Chemical Society, 97, 1987 (1910)], with the compound represented by the formula (IV ) or with a salt thereof, according to a usual method. Conditions and procedures which are well known in the art can be used for this reaction.

   And one can easily prepare the salt of the compound represented by formula (IX) according to a usual method, this salt comprising the same salts as those which have been mentioned above as salts of the compound represented by formula (I). Although the compound represented by formula (IX) or a salt thereof can be isolated and purified, it can be used for the

  <Desc / Clms Page number 52>

 subsequent reaction without prior isolation.



   In addition, 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 amino group level. The reaction is usually carried out at a temperature of -50 to +40 C. The reaction time is usually from 10 minutes to 48 hours.



   Furthermore, the compounds represented by the formulas (I), (IX), (X), (XI) and (XIV) in which R1 is a protecting group for the carboxyl function can be transformed into the compounds represented by the formulas (I), (IX), (X), (XI) and (XIV) in which R is a hydrogen atom, or their salts, according to the usual method; and in the same way, the compounds represented by the general formulas (I), (IX), (X), (XI) and (XIV) in which R is a hydrogen atom can be transformed into the compounds represented by the formulas ( I), (IX), (X), (XI) and (XIV) in which
R1 is a protecting group for the carboxyl function, or in their salts;

   and the salts of the compounds represented by the formulas (I), (IX), (X), (XI) and (XIV) can be transformed into their corresponding free acids, respectively.



   On the other hand, in this acylation reaction, 17 if R, R and R contain groups which are active with respect to the reaction, these groups can be protected, in an appropriate manner, by conventional protective groups, prior to the reaction, and these protective groups can also be removed by a usual method after the reaction.



   The compounds that are represented by the

  <Desc / Clms Page number 53>

 formula (I) and their salts according to the present invention, obtained by the above-mentioned 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, a nitrosating agent is reacted with the compound represented by formula (IX) or with a salt thereof. The reaction is usually carried out in a solvent, and a solvent inert to the reaction, such as water, acetic acid, benzene, methanol, ethanol, tetrahydrofuran, can be used as the solvent. or a similar solvent.

   Preferred examples of the nitrosating agent include nitric acid and its derivatives, for example nitrosyl halides such as nitrosyl chloride, nitrosyl bromide and similar halides; alkali metal nitrites such as sodium nitrite, potassium nitrite and the like; alkyl nitrites such as butyl nitrite, pentyl nitrite and similar nitrites. If a nitrous acid salt is used as the nitrosating agent, it is preferable to carry out the reaction in the presence of a mineral or organic acid such as hydrochloric acid, sulfuric acid, formic acid, acid acetic or a similar acid.

   If an alkyl nitrite is used as the nitrosating agent, it is preferable to carry out the reaction in the presence of a strong base such as an alkali metal alcoholate or a similar strong base. The reaction is usually carried out at -15 ° C to + 30 ° C, and the reaction time is usually 10 minutes to 10 hours. The salt of the compound represented by formula (X) can easily be prepared according to a usual process, and this salt comprises the

  <Desc / Clms Page number 54>

 same salts as those which have been mentioned above as salts of the compound represented by formula (I). Although the compound represented by formula (X) or a salt thereof, thus obtained, can be isolated and purified by a well known process, it can be used in the subsequent reaction without first isolating it.



   (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 represented by formula (X) is subjected to ) or to a salt thereof an etherification reaction or a phosphorylation reaction.



   The etherification reaction or the phosphorylation reaction can be carried out by a usual method such as that described in the Japanese patent applications published under Nos. 137.988 / 78, 105.689 / 80,
149.295 / 80, or by a similar process.



   For example, the alkylation can be carried out according to a usual process. The reaction is generally carried out at a temperature of -20 ° C. to + 600 ° C., and the reaction lasts from 5 minutes to 10 hours.



   As solvent, use may be made of a solvent inert with respect to the reaction, for example tetrahydrofuran, 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, a lower alkyl halide such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide or the like can be used, for example. dimethyl sulfate, diethyl sulfate, diazomethane, diazo ethane, methyl para-toluenesulfonate or the like. If an alkylating agent is used

  <Desc / Clms Page number 55>

 other than diazomethane or diazoethane, the reaction is carried out in the presence of an alkali metal carbonate such as sodium carbonate, potassium carbonate or the like; an alkali metal hydroxide such as sodium hydroxide, potash or the like; or an organic base such as triethylamine, pyridine, N, N-dimethylaniline or a similar organic base.
 EMI55.1
 



  1
On the other hand, the salt of the compound represented by the formula (XI) can easily be obtained according to a usual process, and this salt comprises the same salts as those which have been mentioned above as salts of the compound represented by the formula ( I).



   In addition, a protective group can be introduced and eliminated according to a usual process, which makes it possible to transform a given compound into a corresponding desired compound.



   Although the compounds which are represented by the formula (XI) and their salts thus obtained can be isolated and purified by a usual process, they can be used in the subsequent reaction without first isolating them.



    (e) Cyclization reaction
The compound represented by formula (Ia) or (Ib), or a salt thereof, according to the present invention, can be obtained by reacting the compound represented by formula (IX), (X) or (XI) , or a salt thereof, with the thioformamide or thiourea represented by formula (XII). This reaction is usually carried out in a solvent. As solvent, use may be made of a solvent which is inert to the reaction, for example water, methanol, ethanol, acetone, tetrahydrofuran, dioxane, N, N-dimethylformamide,

  <Desc / Clms Page number 56>

 
 EMI56.1
 N, N-dimethylacetamide, N-methylpyridone, alone or as a mixture of two or more.

   Although it is not essential to add an acid eliminating agent, the reaction is sometimes carried out regularly if an acid eliminating agent is added in an amount such that the skeleton of the cephalosporin is not not influenced. The acid removing agent used in the reaction includes inorganic and organic bases such as alkali metal hydroxides, alkali metal bicarbonates, triethylamine, pyridine, N, Ndimethylaniline and the like. The reaction is usually carried out at a temperature of 0 to 1000C. 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 1 to 48 hours, preferably 1 to 10 hours.

   Furthermore, in the compound represented by the formula (Ia) or (Ib), it is possible to protect the carboxyl group and to remove the protective group, or to transform the product into a salt, according to a usual process. , to transform the compound obtained into the corresponding desired compound. If 1 2 5 in the formula (Ia) or (Ib), R, R and R contain groups active with respect to the reaction, these groups can be adequately protected using a protective group conventional, prior to the reaction, and remove this protective group by a usual method after completion of the reaction. The desired compound, represented by the formula (Ia) or (Ib), or its salt, thus obtained, can be isolated by a usual method.



  (f) Oximination The compound represented by the

  <Desc / Clms Page number 57>

 formula (Ib) or a salt thereof 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 formula (XV) include hydrochlorides, hydrobromides, sulfates and the like. This reaction is usually carried out not only in a solvent such as water, an alcohol, N, N-dimethylacetamide or the like, but also in other solvents inert to the reaction or in a mixed solvent made up of the previous ones.

   The reaction is carried out at a temperature of 0 to 100 ° C., preferably from 10 to 50 ° C. The reaction time is usually from 10 minutes to 48 hours. The compound represented by formula (XV) or a salt thereof is used in an amount of from about 1 mole to several moles per mole of the compound represented by formula (XIV) or a salt thereof.



  Although the salt of the compound represented by formula (XV) can be used as it is in the reaction, it can also be reacted in the presence of a base, for example an inorganic base such as an alkali metal hydroxide (e.g. soda, potash or similar hydroxide), an alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide or similar hydroxide), an alkali metal carbonate (e.g. carbonate of sodium, potassium carbonate or a similar carbonate), an alkaline earth metal carbonate (for example magnesium carbonate, calcium carbonate or a similar carbonate), an alkali metal bicarbonate (for example sodium bicarbonate, potassium bicarbonate or a similar bicarbonate),

   an alkaline earth metal phosphate (e.g. magnesium phosphate, calcium phosphate or a phosphate

  <Desc / Clms Page number 58>

 
 EMI58.1
 similar), an alkali metal hydrogen phosphate (e.g. disodium or dipotassium) or an alkali metal acetate (e.g. sodium acetate or potassium acetate), an organic base such as a trialkylamine (e.g. trimethylamine, triethylamine or a similar amine), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4. 3. 0] -5-nonene, 1,4-diazabicyclo- [2. 2.2] octane, 1,5-diazabicyclo [5. 4. 0] -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) Alcoxylation
One can synthesize the compound which is represented by the formula (IV) in which R3 is an alkoxy radical, starting from the compound which is represented by the formula (IV) in which R is a hydrogen atom, by a process known in itself, for example by the method which is described in Journal of Synthetic Organic Chemistry, Japan, 35, (7), 563-574 (1977).



   Furthermore, it is possible to synthesize the compounds which are represented by the formulas (I), (la), (Ib), (IX), (X), (XI) and (XIV) in which R3 is an alkoxy radical, with starting from the respective compounds which are represented by the formulas (I), (la), (Ib), (IX), (X), (XI) and (XIV) in which R3 is a hydrogen atom, of a in a manner known per se, for example by the method which is described in the Japanese patent applications published under Nos. 24.888 / 79 and 103.889 / 79.



   The compound which is represented by formula (I), or a salt thereof, thus obtained, can be administered to humans and animals under the

  <Desc / Clms Page number 59>

 in the form of a free acid or in the form of a pharmaceutically acceptable salt or ester for the purpose of treating and protecting against bacterial infections. 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 for the compound to be put in a galenical form usually used in cephalosporin-based medicines, for example in the form of tablets, capsules, powder, fine granules, granules, syrups, d injections (including drip), suppositories, or a similar form.

   When the above-mentioned medicament is put in a galenical form, diluents and / or additives can be used, for example vehicles such as starch, lactose, sugar, calcium phosphate, calcium carbonate or compounds similar; binding agents such as gum arabic, starch, microcrystalline cellulose, carboxymethylcellulose, hydroxypropylcellulose or the like; lubricants such as talc, stearate or similar lubricants; disintegrating agents such as carboxymethylcalcium, talc or the like.



   When the compound which is represented by 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 about 50 to 5000 mg, one to four times a day.



   The invention will be explained below by means of reference examples and preparation examples which

  <Desc / Clms Page number 60>

 are for illustration only and not for limitation.



  Reference example NO 1 (1) 6.1 ml of an aqueous solution was added to a solution of 20.0 g of ethyl N- (2,2-diethoxyethyl) oxamate in 60 ml of ethanol ethylamine 70% by weight, 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 obtain 17.0 g (85.1% yield) of N-ethyl-N'- (2, 2- diethoxyethyl) oxamide having a melting point of 131-132 C.



    IR (KBr) cm-1: VC = O 1650
Similarly, the compounds shown in Table 3 below were obtained.

  <Desc / Clms Page number 61>

 
 EMI61.1
 



  TABLE 3 (CH3CH20) 2CHCH2NHCOCONHR6
 EMI61.2
 Compound (KBr) cm recrystallization - R6 tion '"' C = O -H Acetate 141-142 1650, 1635 ethyl - Ethanol 135-136 1645 (2) 84-85 1645 / CH3 tone 145-146 1650, 1635. .



  'CH - (CH -) - CH n-Hexane 111-112 1645 - n-Hexane 92-93 1650 - n-Hexane 87-88 1650 - (CH) -CH-n-Hexane 110-111 1645 - n-Hexane 83-84 1645 - 154-155 1640 - -) n-Hexane 113-114 1655 * - CH Ethanol 118-119 CH - Ethanol 157-158 1645 OCH OCH-.



  OCH3 1655 - -0) -OCH

  <Desc / Clms Page number 62>

 (2) To a solution of the 17.0 g of N-ethyl-N'- (2,2diethoxyethyl) 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, the solvent was distilled off 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 (yield 61.8%) of 4-ethyl-2,3-dioxo-1,2,3,4tetrahydropyrazine having a melting point of 173-174 C.



   IR (KBr) cm-1 vC = O 1680-1620.



   Similarly, the compounds shown in Table 4 below were obtained.

  <Desc / Clms Page number 63>

 
 EMI63.1
 TABLE 4
 EMI63.2
 
 EMI63.3
 Composed of PF IR (KBr) cm 1 Station -H> 280 1680-1640 -ci Ethanol 220-231 1690-1635 3 - 182-183 1C80-1640 CH3 - 215-219 1680, 1625 I - (CH) 1680, 1640 -).

   171-172 1685, 1660, 1620 1685, 1660, -) CH 141-142 1685, 1 1620 - (CH) -CH 145-146 1670, 1635 - (CH) -CH-Ethanol 145-146 1660, 1625 Acetone 254 -255 1670, 1635 - 225 1665, 1635 acetic 1720, 1675, - CHCH-OCOCH-Methanol 178-180 1720, 1625 i - Ethanol 229-230 1700-1625 CHg OCH3 1 H3 1740-1620 1 CH-OCH

  <Desc / Clms Page number 64>

 
 EMI64.1
 (3) To a suspension of 5.2 g of 4- 4-dimethoxybenzyl) -2, 3-dioxo-1, 2, 3, 4-tetrahydropyrazine obtained in paragraph (2) above, in 26 ml of N , N-dimethylformamide, 4.1 g of potassium carbonate was added, and the mixture was stirred at room temperature for 30 minutes. Then 5.8 g of 4-bromomethyl-S-methyl-1,3-dioxol-2-one was added thereto and the mixture was reacted at 50-60 C for three hours.

   The reaction mixture was introduced into a mixed solvent composed of 200 ml of ethyl acetate and 200 ml of water, after the organic layer had been separated, it was washed with 100 ml of water and was dried over anhydrous magnesium sulfate.



  The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography (silica gel C-200 from Wako; eluent: chloroform) to obtain 4.9 g (yield 66.0%) of 1 - (2,4-dimethoxybenzyl) -4- (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl-2,3-dioxo-1, 2,3, 4-tetrahydropyrazine having a point of 154-156 C.



   IR (KBr) cm: vC = 01820, 1675.1630.



   Similarly, the compounds shown in Table 5 below were obtained.

  <Desc / Clms Page number 65>

 
 EMI65.1
 TABLE 5
 EMI65.2
 
 EMI65.3
 Compound p) R) R6 R6 tu 1775, 1700, 1650 0 -W 1640 -CH2OCOC 1750, 1690, 1660, 1640 -CH2COOC

  <Desc / Clms Page number 66>

 (4) In a mixed solvent composed of 37 ml of trifluoroacetic acid and 10.8 g of anisole, 3.7 g of 1- (2,4-dimethoxybenzyl) -4- (5-methyl- 2-oxo-1, 3dioxol-4-yl) methyl-2, 3-dioxo-1, 2,3, 4-tetrahydropyrazine obtained in paragraph (3) above, and the mixture was reacted at 50-60 C for two hours. The solvent was then removed by distillation 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 (90.9% yield) of 4- (5-methyl-2-oxo-1, 3-dioxol- 4yl) methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine having a melting point of 225-226 C.



   IR (KBr) cm: 1825, 1805,1725, 1690,1670.



   Similarly, the compounds shown in Table 6 below were obtained.

  <Desc / Clms Page number 67>

 
 EMI67.1
 TABLE 6
 EMI67.2
 
 EMI67.3
 1 Compound P. IR (KBr) cm * -: v R6 y 1790, 1775, 1730, 1690 - 1740, 1700, 1660 000 - 1730, 1670-1630 2
 EMI67.4
 (5) To a solution of 2.6 g of 1-carboxymethyl-2, 2, 3, 4-tetrahydropyrazine in 13 ml of N, N-dimethylacetamide was added 3.9 g of diphenyldiazomethane at room temperature, and mixing for ten minutes. The reaction mixture was introduced into a mixed solvent composed 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 (yield 80.4%) of 1-diphenylmethyloxycarbonylmethyl- 2, 3-dioxo-1, 2, 3, 4-tetrahydropyrazine having a melting point of 97-980C.

  <Desc / Clms Page number 68>

 
 EMI68.1
 IR (KBr): 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 (below: 7-ACA) and 1.54 g of 4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was introduced into 50 ml of methanol, while cooling, then 3.16 g of pyridine was added thereto dropwise.

   The precipitated crystals were collected by filtration, washed sufficiently with 30 ml of methanol, then dried to obtain 3.10 g (yield 88.1%) of 7-amino-3 - acid {{1 - (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl} - -céphem-4-carboxylic having a melting point of 191-195 C (decomp.)
IR (KBr) cm: vC = O 1795, 1670.1616.



  NMR values 6 (CF3COOD):
1.44 (3H, t, J = 7 Hz, NCH2CH3),
 EMI68.2
 3, 69 4, 08 (2H, q, J = 7 Hz,> CH),
 EMI68.3
 5, 14, 5, 51 (2H, ABq, J = 15 Hz, S OCH2- 5.48 (2H, s, C6-H, CH), 6, 74, 7, 00 (2H, ABq, J-6 Hz, / == HH (2) The transformation reaction was carried out at position 3 which was mentioned in paragraph (1) above, under the reaction conditions which are indicated in Table 7 below, to get the acid
 EMI68.4
 7-amino-3- 3-dioxo-1, 2, 3, 4-érahydropyrazinyl) methyl} -A-cephem-4-carboxylic with the yields also indicated in Table 7 below.

  <Desc / Clms Page number 69>

 
 EMI69.1
 TABLE 7
 EMI69.2
 NO Starting material Acid or Conditions Quant. reaction compound (Rend.) 7-ACA acid HN 2 3 complex 1 2.72 g 1.54 g Sulfo-Trifluoride Temp.

   2.6 g ambient boron lane (73.9 (10 ml) (2.71 2 hours 2 2.72 1.54 g Nitro-Complex Temp. 2.85 g methane Trifluoro-ambient (81.0%) ( 14 ml) 16 hour boron-diethyl ether rure.



  (5.7 g)
 EMI69.3
 (3) In a similar manner to that of paragraph (1) above, the compounds indicated in Table 8 below were obtained.



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

  <Desc / Clms Page number 70>

 



  TABLE 8
 EMI70.1
 
 EMI70.2
 Compound No. Jde NMR Values (d.-DMSO) P.



  (0 0 (3H, t, J = 6Hz,) 0 0 2) 5CH3) 1 1-N) 5-1910 80'105-49 NCH, CH,), 1 -NN (CH2) SCH3 18;) S- 191; 0 1680 S == comp.) -H), 55-388 1620 2 155 j88 (2H, m, NCH) CHg), S} OS S (2H, ABq, J = 15Hz,), rH- 2 4, d , J = 5Hz, CH), 6 (1H, d, J = 5Hz, C7-H), 6) (2H, 7H

  <Desc / Clms Page number 71>

 TABLE 8 (continued)
 EMI71.1
 0) (3H, t, J = 6Hz,) 0 0 1.50 (12H, m, "> NCH) ..

   H 2-NN (CH) CH- 5 1800, 3) (2H, is, C2-H), 86 \ = d 5 (2H, m, NCH) CH-), 1620 5) ABq, J = 15Hz,) , CH 4, d, J = 6Hz, C6-H), (1H, d, J = 6Hz, C7-H), (2H, s. == <) HH 0 (3H, t, J = 7Hz,) 3-NN (CH2) 1800, 1, 10-1) 95 (6H, m, NCH2 (CH) '"' c =: I (decomp.) 1630 363 (2H, ls, C2-H), (2H, t, J = 7Hz, NCH2 (CH2) 3CH3), 34, 482 (2H, ABq, J = 15HZ, Ci

  <Desc / Clms Page number 72>

 TABLE 8 (continued)
 EMI72.1
 5 (2H, ls, C6-H, 6J76 (2H, is, \ c =) HH 1 3, ls, 1790, 5 s li (2H, ABq, J = 15Hz,), 4 \ k) - N li ( 2H, s, C6-H, 0 / o 0 58 (2H, 7, measured in CF3COOH

  <Desc / Clms Page number 73>

 (4) The transformation reaction was carried out at position 3 which was mentioned in paragraph (1) above, under the reaction conditions which are
 EMI73.1
 shown in Table 9 below, to obtain 7-amino-3- 6-dioxo-1, 2, 3, 6-tetrahydropyridazinyl acid)

  ] - -A-cephem-4-carboxylic with yields also indicated in Table 9 below.



   TABLE 9
 EMI73.2
 
 <tb>
 <tb>? <SEP> Product <SEP> from <SEP> Acid <SEP> or <SEP> Conditions <SEP> Quant.
 <tb> start <SEP> compound <SEP> from <SEP> reaction <SEP> (Return)
 <tb> Solvent <SEP> complex
 <tb> 7-ACA <SEP> Hydrazide <SEP> of acid
 <tb> maleic
 <tb> 1 <SEP> 2.0 <SEP> g <SEP> 0.91 <SEP> g <SEP> Acid <SEP> Trifluo-Temperature <SEP> 1.72 <SEP> g
 <tb> trifluoro- <SEP> rure <SEP> from <SEP> boron-ambient <SEP> (72.3 <SEP>%)
 <tb> acetic <SEP> ether <SEP> 16 <SEP> hours <SEP>
 <tb> 10 <SEP> ml Diethyl <SEP>
 <tb> 4, <SEP> 17 <SEP> g
 <tb> 2 <SEP> 2.72 <SEP> g <SEP>;

    <SEP> 1, <SEP> 23 <SEP> g <SEP> Sulfolane <SEP> Trifluoride <SEP> Temperature <SEP> 2.75 <SEP> g
 <tb> 10 <SEP> ml <SEP> from <SEP> boron <SEP> ambient <SEP> (84.9 <SEP>%)
 <tb> 2.71 <SEP> g <SEP> 3 <SEP> hours
 <tb>
 (5) In a similar manner to that of paragraph (1) above, the crude crystals were obtained, the formula of which is indicated in Table 10 below.

  <Desc / Clms Page number 74>

 
 EMI74.1
 TABLE 10
 EMI74.2
 
 EMI74.3
 Compound No. R2 OK 1 - N N-H 2 - '== 0 0 3 - CHCH- 0 0 OHO 4, CH,' -N 3 5 -N N (CH) -CH-.



  \ - / 233 6 '/ - 6 7 Q "1 10 - \ / JL-L J

  <Desc / Clms Page number 75>

 
 EMI75.1
 TABLE 10 (continued)
 EMI75.2
 8 HO - CHOCOCH- \ / z 9 - N-CH, O-N 10 -N Il CH3 N -N CHCHjL 12 1 - 0 it 0 13 HNhCl 1

  <Desc / Clms Page number 76>

 
 EMI76.1
 TABLE 10 (continued)
 EMI76.2
 0 0 * 3 1 <-N CH3 HN "" HN \, 0 15 0 r N '"/ 0 CHN N 16 1" 0
 EMI76.3
 Note: obtained the compounds NO 10, 11, 12, 13, 14 and 15 using the sulfolane as solvent in the reaction.



  * 1: This compound was obtained by the procedure consisting of introducing into methanol, filtering the insolubles and adding pyridine to the filtrate.



  * 2: We adopted this representation because it was not confirmed if the chlorine atom occupied position 4 or position 5, nor

  <Desc / Clms Page number 77>

 if the product was made up of a single compound or a mixture (such representations in the tables which will be found below have the same meaning).



   * 3: This representation means that the product was formed from a mixture of a compound substituted in position 4 and a compound substituted in position 5 (such representations in the tables that will be found below have the same meaning ).



  EXAMPLE 2
To a suspension of 3.0 g of 7-amino acid
 EMI77.1
 3-- 2, 3, 4-tetrahydropyrazinyl)] - 3 methyl} -A-cephem-4-carboxylic obtained in Example 1- (1) in 30 ml of methanol, 1.62 g of acid were added para-toluenesulfonic monohydrate to form a solution, then 5.0 g of diphenyldiazomethane was slowly added to this solution, after which the resulting mixture was reacted at room temperature for 15 minutes. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was dissolved in a mixed solvent composed of 20 ml of ethyl acetate and 20 ml of water.



  The pH of the solution was adjusted to 7.0 using sodium bicarbonate. The organic layer was then separated and dried over anhydrous magnesium sulfate, then the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (silica gel C-200 from Wako eluent: 1: 4 mixture by volume of benzene: ethyl acetate) to obtain 3.1 g (yield 70.3%) of 7 -amino-
 EMI77.2
 3- 3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl) -A-cephem-4-carboxylate diphenylmethyl having a melting point of 183-186 C (decomposition).



  IR: o In a similar way, the compounds are obtained which are indicated in Table 11 below.

  <Desc / Clms Page number 78>

 
 EMI78.1
 TABLE 11
 EMI78.2
 
 EMI78.3
 Compound PF (0 IR (KBr) cm -1 R2 0 0 1765, 1725, -N 1690, 1630 0 -} 1725, '= / 3 0} 1765, 1730, - N (CH2) 1635 -V' == 1 cl3 5 1760, - (decomp.) 1665, 1635 CH3 0 lao-189 1760, 1725, - N (CH) 1680, 1630, 0 OHO 1765, 1730, - 1685, 1630 2 4 3

  <Desc / Clms Page number 79>

 
 EMI79.1
 TABLE 11 (continued)
 EMI79.2
 Compound P.

   (oQ) R 0 0 1730, 17 -) (decomp.) 1685, 1635 1 l H 1765, 1730, - N (CH2) 1635 "=== 1 0 164-172 1730, - N (CH) CH 1635 0 - N-0 1725, (decomp.) 1680, 1625 1 1 155-160 1725, -N 1680, 1630 2 0 oxo 1770, 1725, - NCH2CH20COCH3 1678, 1623 0 0 0 - 172-175 1760, 1720, - 1630 = in 82-85 1775, 1720, - ri (decomp.) 1650 0

  <Desc / Clms Page number 80>

 
 EMI80.1
 TABLE 11 (continued)
 EMI80.2
 Compound (KBr) cm R2 CH3 \ 108-114 1765, 1725, (dcomp.) 1650 0, 0 132-135 1780, 1730, HN "- 0 H 178-181 1780, 1730, ci (d, ecomp.) 1660 6 0 0 HNCH3 137-139 1780, 1730, N tTH3. 1660 CH3 0 fH3.

   - 90-93 1770, 1720, (decomp.) 1660 -N T 0 0 N 138-143 1770, 1720, "T)) 1660 0 0

  <Desc / Clms Page number 81>

 EXAMPLE 3
In a mixed solvent composed of 25 ml of trifluoroacetic acid and 10 ml of anisole, 4.9 g of 7-amino-3- [1- (2, 3-dioxo-1,2, 3, 4) were dissolved. -tetrahydropyrazinyl) -methyl] - # diphenylmethyl-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 50 ml of diethyl ether was added to the residue, after which the crystals were collected by filtration.

   These crystals were washed sufficiently with 40 ml of diethyl ether, then dried to obtain 4.25 g (yield 97.0%) of trifluoroacetic acid salt of 7-amino-3- {[1 - (2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl} - -A-cephem-4-carboxylic having a melting point of 105-106 C (decomposition).
 EMI81.1
 



  IR (KBr) 1780, 1700-1630 NMR values 6 (CF3COOD): 3. 72 (2H.
 EMI81.2
 z.



  5, 14, 5, 52, (2H, ABq, J = 15 Hz, S 5, 44 (2H, s, CH, -H), JL-CH 6, 78, 6, 98 (2H, ABq, J = 6 Hz,) HH
Similarly, the compounds which are shown in Table 12 below were obtained.

  <Desc / Clms Page number 82>

 



  TABLE 12
 EMI82.1
 
 EMI82.2
 Compound "--- ,,, 6 / <DF compound IR (Ker) cm-1: Values (cp3COOD * 2 R2 C = O -DMSO + D 0 0 (2H, 1 CH), / - \ / 3 (decomP.) CH - gg), '' CH , - 5) 06 (1H, d, J = 5Hz, C6-H), 5 ... d, J = 5Hz, C7-H), 6 73 (2H, ls, = HH * 3 00 t, J = 7Hz,) CHg), 152-155 - N 675, 35-208 NCHCH), '=== 1 (decomp.) 1635 3) (2H, ls, C2-H), 3/77 (2H, t, J = 7Hz, 2) 2 2 3 s 4) (2H, ABq, J = 15Hz,), CH2-

  <Desc / Clms Page number 83>

 TABLE 12 (continued)
 EMI83.1
 5. -H, 73 (2H, 15, HH - 0 0 1, 46 (6H, d, J = 7HZ,> NCH H - (decomp.) Cl 1620 NCH, '' * "CH- 5, 46 (2H , ls, C6-H,.



  H H * 2

  <Desc / Clms Page number 84>

 TABLE 12 (continued)
 EMI84.1
 1-1 OHO (3H, t, N), (decomp.) -) CH 1635 1, (4H, m, INCH2 (CH) CH), 362 -H), 3, (2H, t, J = 7Hz, NCH) CH), 2 2s2 3 4.56, 5) (2H, ABq, J = 15Hz, sil), "ICH2 5, 6, (2H, 15, H * 1 * 1 0. -rH), 167- 169> \ - 1680 - HS 69 (2H, is, CH), 4, H

  <Desc / Clms Page number 85>

 TABLE 12 (continued)
 EMI85.1
 s 5 21-5.



  CH 5) (2H, s, C6-H, 6, (2H, ABq, J = 6Hz, HH * 2 0 0 089 (3H, t, J = 7Hz,) / * \ - - 85 (20H, fi ,) "== 1 COfip.) 1635 3} 76 (2H, t, J = 7Hz, NCH) QCH),, le 2 2 10 3 4fui57, 21 (2H, ABq, J = 15Hz,), CH 5 32 (2H, ls, C6-H, / b 7 6167 (2H, is, HH * 1

  <Desc / Clms Page number 86>

 TABLE 12 (continued)
 EMI86.1
 0 (2H, ls, CH), H 1780, - (4H, m. NCHCHO-), / 1635 57, 5) 16 (2H, ABq, J CH 5, 6, HH * 1 * 1 0,), ' -.



  CH3 - CH3 72 (2H, ls, C2-H), 1630 5, (2H, ABq, J = 15Hz,), CH 5749 (2H, s, C6-H, 7 (2H, 15, * 2

  <Desc / Clms Page number 87>

 
0 2, 03 (3H, s, -OCOCH3), 3-59- TABLE 12 (continued)
 EMI87.1
 1
 EMI87.2
 389 -H), (2H, ABq, 1780 f "1675). S, C6-H, C7-H), -".



  1640 H 0; .



  8) 88 (1H, s, * 2 * CH 73 (2H, 1s, C2-H), cl 241-243 'N.



  J = 15HZ,) - 2 "'-H o 79 (2H, ABq, J = 10Hz, H * 2

  <Desc / Clms Page number 88>

 TABLE 12 (continued)
 EMI88.1
 1. 36 (3H, t, J = 7Hz, * / - i 'q, J = 7Hz, -CHCH-), (2H, 1s, CHCH-219-222 "(dcomp.) (2H, ls, C6- H, (2H, 1600 N), 1 ci N 0! * 2 * (2H, 1s, C2-H), 5) (2H, ABq, 2 9 j 0 1795, J = 16HZ, '), (2H, s, C6-H, C7-H), 1640, HN> 200 - 1 - 59 (1H, s, '- H) O 0'

  <Desc / Clms Page number 89>

 TABLE 12 (continued)
 EMI89.1
 Q 50 5H, 0 3 e50 (l5H S A. -H),> 200 1600 If-rHo 7) -H -H * '* 2 HN HN 0,

  <Desc / Clms Page number 90>

 
 EMI90.1
 TABLE 12 (continued) ** (2H, is, C2-H), 139-140 1710, / 1690 04 (1H, d, J = 5Hz, \) 1620 2 - N NH \ 6-H), 20 34, 6 7-34 6) HH * 3 ** 3, (3H, s, NCH), 48 (2H, ls, C2-H), 0 0 152-155 1780, 4) (2H, ABq, J = 15Hz, S \ / 1660, - == 3 87 (1H, d, J = 5Hz, C6-H), 03 J = 5Hz, C7-H), 70 (2H, Is, ze HH * 3 Note * = Free compound;

   the desired compounds were obtained by reacting in a mixed solvent composed of trifluoroacetic acid and anisole, then removing the solvent, dissolving the residue in water and adjusting the pH to 3.5 to 28% ammonia aid.



    ** = Free compound; obtained by treating the salt of trifluoroacetic acid with pyridine in methanol.

  <Desc / Clms Page number 91>

 



  EXAMPLE 4
To a suspension of 5.0 g of 7-amino-3- acid
 EMI91.1
 \ [1- (3-methyl-6-oxo-1, cephem-4-carboxylic) In 15 ml of acetone, 2.36 g of 1.8-diazabicyclo [5. 4. 0] -7-undecene was added and 4.51 g of pivaloyloxymethyl iodide at 10-15 C., and the mixture was reacted for 30 minutes. After completion of the reaction, the reaction mixture was introduced into a mixed solvent composed of 50 ml of water. and 50 ml of ethyl acetate, then the organic layer was separated, washed with water and dried over anhydrous magnesium sulfate.

   To this was added 10 ml of an ethyl acetate solution containing 1.40 g of oxalic acid, and the precipitated crystals were collected by filtration and washed with ethyl acetate to obtain 4.59 g (yield 56.2%) of oxalic acid salt of 7-amino-3- {[1- (3-methyl-6-oxo-1,6-dihydropyridazinyl)] methyl} -
 EMI91.2
 of pivaloyloxymethyl having a melting point of 145-147 C (decomposition).



  IR (KBr) cm: 1790, 1750, 1660 NMR values 6 (d6-DMSO): 1, 21 (9H, s, 2.29 (3H, s, CH3), 3.52 (2H, es, C2- H),
 EMI91.3
 4, 94, 5, 33 (2H, ABq, J = 15 Hz, 5, 14 (1 d, J = 5 Hz, C6-H), 5, 76-6, 23 (3H, m, CH, -OCHO -), 7, 01, 7, 53 (2H, ABq, J-10 '.



  7, 44 (3H, es, EXAMPLE 5
 EMI91.4
 (1) To a solution of 2.69 g of 1- cl2-oxo-1, 3-dioxol-4-yl) methyl-2,3-dioxo-1, 2,3, 4-tetrahydropyrazine in 27 ml of N , N-dimethylformamide, added

  <Desc / Clms Page number 92>

 1.52 g of potassium carbonate, and the resulting mixture was stirred at room temperature for 20 minutes. It was then added 4.67 g of tert-butyl 7-phenylacetamido-3-bromo-2, methyl-A-cephem-4-carboxylate, while cooling in ice, and the resulting mixture was reacted with room temperature for two hours.



  The reaction mixture was introduced into a mixed solvent composed of 200 ml of ethyl acetate and 150 ml of water, then the organic layer was separated, washed with 150 ml of water, then dried it over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was dissolved in 100 ml of chloroform. To the solution obtained was added 2.45 g (70% purity) of m-chloroperbenzoic acid, and the mixture was reacted at room temperature for one hour. The solvent was removed by distillation under reduced pressure, and to the residue was added 100 ml of ethyl acetate and 100 ml of water. The organic layer was separated, washed with 100 ml of water, and then dried over anhydrous magnesium sulfate.

   The solvent was removed by distillation under reduced pressure, then the resulting residue was purified by column chromatography (Wako C-200 silica gel, eluent = chloroform) to obtain 2.70 g
 EMI92.1
 (yield 43.2%) of 7-phenylacetamido-3- 2-oxo-1, 3-dioxol-4-yl) methyl-2, 3-dioxo-1, 2, 3, 4-tetrahydropyrazinyl]] methyl} - T-butyl A-cephem-4-carboxylate-1-oxide having a melting point of 135-136 C (decomposition).



   IR (KBr) cm: 't = 0 1820, 1790,1720, 1685,1650.



  (2) In a mixed solvent composed of 12 ml of N, Ndimethylformamide and 6 ml of acetonitrile, dissolved
 EMI92.2
 3.0 g of 7-phenylacetamido-3,1,3-dioxol-4-yl) methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl]] methyl} -A-cephem-4-carboxylate -1-tert-oxide

  <Desc / Clms Page number 93>

 butyl. To the resulting solution was added 1.0 g of stannous chloride and 1.58 g of acetyl chloride, in this order, while cooling in ice, 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, after which the pH of the resulting mixture was adjusted to 6.0 using sodium bicarbonate.

   The organic layer was then separated, washed with 50 ml of water, then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography (silica gel C-200 from Wako; eluent: 3: 2 mixture by volume of toluene: acetate
 EMI93.1
 ethyl) to obtain 2.12 g (72.4% yield) of 7-phenylacetamido-3-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl]] of tert-butyl having a point 120-122 C (decomposition).



  IR (KBr) cm: 1820, NMR values 6 (CDCl): 1.58 (9H, s, -C (CH), 2.28 (3H, s, -CH-)
 EMI93.2
 3, 17, 3, 61 (2H, ABq, J = 18 Hz, C2-H),
 EMI93.3
 3.77 (2H, s, / 0) -CH-).



  4, 53, 5, 13 (2H, ABq, J = 15 Hz, H- 4, 71 (2H, s,> 5, 03 (1H, d, J-5'5z, 5, 93 (1H, dd, J = 5 Hz, J = 8 Hz, C7-H), 6, 53, 6, 89 (2H, ABq, J = 6 Hz, HH

  <Desc / Clms Page number 94>

 
 EMI94.1
 7, 32-7, 51 (5H, m, / Q \),
 EMI94.2
 7.57 (1H, d, J = 8Hz, -CONH-).



   In a similar manner to that of paragraphs (1) and (2) above, the compounds which are shown in Table 13 below were obtained.

  <Desc / Clms Page number 95>

 



  TABLE 13
 EMI95.1
 
 EMI95.2
 Compound R6 152),, 1780, C2-H, (c-CH2-), 30, 5) 12 (2H, ABq, 1 180-183 1710,,), 12 (1H, d, J = 5Hz, 1680, 1645 2 C6-H), 5, dd, J = 5Hz, J = 8Hz, C7-H), 6 07, 6, (2H, ABq, J = 6Hz, HH 7, 45 (5H, m, (5H, M, -CONH-) *

  <Desc / Clms Page number 96>

 TABLE 13 (continued)
 EMI96.1
 1.) 56 (9H, s, 1780, -C (2H, ABq, J = 18Hz, 105-108 1740, - comp.) (2H, s, (o) -CH2-), 58, 1660 5) 11 (2H, ABq, J = 15Hz, S)), 03 CH, d, J = 5Hz, C6-H), (2H, s, NCH-), 5) 93 (1H, dd, J = 5Hz, J = 9Hz, C7-H), 6) 88 (2H, ABq, J = 7Hz, H), HH d, J = 9Hz, 43 (5H, s, - ** 1 (2H, 18, 1770, 61 (2H, s, (o \ -CH2-), (2H, - - (dcomp.) 91 (2H, ls, S zij 'cl2-

  <Desc / Clms Page number 97>

 TABLE 13 (continued)
 EMI97.1
 518 d, J = 5Hz, C6-H), 5 dd, 6 J = 5Hz, J = 8Hz, C7-H), 6.

   ABq, J = 6Hz,) = <), 88 (1H, s, -CH H H 6. 47 x 3), 7/95 d, J = 8Hz, -CONH-) **

  <Desc / Clms Page number 98>

 
 EMI98.1
 (3) 2.0 g of 7-phenylacetamido-3-2-oxo-1, 3-dioxol-4-yl) methyl-2, 3-dioxo-1, 2 were dissolved in 30 ml of anhydrous methylene chloride , 3, 4-tetrahydropyrazinyl]] of tert-butyl.



  To this solution was added 1.59 g of N, N-dimethylaniline and 0.57 g of trimethylsilyl chloride, in this order, and the resulting mixture was stirred at room temperature for one hour. The reaction mixture was cooled to -40 ° C, and 0.89 g of phosphorus pentachloride was added thereto, then the mixture was reacted between -30 and -20 ° C for 2.5 hours. The reaction mixture was then cooled to -40 ° C, and 5.2 g of anhydrous methanol was added thereto, after which the reaction was continued with cooling in ice for one hour. To the reaction mixture was added 20 ml of water and stirring was continued for another 30 minutes. The pH of the reaction mixture was then adjusted to 0.5 using 6N hydrochloric acid, and the aqueous layer was separated.

   To this aqueous layer was added 50 ml of ethyl acetate, and the pH of the mixture was adjusted to 6.5 using sodium bicarbonate. The organic layer was separated, washed with 50 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the residue was added 50 ml of diethyl ether. The crystals were collected by filtration to obtain 1.05 g (64.8% yield) of 7-
 EMI98.2
 3-amino-3-dioxol-4-yl) methyl-2, 3-dioxo-1, 2, 3, 4-tetrahydropyrazinyl]] tert-butyl carboxylate having a melting point of 185-188 C (decomposition).



  IR (KBr) cm ': 1820, 1765, 1705, 1690, 1635 NMR values 6 (CDC1-. -DMSO): J b 1, 52 (9H, s, -C 2, 24 (3H, s, -CH -), 3, 46 (2H, 4, 35, 5, 08 (2H, ABq,
 EMI98.3
 J =) -CH-

  <Desc / Clms Page number 99>

 
 EMI99.1
 4, 76-5, 09 (4H, m, -, -H, 6, 74 (2H,).



  H H
 EMI99.2
 Similarly, the compounds shown in Table 14 below were obtained.

  <Desc / Clms Page number 100>

 



  TABLE 14
 EMI100.1
 
 EMI100.2
 Compound IR (KBr) Values ------.------ "- 'c = - C1, ......'. ' R 1 (9H, s, -C) 48 (2H, lis, - 111-113 1780, 4) 28, 5) (2H, ABq, J = 15Hz, S (decomp.) 1690, 2 4) 82 (1H , d, J = 5Hz, C6-H), d, J = 5Hz, C7-H), (2H, ABq, J = 6Hz, \ / ''! * 132-134 1775, 1. (9H, s, - 1715, -C (2H, ls, C2-H), *** (Hydrochloride) 1640 5/13 (2H, ABq, J = 15Hz, S), -CH-

  <Desc / Clms Page number 101>

 TABLE 14 (continued)
 EMI101.1
 5) 30 (2H, s,> NCH-), 75 (2H, ls, C6-H, C7-H), 6) (2H, 15, = <) HH * 1. 74 1780, 05, 3, (2H, ABq, J18Hz, C2-H), - 2 (decomp.) 1715, 4 40, 4 99 (2H, ABq, J = 15Hz, S 1690, '1650 -CH- 4J55 (2H, s,) d, J = 5Hz, 1 11, 2 C6-H), 484 d, J = 5Hz, C7-H), 6) 09, 6) (2H, ABq, J = 6Hz, == <), 6 H H s, 2), Note *** The imino ether was poured into water, and the hydrochloride which was deposited was isolated.

  <Desc / Clms Page number 102>

 



  Example 6 (1) 2.29 g of 2- (2-formamidothiazol-4-yl) -2- (syn) acid are dissolved in 2.29 ml of N, N-dimethylacetamide and 4.58 ml of acetonitrile -methoxyiminoacetic, and to the resulting solution is added dropwise 1.62 g of phosphorus oxychloride, after which the mixture is subjected to a reaction for one hour at a temperature of -5 to ooc. Subsequently, 5.18 g of 7-amino -3 - {[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl - # 3-cephem-4- are added. diphenylmethyl carboxylate to the reaction mixture and reacted at -5 to 0 ° C for one hour.

   Once the reaction is complete, the mixture is poured into a mixed solvent of 80 ml of water and 80 ml of ethyl acetate and the pH of the solution is adjusted to 6.5 with sodium hydrogen carbonate. Subsequently, the organic layer is separated and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and 60 ml of diethyl ether are added to the residue.



  Then the crystals are collected by filtration and we obtain
 EMI102.1
 6.05 g (yield: 83.0%) of 7- [2- (syn) -methoxyiminoacetamido] -3- 2, 3, 4tetrahydropyrazinyl)] methyl) -A-cephem-4-carboxylate having a diphenylmethyl point 165-168 IR fusion (KBr): 1720, 1680, 1640 NMR (d6-DMSO) S b values (2-formamldothiazol -4-yl) -2-1, 18 (3H, t, J = 7Hz, N- CH2CH3), 3.59 (2H, ls, C2-H), 3 "ï2 (2H, q, J = 7Hz, N-CH2CH3),
 EMI102.2
 3,
 EMI102.3
 4, 42, 5, 04 (2H, ABq, J = 15Hz, S), J-CH-

  <Desc / Clms Page number 103>

 
 EMI103.1
 5730 d, J = 5Hz, C6-H), 6, dd, J = 5Hz, J = 8Hz, C7-H),
 EMI103.2
 6, ABq, J = 6Hz, /), H
 EMI103.3
 7, 04
 EMI103.4
 N-TT- 7,), S H
 EMI103.5
 8, 63 (1H, s, HCO-), 9, d, J = 8Hz, -CONH-), 12, 68 (1H, is, HCONH-) Similarly,

   the compounds shown in Tables 15, 16 and 17 are obtained.

  <Desc / Clms Page number 104>

 
 EMI104.1
 TABLE 15
 EMI104.2
 
 EMI104.3
 (syn-isomer)
 EMI104.4
 Compound (KBr) cm-1: Compound-1 R 1780, 1720, H 1680-1640 - N \ = / 3 HO 1785, 1720 (decomp.) 1685, 1645 -N 2 3 0 131-136 1783, 1725, ( decomp.) 1680, 1645 -N 2 5 3 K 1780, 1720, (decomp.) 1680-1640 -) -CHOH 1780, 1725, (decomp.) 1675, 1640 -N 'r - / HO H 126-138 zo; '- -CH-O) -N N CH2-D

  <Desc / Clms Page number 105>

 
 EMI105.1
 TABLE 15 (continued)
 EMI105.2
 nr -SO, 1720, (decomp.) 1640 - CH- '= 0 1780, 1720, (decomp.) 1690-1650 HN - X 1 148-151 1780, 1730, 1690, 1660 0 o 0 H 1775, 1720, (decomp.) 1670 ss CH, Y 0 0 0

  <Desc / Clms Page number 106>

 
 EMI106.1
 TABLE 16
 EMI106.2
 
 EMI106.3
 (syn-isomer)
 EMI106.4
 Compose ,,,.

   (KBr) cm: R2 Q P-176-179 - NH 1680, 1640 '==' 0 152-155 1780, 1720, (decomp.) 1680, 1640 -N ' <- / 0 158-160 1780, 1720, zo CH 1680, 1640 - CH 0 166-167 1780, 1720, 3 1685, 1645 -N 2 3 3 162-165 1780, 1720, 1680, 1640 -NNH === = / \ - / 0-cl 1780, 1720, 3 1682, 1640 -N 2 3

  <Desc / Clms Page number 107>

 
 EMI107.1
 TABLE 16 (continued)
 EMI107.2
 0 138-144 1780, 1715, 3 -N 2 0-CH 88-90 1780, 1720, 3 cl-'1690-1620 - = CH- 0 0 13 1723, uu '"2" 3 - 2 CH2CH3 1780, 1720 , 2 "3 '-" 3 1660 f1' - Il -CH 190-192 1780, 1720, (decomp.) 1665 HN 1-cri 0 T 0

  <Desc / Clms Page number 108>

 
 EMI108.1
 TABLE 16 (continued)
 EMI108.2
 0 183-185 1780, 1720, 0 3 t I 1670 '- 0 o + - 0 0 + 1 -N CH 3 d] -CH. 0 0 1 128-131 - -N--) 0 1

  <Desc / Clms Page number 109>

 
 EMI109.1
 TABLE 17
 EMI109.2
 
 EMI109.3
 (syn-isomer)
 EMI109.4
 Composed to me.

   H cm:) - -N oy 0 154-156 1775, 1710, O 1700, 1680, 1650 '- 0 1 85-88 1785, 1730, - OCOC 3 3 144-146 0 HO (decomp.) 1715, 1690, 1650 - COOCH 1650 '

  <Desc / Clms Page number 110>

 
 EMI110.1
 (2) To a solution of 6.05 g of 7- to 1, 2, 3, 4-tetrahydropyrazinyl) methyl) -A-cephem-4-carboxylate of diphenylmethyl in 31 ml of methanol is added 0.5 ml of concentrated hydrochloric acid and the mixture is reacted for two hours at 35 ° C. After the reaction is completed, the solvent is removed by distillation under reduced pressure. 100 ml of ethyl acetate and 100 ml of water are added to the residue and the pH of the resulting solution is adjusted to 6.0 with sodium hydrogen carbonate. The organic layer is separated and dried over anhydrous magnesium sulfate.

   The solvent is removed by distillation under reduced pressure and 50 ml of diethyl ether are added to the residue. The crystals are collected by filtration and 5.1 g (yield: 87.7%) of 7- [2- (2-aminothiazol-4-yl) -2- (syn) - are obtained.
 EMI110.2
 methoxyiminoacetamido] -3- 2, 3, 4-tetrahydropyrazinyDmethyl-A-cephem-4-carboxylate having a melting point of 165-167 IR (KBr) cm: vC = O 1780, 1720, 1680, 1640 NMR (d -DMSO) values:

   b {[1- (4-ethyl-2, 3-dioxo-l, 1.18 (3H, t, J = 7Hz,> N-CH CH), 3.55 (2H, 1S, C2-H), 3.75 (2H, q, J = 7Hz, N-CH CH-),
 EMI110.3
 3,
 EMI110.4
 4, 41, 5, 02 (2H, ABq, J = 15Hz, S,) -CH-
 EMI110.5
 5, d, J = 5Hz, C6-H),

  <Desc / Clms Page number 111>

 
 EMI111.1
 6.01 (1H, dd, J-5Hz, J = 8Hz, C7-H),
 EMI111.2
 6, 52, 6, 65 (2H, ABq, J = 6Hz, H N 6, 68 (1H, s, Nua), S H 7, 07 7, 84 (10H, m,
 EMI111.3
 9, d, J = 8 Hz, -CONH-) Similarly, the compounds indicated in Table 18 are obtained.

   

  <Desc / Clms Page number 112>

 
 EMI112.1
 TABLE 18
 EMI112.2
 
 EMI112.3
 (syn-isomer)
 EMI112.4
 R2 R4 O 158-166 1780, 1720, - NN-CH 1680, 1640 '==' 3 0 0 H 151-156 1780, 1720, (decomp.) 1680, 1640 - N- 2 4 3 0 150-156 1780 , 1720, '/ "" 1680, 1640 -) -CH- "C = 0 1775, 1723, (decomp.) 1685, 1640 -N NN- CH, 1 3 HO H 161-166 1780, 1720, 1680, 1640 -N NCH-0 2 0 - tJ'2- 0 0 Br (decomp.) 1680, 1640 - = 2 3

  <Desc / Clms Page number 113>

 
 EMI113.1
 TABLE 18 (continued)
 EMI113.2
 Q H 1780, 1720, (decomp.) Hr) 1 - 0 CH? 1780, 1720,) 1660 N "Y 0 o

  <Desc / Clms Page number 114>

 (3) In a mixed solvent of 25.5 ml of trifluoroacetic acid and 7.86 g of anisole, 5.1 g of 7- [2- (2-aminothiazol-4- yl) -2- ( syn) -methoxyiminoacetamido] -3- [1- (4-ethyl-2,3-dioxo- 1,2,3,4-tetrahydropyrazinyl)

  ] methyl} - # 3-cephem-4-carboxylate of diphenylmethyl and the solution is subjected to a reaction at room temperature for two hours. Once the reaction is complete, the solvent is removed by distillation under reduced pressure. To the residue is added 40 ml of diethyl ether and the crystals are collected by filtration to obtain 4.3 g (yield: 91.1%) of trifluoroacetic acid salt of 7- [2- (2-aminothiazol acid) -4-yl) -2- (syn) -methoxyiminoacetamido] -3- {[1- (4-ethyl-2,3-dioxo-1, 2,3, 4-tetrahydropyrazinyl) methyl} - # 3- cephem- 4-carboxylic having a melting point of 155-157 C (decomp.).



  * IR (KBr) cm-1: v 1775,1710-1630
 EMI114.1
 NMR r values 1, 21 (3H, t, J = 7Hz,> N-CHCH), 3, 52 (2H, ls, C2-H), 3, (2H, q, J = 7Hz, 3, 96 (3H , s,
 EMI114.2
 4, (2H, ABq, J = 15Hz, S), J-CH., -
 EMI114.3
 5, 21 (1H, d, J = 5Hz, C6-H), o 5, 83 (1H, dd, J = 5Hz, J = 8Hz, C7-H), 5, 86 (3H, ls, -NH) , 3
 EMI114.4
 6, 71 (2H, 15, H H

  <Desc / Clms Page number 115>

 
 EMI115.1
 6.95 (1H, s, Nec), S H
 EMI115.2
 9, d, J = 8 Hz, -CONH-) Similarly, the compounds indicated in Tables 19 and 20 are obtained.

  <Desc / Clms Page number 116>

 
 EMI116.1
 



  TABLE 19 N-n --- C ---- CONH-r- <CF3COOH.



  S OCH-COOH Compound IR (KBr) values -l R2 2 3, (3H, s,> N-CH3) '3, (2H, 1s, C2-H) o 4, 90 (2H, HH 95- 102 - N-CH 'ABq,), 25 (1H, d, -CHLJ = 5Hz, C6-H), 5) dd, J = 5Hz, J = 8Hz, 6, 68 (2H, 1s, == s, NT H - SH 985 d, J = 8Hz, -CONH-) I

  <Desc / Clms Page number 117>

 TABLE 19 (continued)
 EMI117.1
 0, (3H, t, J = 7Hz,> N- 1770, (6H, m,> N-CH2 (CH2) 53 (2H, 115-125 H 1660, ls, C2-H), 3, (2H, t, J = 7Hz, - CH) 1635> N-CH2 4, 5, 05 (2H, ABq, J = 15Hz, 81 ICH 5, J = 5Hz, C6-H), 5, dd, J = 5Hz, J = 8Hz, C7-H), 6/68 (2H, ls, s, 6, TT), 6, 95 s, Je), H 9, d, J = 8Hz, -CONH-)

  <Desc / Clms Page number 118>

 
86 TABLE 19 (continued)
 EMI118.1
 0, (3H, t, J = 7HZ,> N- (CHCH), 1, 04- 0 0 1770, 1, (8H, m,> NCH2 (CH2) 53 (2H, H 155-160 1670, - ( 2H, t, J = 7Hz, (decomp.)> NCH2 (CH).

   3.97 (3H, s, (2H, CH 523 d, J = 5Hz, C6-H), dd, J = 5Hz, J = 8HZ, C7-H), (3H, ls, 1 -), (2H , 1s, 'A ..), HV' 'J = 8Hz, -CONH-) SH

  <Desc / Clms Page number 119>

 
87 TABLE 19 (continued)
 EMI119.1
 0, 04- 1, (20H, m,> NCH2 (CH2) 0CH3), 51 (2H, o 0 H 140-147 1770, ls, (2H, t, J = 7Hz, H'1675 - N-) CH ) QCH), 92 (3H, s, 4, (2H, ABq, J = 15Hz, X), Ci 5, 20 (1H, d, J = 5Hz, C6-H), dd, J = 5Hz, J = 8Hz, C7-H), (3H, ls, -), (2H, ls,> == <), H S, "T), 75 (1H, d, J = 8Hz, -CONH-) S S H è

  <Desc / Clms Page number 120>

 TABLE 19 (continued)
 EMI120.1
 3, (2H, ls, CH), 3, 91 1770, 41, (2H, ABq, J = 15Hz,), H 130-135 1670, CH - -CH, - "" "-N-CH 4) '95 (2H, 5 ,, d, J = 5Hz, C6-H), 82 dd, J = 5Hz, J = 8Hz, C7-H), 6, 15 (3H, Js, -NH), 68 (2H , (1H, HH a H lS, d, J = 8Hz, -CONH-) 1, 21 (3H, t, J = 7Hz,> NCH2CH3) '3, (2H, 1775, 0 0' s, -H) , 81 (2H, q, J = 7Hz,> NCH2CH3), H 147 1680, - NCH -.

   NCH 2CH3 3; 91 (3H, s, -OCH 3), 4y42, 5, 10 (2H, ABq, J = 15Hz,), 19 (1H, d, J = 5Hz, JL-CH-

  <Desc / Clms Page number 121>

 TABLE 19 (continued)
 EMI121.1
 C6-H), 5, dd, J = 5Hz, J = 8Hz, C7-H), 6, (2H, 1s, c = <), d, J = 8Hz, HH - 3, .. (2H, 1s, C2-H), 89 (3H, s, -OCH), '4, (2H, S d, J = 5Hz, 10, HH 195-198 -! Dd, J = 5Hz, J = 8Hz, CH), H 89, (2H, ABq, 0 o J = 10Hz, X 9, d, J = 8Hz, -CONH-) I

  <Desc / Clms Page number 122>

 TABLE 19 (continued)
 EMI122.1
 231 -CH3), 44 (2H, 1s, C2-H), 1770, 3/96 98, (2H, ABq, ¯z53 1710, S 5, 23 (lH, d, J = SHz, CH3 188-189 1680 (d / ICH -CH, - IN C6-H), 6), T ').

   S X H 7, 7, 50 (2H, ABq, J = 1QHz, 9, 87 (1H, d, J = 8Hz, -CONH-)

  <Desc / Clms Page number 123>

 TABLE 19 (continued)
 EMI123.1
 2, (3H, s, -CH), 46 (2H, Is, C2-H), 0 o 90 42, (2H, ABq, H - N (2H, s,> NCH2-) '0' '5, 18 d, J = 5Hz, C6-H), dd, J = 5Hz, J = 8Hz, C7-H), (2H, s, Y =), HH 6 84 (IH, s, NN d, J = 8Hz , S - E

  <Desc / Clms Page number 124>

 TABLE 19 (continued)
 EMI124.1
 3,., (2H, Is, C2-H), 3, 99 (3H, 5, 1770, 19 (2H, ABq, j = 15Hz, S 1700 HH 175-180 1630 (o) (decomp.) D, J = 5Hz, C6-H), 94 (1H, dd, J = 5Hz, J = 8Hz, C7-H), 68 (2H, ABq.



  J = 6Hz, = 99, Y), HHH 7, 66-8,., (5H, m, zig zozo 9, 92 d, J = 8Hz, -CONH-) 1. 3.54 (2H, ls, C ., - H), H 108-110 1 0 98 (3H, s, (2H, ABq, 1690, - NN-CH20COC 1650 J = 15Hz, 1), d, J = 5Hz, -CHC6-H), 5 , 77 (2H, s,> dd, J = 5Hz, J = 8Hz, CH),

  <Desc / Clms Page number 125>

 TABLE 19 (continued)
 EMI125.1
 6. s, NH - H 9, d, J = 8Hz, -CONH-) 3, (2H, Is, 3, 96 (3H, s, -OCH), 0 0 '452, (2H, ABq, J = 15Hz, s H - -CH. -CH- 2 4, (2H, s,> NCH2 -) '5. D, J = 5Hz, C6-H), 5. dd, J = 5Hz, J = 8Hz, C7 -H), N 6 (2H, s,) C =), TT). H 9. d, J = 8Hz, -CONH-)

  <Desc / Clms Page number 126>

 TABLE 20
 EMI126.1
 N CF-COOH.



  S \ -) OR COOH Compound -------------- -1 R2 0) '90 (3H, t, J = 7Hz,> N-CHCHLCH-), 32- 1770, 2, (2H, m,> NCHCHCH-), 53 (2H, ls, 0 0 -J -H), 73 (2H, t, J = 7Hz,> N-CHCHCH-), - 31P96 5, 14 (2H, ABq , J = 15Hz, 5, d, J = 5Hz, J-CHC6-H), 5, dd, J = 5Hz, J = 8Hz, C7-H), 6J (3H, ls, -NH), 69 3 HHN d, J = 8Hz, S -

  <Desc / Clms Page number 127>

 
C CONHTABLEAU 20 (continued)
 EMI127.1
 1.25 (6H, d, J = 7Hz,> N-CH (CH), 48 (2H o / CH3 - '"CH -CHm,> N-CH 21 d, J = 5Hz, C6-H), 5 , 86 (1H, dd, J = 5Hz, J = 8Hz, C7-H), (3H, ls, -NH),), H 6, s,: SSH -

  <Desc / Clms Page number 128>

 TABLE 20 (continued)
 EMI128.1
 0, (3H, t, J = 7HZ,> N (CH2) 3CH), --193 (4H, m,> N-CH2 (CH2) (2H, -CH, 0'1'2-'4 - Ö (CH2) 3CH3 -CH lSS-IS7 1680 -) CH 92 (3H, s, 1630 4, 41, 5 ..

   (2H, ABq, J = 15Hz,;), C¯ 5, d, J = 5Hz, C6-H), 5, 81 (1H, dd, J = 5Hz, J = 8Hz, C7-H), 6, (2H, ls, HH 6, 87 (1H, s,: (3H, Js, -NH), 6, 87 Is, -NH3), SH 9. 81 d, J = 8Hz, -CONH-)

  <Desc / Clms Page number 129>

 TABLE 20 (continued)
 EMI129.1
 u H * H.



  086-2 / 06), H H <. o), 3 - N> 20-4,), 36, H (2H, ABq, J = 15Hz, S (3H, ls, CH -), 23 d, J = 5Hz, C6-H), (1H, dd, J = 5Hz, J = 8Hz, C7-H), 62 (2H, Is,) X), 80 f), H - SH 9/66, 1 I

  <Desc / Clms Page number 130>

 TABLE 20 (continued)
 EMI130.1
 1, (3H, s, (2H, ls, C2-H) 3, (4H, m,> NCH2CH20-), (3H, - "'" 04 (2H, ABq, J = 15Hz, 1710 -) OCOCH- ) 2 2 3? 1630 SJ d, J = 5Hz, C6-H), 79 (lH, dd, J = 5Hz, J = 8Hz, C7-H),) (3H, ls, HS -), 75 d, J = 8Hz, -CONH-) 3 Ir 0il88 (3H, t, J = 7Hz,> N (CH2) 0 (12H, m,> NCH2 (CH) 53 (2H, -CH-131-135,.



  - t -7n '' 2 "'' n -) CH '> NCH)), 96 4, (2H, ABq, J = 15Hz, l ARCH2-

  <Desc / Clms Page number 131>

 TABLE 20 (continued)
 EMI131.1
 5 d, J = 5Hz, C6-H), 588 dd, J = 5Hz, J = 8Hz, C7-H), 6/72 (2H, 1s, 6/98 (3H, 1 HH 1- H -), 93 d, J = 8Hz, -CONH-) 3 2 "(6H, s, -N. 51 (2H, 1s, C2-H)," CH- 0, - 0 - N-N'3 "Sl 3 42 , (2H, ABq, CH 3 5, 22 (1H, d, J = 5Hz, 1620 C6-H), 5/96 dd, J = 5Hz, J = 8Hz, C7-H), 6 ,, (2H, ABq, J = 6Hz,) m) 6.

   H H s, Á) '7, 744), S S d,

  <Desc / Clms Page number 132>

 TABLE 20 (continued)
 EMI132.1
 il * 20 (3H, t, J = 7Hz,> NCH2CH3) '1, (3H, t, 169-174 1775, J = 7Hz, (2H, ls, C2-H), 0 0 (from comp. 1645 00-CH '' 3, 47 (2H, q, J = 7HZ, (2H, H - N 5, 13 (2H, ABq, 2 3 J = 7Hz, -OCH 2CH3), 4y J = 15Hz,), d , J = 5Hz, ICH C6-H), 5.90 (1H, dd, J = 5Hz, J = 8Hz, C7-H), 6.70 (2H,), s, NT HSH 9, d, J = 8Hz, -CONH-) CH2CH3 1 "(3H, t, J = 7Hz, CH3CH2 -) '2", (2H, N 153-156 1780, q, J = 7Hz, CH3CH2-), 46 (2H, 1s, C2-H), 1 -N 1690 3.96 (3H, s, 5, 40 (2H, ABq, - 0 23 (1H, d, J = 5HZ, 0

  <Desc / Clms Page number 133>

 TABLE 20 (continued)
 EMI133.1
 C6-H), 5, dd, J = 5Hz, J = 8Hz, C7-H), 6, (2H, ABq, J = 10Hz, H), H 6, S S H 7, ..

   (3H, ls, -NH), d, J = 8Hz, - 0 2, 05 (15H, 5), 5H, s, HN 34 (2H, ls, C2-H), 87 (3H, 1 s> 200 1770, s, -OCH-), 97 ")), 1710, ICH 0 '+ 5, d, J = 5Hz, C6-H), 73 0 1) J = 8Hz, C7-H), 77 -H t 94 5H, M "r'tj -" CHg H 0

  <Desc / Clms Page number 134>

 TABLE 20 (continued)
 EMI134.1
 s, yHx05), 75 (3H, ls, -NH), 967 d, J = 8Hz, -CONH-) 3, (2H, ls, CH), (3H, s, 4, 65 (2H, ABq, J = 15Hz,), CH 1770, r-CH - 5, 78 (1H, dd, - CH 144-147 - tT- "SH 0 7) '31, 7, (2H, ABq, J = 5Hz, JC) ' H 7, d, J = 8Hz, - 1 1 1

  <Desc / Clms Page number 135>

 TABLE 20 (continued)
 EMI135.1
 3.40 (2H, is, C 0 1775, 7, 24 (2H, ABq, J = 15Hz, s HNk-OH "> 2nû -CH- 1 3 1665 my 60 '' J = 5Hz, -H), 78 dd, 1630 J = 5Hz, J = 8Hz, CH), SSH 7, d, J = 8Hz, - 3) (2H, ls, C2-H), (3H, s, -OCH), 0 0 447, 15 ABq, J = 15Hz, s H -N (decomp.) 24 d, J = 5Hz, C6-H), 5J 1630 6 J = 5Hz, J = 8Hz, C7-H), 6, (2H, ABq, J = 6Hz, = T), H (3H, Is, -NH), 85 d, J = 8Hz, -CONH-)

   (3H, lS, -NH3) '

  <Desc / Clms Page number 136>

 
 EMI136.1
 (4) In 30 ml of water is dissolved 6.35 g of trifluoroacetic acid salt of 7-iminoacetamido] -3-l [1- 2, 3, 4-ttrahYdropyrazinyl) A3 methyli-Z-cephem- 4-carboxylic acid and the resulting solution is adjusted to pH 7.4 with sodium hydrogencarbonate. This solution is then purified by passing it through a column of "Amberlite to obtain 4.7 g (yield: 86.6%) of 7- [2- 2, 3,
2 - H), 3.90 (3H, s, -OCH3) '- sodium 4-carboxylate having a melting point of 200 C or more.
 EMI136.2
 



  IR (KBr) cm ')' 1670, 1650-1620 Similarly, the following compounds are obtained: sodium o- [2- - 2, 3, 4-tetrahydropyrazinyl)] methyl).



  P. F.: 190-195 (decomp.) IR (KBr) cm: 1650, 1630 o 7- [2- - 2, 3, 6-tetrahydropyridazinyl)] methyl -: cephem-4-carbDxylate sodium. o 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- {[1- (3-m, ethyl-6-oxo-1,6-dihydropyridazinyl)] methyl ] - # 3- sodium cephem-4-carboxylate.



  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 phosphorus oxychloride at-10 C and the mixture is subjected to a reaction for one hour at-5 to 00 C. This solution is added dropwise to a solution of 19.4 ml of methylene chloride
 EMI136.3
 anhydrous containing 1.94 g of 7-amino-3- 3-dioxoA 3 1, 2, 3, -céphem-4-carboxylic acid and 2.25 g of bis (trimethylsilyl) acetamide at -5 to Once

  <Desc / Clms Page number 137>

 {[1-w-ethYl-2, the dropwise addition complete, the mixture is subjected to a reaction at the same temperature for 30 minutes and then at a temperature of 0 to 100 ° C. for 30 minutes.

   After the completion of the reaction, the methylene chloride is removed by distillation under reduced pressure and a mixed solvent of 100 ml of a saturated aqueous solution of sodium chloride and 100 ml of acetonitrile is added to the residue. Subsequently, the organic layer is separated and washed twice with 50 ml portions of a saturated aqueous solution of sodium chloride and then the solvent is removed by distillation under reduced pressure. The resulting residue is dissolved in 50 ml of methanol
 EMI137.1
 after which 1 g of diphenyl-diazomethane is added 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 removed by distillation under reduced pressure and the residue is purified by column chromatography
 EMI137.2
 (Wako silica gel C-200; eluent: = 3: 1) to obtain 1.6 g (yield: 8%) of 7-aminothiazol-4-yl) - 2, 3, 4-tetrahydropyrazinyl) methyl) t OJ - of diphenylmethyl having a melting point of 98-100 C (decomp.).



   IR (KBr) cm: \ 1780,1720, 1680,1630
 EMI137.3
 NMR (d6-DMSO) b S values: 1.17 (3H, t, J = 7Hz,> NHCCH), 1.44 (9H, s, -C (CH3) 3), 3.62 (2H, Is, C2-H), 3.74 (2H, q, J = 7Hz,> N-CH2CH3),
 EMI137.4
 , Ln ui * lJ1 Pi in M m o - .. hJ o razz ..



   > w 1 t-li <-) there Ul M N N 0 N n! m ()

  <Desc / Clms Page number 138>

 
 EMI138.1
 5, d, J = 5Hz, C6-H), 5, dd, J = 5Hz, J = 8Hz, C7-H),
 EMI138.2
 6, 55 H H 6, N 6, S 7, x 5), 8, 86 (1H, 1s,
 EMI138.3
 9, d, J = 8 Hz, -CONH-) Similarly, the compounds indicated in Tables 21 and 22 are obtained.

  <Desc / Clms Page number 139>

 
 EMI139.1
 



  TABLE 21 TABLE CN il 2 l CH RH OR COOCH (D) (syn-isomer) Compound i Compound PF (C) IR (KBr) cm R2 0 0 CH3 -) 118-120 1780, 1720, 1690-1640 m 1 - N '== 1 2 3 1 CH3 0 0 - -H-CH, ""' "" '"" \ N 0 0 H 1785, 1725, 1690, 1645 - NN-CH-CHCOOC) 3 2 3 3 (decomp .)

  <Desc / Clms Page number 140>

 TABLE 21 (continued)
 EMI140.1
 0 0 - -N-CH, "" SO, 1725, 1685, 1640 CH3 o U H 6-130)) - L. L.



  - N "-" (decomp.) O 0 CH3 N-CH 1780, 1720, 1660 -N t) -CHCOOC 3 3 (decomp.) O 0

  <Desc / Clms Page number 141>

 TABLE 22
 EMI141.1
 
 EMI141.2
 Compound-i Compound IR (KBr) cm: R2 00 OHO 1820, 1780, 1720, 1690, 1650 - ---- r - CHL \ === / Y 0 0.



  W / o OH 164-167 1785, 1730, 1710, 1690, 1660 - 0D oxo 1785, 1740, 1730, 1710, 1680, - '== 1

  <Desc / Clms Page number 142>

 (OC) TABLE 22 (continued)
 EMI142.1
 f - COOCH) == - 152-154 1785, 1750, 1720, 1690, 1655 (decomp.)

  <Desc / Clms Page number 143>

 (2) In a mixed solvent of 8 ml of trifluoroacetic acid and 3 ml of anisole, ze is dissolved 6 g of 7- [2- (2-tritylaminothiazol -4-yl) -2- (syn) -t- butoxycarbonylmethoxyiminoacetamido] -3- [1- (4-. t 3 t-ethyl-2, 3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl-A-cephem-4-carboxylate diphenylmethyl, and subjected to a reaction at room temperature for one hour.

   Once the reaction is complete, the solvent is removed by distillation under reduced pressure and 10 ml of diethyl ether are added to the residue, then the crystals are collected by filtration, they are dissolved in 20 ml of a 50% aqueous solution in weight of formic acid and the solution is reacted at 45-550 C for one hour. Once the reaction is complete, the precipitated crystals are separated by filtration and the solvent is removed by distillation under reduced pressure. 10 ml of ethyl acetate are added to the residue and the crystals are collected by filtration, then the crystals are washed sufficiently with 10 ml of ethyl acetate and dried to obtain
 EMI143.1
 nir 0.7 g (yield: 80.7%) of 7- - 1, 2, 3, 4-tetrahydropyrazinyl)] -A3-cephem-4-carboxylic acid having a melting point of 139-1400 (decomp. ).



  IR (KBr) cm: li 1775, 1695, 1680, 1635 NMR (d-DMSO) d values: b [2- (2-aminothiazol-4-yl) 1, 22 (3H, t, J = 7Hz, NCH2CH3) , 3.53 (2H, ls, C2-H),
 EMI143.2
 3.74 (2H, q, J = 7Hz,> NCHCH), 4.70 (2H, s, -OCHCO-),
 EMI143.3
 4, (2H, ABq, J = 15Hz, S), J-CH-
 EMI143.4
 5, 23 (1H, d, J = 5Hz, C6-H), 5, 90 (1H, dd, J = 5Hz, J = 8Hz, C7-H),
 EMI143.5
 6, (2H, ls,), H H

  <Desc / Clms Page number 144>

 
 EMI144.1
 6.94 (1H, s, N 71 "S H
 EMI144.2
 9, 70 (1H, d, J = 8Hz, -CONH-) Similarly, the compounds indicated in Table 23 are obtained.

  <Desc / Clms Page number 145>

 TABLE 23
 EMI145.1
 N H2N s S N OR (syn-isomer) Compound Compound P.

   NMR (d? Rn R2 * 1 1, (3H, t, J = 7Hz,> NCHCH), cl 1775, 1, (6H, s, CH-), (decomp.) - CHL-C-COOH -C- COOH \ - 't CH, 20 CH3 31in54 (2H, Js, -H), 75 (2H, q, J = 7Hz,> NCH2CH3)' 449, 16 (2H, ABq, J = 15Hz, 2 5, d, J = 5Hz, C6-H), (1H, dd, J = 5Hz, J = 8Hz, C7-H), 672 ===), HH

  <Desc / Clms Page number 146>

 TABLE 23 (continued)
 EMI146.1
 (1H, SJ = 8Hz, -CONH-) (O (2H, ls, C2-H), 4, o '- 1770, S ABq, J = 15Hz, S -N = 1640 4.60 (2H, 5, 19 (1H, d, J = 5Hz, C6-H), b 584 dd, J = 5Hz, J = 8Hz, C7-H), 6, (2H, ABq, J = 6Hz,) HHS 9, d, J = 8Hz, -CONH-)

  <Desc / Clms Page number 147>

 TABLE 23 (continued)
 EMI147.1
 * 1 3, (3H, S,> NCH3) '(2H, 0 0 H 1770, 1s, (2H, ABq, - 88-91 1680, 3 2 = / "" (2H, 1630 1630 ls, d, J = 5Hz, C6-H), dd, b J = 5Hz, J = 8Hz, C7-H), 6 ,, (2H, ls, 97 HH SIKH 9, d, J = 8Hz, -CONH-) * 1 0 zo H CH 1770, 2, (2H, - "-CHCOOH 155-158 1710, CH3 CH (ddcomp.) 3 1630 ls, C2-H), (2H, ABq, J = 15Hz, S), (2H,

   s, CH

  <Desc / Clms Page number 148>

 TABLE 23 (continued)
 EMI148.1
 - 15 (1H, d, J = 5Hz, C6-H), 5, 79 (1H, dd, J = 5Hz, J = 8Hz, C7-H), 6,) 91 HS 9, d, J = 8Hz, -CONH-) 2, (3H, s, -CH), 50 (2H, o H 1820, Is, C2-H), 4, 70 (2H, s,> NCH2-), - -FrCH-CH 151- 154 1770,, OyO 1640 0 CH- 2 527 d, J = 5Hz, C6-H), 5, dd, J = 5Hz, J = 8Hz, CH), 75), HHN 6p97 81 (li d, J = 8Hz , -CONH-)

  <Desc / Clms Page number 149>

 TABLE 23 (continued)
 EMI149.1
 3, 75 (2H, 15, C2-H), 0 0 H 1785, (2H, ABq, J = 15Hz, S - "y" -CH2COOH, 1690, == - - 2 4, 74 (2H, 5, d, J = 5Hz, C6-H), 97 dd, J = 5Hz, J = 8Hz, C7-H), (2H, ABq, J = 6Hz,), HHN (lH, s, gAn 7, 61-8 ...

   (5H, m, H (O) - \ 0), d, e J = 8Hz, -CONH-) 1790, 1, (9H, s, -C - COOH 178-183 1730, 0 (2H, ls, C2 -H), 4, (2H, - ABq, J = 15Hz, SJL), 70 (2H, CH CH2- -

  <Desc / Clms Page number 150>

 TABLE 23 (continued)
 EMI150.1
 s, d, J = 5Hz, C6-H), 5. 73 (2H, s,> NCH-), 6, dd, J = 5Hz, J = 8Hz, C7-H), 6, 73 (2H, = =), - 7, 8, 87 (1H, SH d, J = 8Hz, -CONH-) 3, (2H, 18, C2-H), 4, 1780, (2H, ABq, J = 15Hz, S 4 , 0 0-CH2COOH 135-142 1720, H 1680, H (decomp.) 2 - (2H, s,> NCH2-) '- d, J = -5Hz, C6-H), 6, dd, J = 5Hz , J = 8Hz, 74 (2H, is,

  <Desc / Clms Page number 151>

 TABLE 23 (continued)
 EMI151.1
 ==), 05 s, NHH 8, * 2 (2H, 15, C2-H), 4, (2H, s, (2H, ls, o cl 1770, s 5, 10 (lH, d, J = 5Hz , - 190-193 1710, HN 2 1660, CH j),.



  M 77 (1H, dd, J = 5Hz, o J = 8Hz, 83 NI) '6, ABq, S J = 10Hz,) jL. 51 d, J = 8Hz,

  <Desc / Clms Page number 152>

 TABLE 23 (continued)
 EMI152.1
 * 2 2, (3H, s.> -CH3) '(2H, CH 73 (2H, s, 194-197 1710, N-CH2COOH 5, 14 (1H, d, J = 5Hz, 1630 5, 23 (2H , ls, S 0 Ci 5, dd, J = 5Hz, J = 8Hz, C7-H), 96, 46 (2H, ABq, J = 10Hz,) (s, XH NJ), (3H, ls, -NH3 ), S 9, d, J = 8Hz, -CONH-) Note:

   * 1 Salt of trifluoroacetic acid (to purify the product obtained by the process mentioned above, it is converted into a diphenylmethyl ester in the usual way, then it is de-esterified with trifluoroacetic acid to obtain a salt of trifluoroacetic acid.) * 2 Formate

  <Desc / Clms Page number 153>

 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 with stirring at −30 ° C. and the mixture is subjected to a reaction at a temperature of −30 to −20 ° C. for 30 minutes.



  The reaction mixture thus obtained is added dropwise at a temperature of -30 C or lower to a solution of 50 ml of anhydrous methylene chloride containing 5.20 g of 7-amino-3- {[1- (4- 2, 3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl) diphenylmethyl cephem-4-carboxylate and 4.08 g of bis (trimethylsilyl) acetamide.



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

   50 ml of diisopropyl ether are added to the residue and the crystals thus obtained are collected by filtration to obtain 5.85 g (yield: 85.6%)
 EMI153.1
 of 2, 3, 4tetrahydropyrazinyl) methyl) -A-cephem-4-carboxylate of diphenylmethyl having a melting point of 138-142 (decomp.).



  IR (KBr) cm-1: vC = O 1778, 1720, 1680, 1640 NMR (d6-DMSO) i values: b 1.22 (3H, t, J = 7Hz, NCH2CH3) '3.40 (2H, ls , C2-H),
 EMI153.2
 3.85 (2H, q, J = 7Hz, NCH2CH3) '2 3

  <Desc / Clms Page number 154>

 3.87 (2H, 1S, BrCH2COCH2-), 4.18 (2H, Is, BrCH2CO-), 4.47, 4, 96 (2H, ABq, J = 15Hz, S,
 EMI154.1
 J-CH- 5, d, J = 5Hz, C - H), b 5, 90 dd, J-5Hz, J = 8Hz, C7-H),
 EMI154.2
 6 ,, (2H, ABq, J = 6Hz,) c =).



  H H
 EMI154.3
 6, 98 (1H, s, -CH), 7, 40 (10H, lez x 2), 8, 55 (1H, d, J = 8Hz, -CONH-)
Similarly, the following compound is obtained: 4.09 g (yield: 62.6%) of 7- (4-bromo-3-oxo-butylamido) -3- [1- (3, 6-dioxo-1 , 2,3, 6-tetrahydropyridazinyl)] methyl] - # 3 cephem-4-carboxylate of diphenylmethyl having a melting point of 124-1260 C (decomp.).



   IR (KBr) cm-1: C = O1780,1725,1660
 EMI154.4
 NMR (d6-DMSO) values: b
 EMI154.5
 0 0 il \ 1 3, (4H, ls, C-), 0 il 4, 52 (2H, s, BrCH2C-), 5, 06 (1H, ls, Echo-
 EMI154.6
 5, d, J = 5Hz, C6-H), 5, 90 (1H, dd, J = 5Hz, J = 8Hz, C7-H),
 EMI154.7
 H 7, 01, 7, (2H, ABq, J = 10Hz,

  <Desc / Clms Page number 155>

 
 EMI155.1
 7, 09 (1H, s, -CH), 7, 24-7,) x 2),
 EMI155.2
 9, d, J = 10Hz, (2) To a solution of 5.50 g of 7- -3- {[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) ] methyl] - # 3- cephem-4-car diphenylmethyl boxylate in 30 ml of acetic acid a solution of 5 ml of water containing 0.74 g of sodium nitrite is added dropwise with ice cooling. one hour, then the resulting mixture is subjected to a reaction at room temperature for two hours.

   After the reaction is complete, the reaction mixture is poured into 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 from Wako; eluent: benzene / ethyl acetate = 2: 1 by volume),
 EMI155.3
 to obtain 3.15 g (yield: 54.9%) of 7-imino-3-oxobutylamido) -3- 2, 3, 4-tetrahydropyrazinyl)] methyl) -A3-cephem-4-carboxylate having a diphenylmethyl point of 127-132 (decomp.).



  IR (KBr) cm: Vc 1778, 1720, 1680, 1635 NMR (CDC13) values è 1, (3H, t, J = 7Hz, NCH 3, (2H, ls, C2-H), 3, (2H, q , J-7Hz,> NCHCH-), 4, (2H, s, BrCH2CO-),
 EMI155.4
 4, 4, 78 (2H, ABq, J = 15Hz, Sil), CH

  <Desc / Clms Page number 156>

 
 EMI156.1
 5, 11 (1H, d, J = 5Hz, C6-H), 5, 80-6, 15 (1H, m, C-H),
 EMI156.2
 6, 13, 6, 52 (2H, ABq, J = 6Hz, / \), H H
 EMI156.3
 7
 EMI156.4
 741 o) 2),
 EMI156.5
 9, d, J = 8 Hz, -CONH-) Similarly, the following compound is obtained 4.771 g (yield: 75.1%) of 7- (4-bromo-2-hydroxyimino- 3-oxobutylamido) ( 3, 6-dioxo-1, 2, 3, 6-tetrahydropyridazinyl)] methyl-diphenylmethyl-A-cephem-4-carboxylate having a melting point of 138-1410 IR (KBr) cm-1:

   N) 1780, 1720, 1660 NMR (d-DMSO) values 6 3, 46 (2H, ls, C2-H), 4, (2H, s, BrCH2CO-)
 EMI156.6
 4, 96 (2H, ls, S - 2-
 EMI156.7
 5, 18 (1H, d, J = 5Hz, C6-H), 5, dd, J = 5Hz, J = 8Hz, C7-H),
 EMI156.8
 ti 6, 89, 7, (2H, ABq, J = 10Hz,

  <Desc / Clms Page number 157>

 
 EMI157.1
 6, 96),
 EMI157.2
 7, 13-7, 72 (10H, m, - &commat; x 2),
 EMI157.3
 9.45 (1H, d, J = 8Hz, -CONH-), (4-bromo-2-hydroxy-13, 36 (1H, s, = N-OH) (3) In 12 ml of N, N- dimethylacetamide is dissolved 3.00 g of 7- (4-bromo-2-hydroxyimino-3-oxobutylamido) -3-f [l- (4-ethyl-2, 3dioxo-1, 2,3, 4-tetrahydropyrazinyl) methyl } - # 3-cephem-4-carboxylate of diphenylmethyl from (2) above and 0.42 g of thiourea and the resulting solution is subjected to reaction at room temperature for three hours.

   When the reaction is complete, the reaction mixture is poured into a mixed solvent of 120 ml of water and 240 ml of ethyl acetate. Then the mixture is 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 the organic layer has dried over anhydrous magnesium sulfate, the solvent is removed by distillation under reduced pressure. 20 ml of diethyl ether are added to the residue and the crystals are collected by filtration to obtain 2.10 g
 EMI157.4
 (yield: 72.3%) of 7-iminoacetamido] -3- 2, 3, 4-tetrahydropyrazinyl) methyl-diphenylmethyl-A-cephem-4-carboxylate having a melting point of 137-140 (decomp.).



  IR (KBr) cm-1: vC = O 1778, 1720, 1680, 1640 NMR (d6-DMSO) values: b [2- (2-aminothiazol-4-yl) -2- (syn) -hydroxy-1, 19 (3H, t, J = 7Hz, NCH2CH3), 3.48 (2H, 1S, C2-H),
 EMI157.5
 3, (2H, q, J = 7Hz, NCH2CH3) '2 3
 EMI157.6
 4, 46, 5, (2H, ABq, J = 15Hz, S L-CH-

  <Desc / Clms Page number 158>

 
 EMI158.1
 5/28 d, J = 5Hz, Cg-H), 5, dd, J = 5Hz, J = 8Hz, C-H),
 EMI158.2
 6, H H 6, S
 EMI158.3
 7,
 EMI158.4
 753 o) x 2),
 EMI158.5
 9, d, J = 8Hz, -CONH-) (4) In a mixed solvent of 10.0 ml of trifluoroacetic acid and 2.0 ml of anisole, 2.00 g of 7- yl are dissolved) -2 - 2, 3, 4tetrahydropyrazinyl) methyl-A3-cephem-4-diphenylmethyl carboxylate obtained in (3) above and the resulting solution is subjected 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 diethyl ether are added to the residue, after which the crystals are collected by filtration.



  Subsequently, the crystals are washed sufficiently with 10 ml of diethyl ether and dried to obtain 1.62 g (yield:
 EMI158.6
 87.6%) of a trifluoroacetic acid salt of 7-thiazol-4-yl) A 3 2, 3-dioxo-1,2,3,4-tetrahydropyrazinyl)] carboxylic acid having a melting point of 112-118 C (decomp.).



   IR (KBr) mm: vC = O 1780.1680, 1620
 EMI158.7
 NMR (d6-DMSO) values 6 b 1, (3H, t, J = 7Hz,> N-CH-CH-), 3.47 (2H, -H), 3, (2H, q, J = 7Hz, > NCHCH),
 EMI158.8
 4, 45-6, (4H, m, SJ-'C6-H, - -CH- (3H,) Ii 1 H H

  <Desc / Clms Page number 159>

 
 EMI159.1
 Example 9 (1) To a solution of 7.1 g of 7-oxobutylamido) -3-f 2, 3, 4-tetrahydropyraziA 3 nyl)] - methyl) -A-cephem-4-carboxylate of diphenylmethyl in 70 ml of anhydrous methylene chloride, a solution of diazomethane in diethyl ether is added slowly 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 confirmation of the disappearance of the diazomethane, the solvent is removed by distillation under reduced pressure, then the residue is purified by column chromatography (silica gel C-200 from Wako; eluent: benzene / ethyl acetate = 3: 1 in volume) to obtain 2.32 g
 EMI159.2
 (yield: 32.0%) of 7-butylamido] -3- 2,3,4-tetrahydropyrazinyl)] of diphenylmethyl having a melting point of 135-140 (decomp.).



  IR (KBr) cm 1720, 1682, 1638 NMR (CDC13) f-values: 1, (3H, t, J = 7Hz, NCH-CH-), 3.48 (2H, ls, 3, (2H, q, J = 7Hz, NCHCH-), 400), 4, 10 (2H, s, BrCH2CO-),
 EMI159.3
 4, 48, 4, (2H, ABq, J = 15Hz,),
 EMI159.4
 5, 10 (1H, d, J = 5Hz, C6-H), b 6, dd, J = 5Hz, J = 8Hz, C7-H),
 EMI159.5
 6, (2H, ABq, J = 6Hz, H H

  <Desc / Clms Page number 160>

 
 EMI160.1
 6.88 (1H, s, -CH <),
 EMI160.2
 7, 2),
 EMI160.3
 9, d, J = 8 Hz, -CONH-) Similarly, the following compound is obtained 1.70 g (yield: 24.5%) of 7-imino-3-oxobutylamido] -3-f 2, 3, 6-tetrahydropyridazinyl) methyl) - diphenylmethyl cephem-4-carboxylate having a melting point of 145-148 (decomp.).



  IR (KBr) cm: 1780, 1730, 1660 NMR (d6-DMSO) ô b values 3, 49 (2H, ls, C2-H), 4, 4, (2H, s, BrCH2CO-), 5, 02 ( 2H, Is, S), 1 --CH- 5.30 (1H, d, J = 5Hz, C6-H), 6.02 (1H, dd, J = 5Hz, J = 8Hz, C7-H),
 EMI160.4
 H 6, 92, 7, 16 (2H, ABq, J = 10Hz, j \ H
 EMI160.5
 6.99 (1H, s, -CH),
 EMI160.6
 7, x 2),
 EMI160.7
 10, d, J = 8Hz, -CONH-)

  <Desc / Clms Page number 161>

 (2) 2.3 g of 7- [4-bromo-2- (syn) -methoxyimino-3-oxobutylamido] -3 - {[1- (4-ethyl-) are dissolved in 14 ml of N, N-dimethylacetamide 2, 3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl) -A-cephem-4-diphenylmethyl carboxylate and 0.32 g of thiourea, then the resulting solution is reacted at room temperature for three hours .

   Once the reaction is complete, the reaction mixture is poured into a mixed solvent of 50 ml of water and 150 ml of ethyl acetate. Sodium hydrogen carbonate is then added to adjust the pH of the mixture to 6.7 and the organic layer is separated. The aqueous layer is extracted twice with 100 ml portions of ethyl acetate. The combined organic layer is washed with water and dried over anhydrous magnesium sulfate, then the solvent is removed by distillation under reduced pressure and 20 ml of diethyl ether are added to the residue, then the crystals are collected by filtration and obtains 1.92 g (yield: 86.3%) of 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxy-
 EMI161.1
 iminoacetamidoJ-3- 2, 3, 4-tetrahydropyraA zinyl) methyl) -A3-diphenylmethyl-3-carboxylate having a melting point of 165-167 C.



  IR (KBr) cm: r = o SO, 1720, 1680, 1640 Similarly, the following compound is obtained {[l- (4-ethyl-2, 3-dioxo-l, o 7- [2- (2 -aminothiazol-4-yl-2- (syn) -methoxyiminoacetamido] -3 - {[1- (3,6-dioxo-1, 2,3, 6-tetrahydropyridazinyl)] methyl] - # 3-cephem- 4- diphenylmethyl carboxylate.



   P. F.: 175-178 C (decomp.)
 EMI161.2
 IR (KBr) cm ': 1780, 1720, 1685-1660
The same cyclization reaction is carried out as above and then the reaction mentioned in Example 6- (3) or Example 7- (2) is carried out to obtain the compounds indicated in Tables 24, 25 and 26 .

  <Desc / Clms Page number 162>

 



  TABLE 24
 EMI162.1
 / N-n-C-CONH -, - <CF S OCH COOH R2 R2 R2 MO -. t, -N COOH \ == 1 ì 0 0 Y- 0 0 CH3 0 0 'e CH3 "(CH) CH - NN-)' YN-M) 0

  <Desc / Clms Page number 163>

 TABLE 24 (continued)
 EMI163.1
 R R2 oMo - CHOCOCH 'rCH-HN)) 1 -. 0 -N i 0 0 0 O - N- (CH2) -N -1)

  <Desc / Clms Page number 164>

 TABLE 24 (continued)
 EMI164.1
 o CH -) CH - NC = C-CH - N 0) \ == == / CH, oy OMO Ko N (C H2) 1 1C "3-N NN -N 2 3 3 '== 1 0 0 - 2-e 3 3

  <Desc / Clms Page number 165>

 TABLE 24 (continued)
 EMI165.1
 1
 EMI165.2
 o He.

   CH 3 - N N-N HN ---, C H3 1 c 1 - '- 0 - N NCHLCH - N / 2 0 CHLCHL - N Z 1 0 1 o - o Note: * Hydrochloride

  <Desc / Clms Page number 166>

 
 EMI166.1
 TABLE 25
 EMI166.2
 
 EMI166.3
 (syn-isomer)
 EMI166.4
 R2 K - N'NCHCH-NH - CHCOOH \ 0 K - CH, COOH-NH - C-COOH 3 CH3 0 0 zie - NH NH - CH-COOH - 0 0 - COOH. --CHCOOH o 0 0 ,, H / CH3 CH3 I

  <Desc / Clms Page number 167>

 
 EMI167.1
 TABLE 25 (continued)
 EMI167.2
 1 HN han) --CHCOOH 1 "Y CH3 N'HCOOH-NH - CHCOOH 1 - OMO 0. 0 - CH -CH, - 0 0 0 0 0 - <"'" "-N 0 w -) 2

  <Desc / Clms Page number 168>

 
 EMI168.1
 TABLE 25 (continued)
 EMI168.2
 0 0 J --- f - COOH --CHCOOH 2 0 0 VA - CH-HCOOH.

   --CHCOO- 2 0 0 - 0 o K - --CHCOOCHCH- '= 1

  <Desc / Clms Page number 169>

 
 EMI169.1
 TABLE 26
 EMI169.2
 
 EMI169.3
 (syn-isomer)
 EMI169.4
 R R2 oHo - 23 l't CH3 0 H - l '- == 1 CH, 0H, oHo 0 0 - N- (CH2) 1 CH3 oH - N- (CH) 1/1

  <Desc / Clms Page number 170>

 
 EMI170.1
 TABLE 26 (continued)
 EMI170.2
 1 -) -CH- 1 CH3 0 - N (CH) ,, 1 CH3 O - 2 3 3 = 2cH 2CH3 0, 0 - CH- 1 CH3 * t - / t -N HO c - (CH) 'cud

  <Desc / Clms Page number 171>

 
 EMI171.1
 TABLE 26 (continued)
 EMI171.2
 1 1 - - 2 / \ -N oxo 0 CH3 1 -CH 0 - 0 CH f-TJ) '"t JL - - 0 0 0 - OCOC 0 -N 0 N - OCOC 0 0

  <Desc / Clms Page number 172>

 
 EMI172.1
 TABLE 26 (continued)
 EMI172.2
 i 1 1 CH3 - 1 Cl3 CH3 CH 0.



  - OCOC 2 0
 EMI172.3
 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.

  <Desc / Clms Page number 173>

 



  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 oxychloride are added dropwise of phosphorus at −20 ° C. and the resulting mixture is subjected to a reaction at the same temperature for two hours. To this reaction mixture is then added a solution of 26 ml of methylene chloride containing 5.2 g
 EMI173.1
 of 7-amino-3-t [1- 2, 3, 4-tetrahydropyrazinyl)] methylt-A-cephem-4-carboxylate of diphenylmethyl at a temperature of -30 Once the dropwise addition is complete, react the mixture at the same temperature for one hour. After this reaction, 70 ml of water and 50 ml of methylene chloride are added to the reaction mixture.

   Sodium hydrogen carbonate 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, washed with 100 ml of water and 10 ml of a saturated aqueous solution of sodium chloride, in this order, and dried over anhydrous magnesium sulfate. The solvent is then removed by distillation under reduced pressure.



  The residue is purified by column chromatography (silica gel C-200 from Wako; eluent: chloroform / methanol = 20: 1 by volume) to obtain 1.4 g (yield: 20.0%) of 7- [2- (2-forma-midothiazol-4-yl) glyoxylamido] -3 - [{1- (4-ethyl-2,3-dioxo-1, 2,3, 4tetrahydropyrazinyl) methyl] - # 3-cephem-4-carboxylate of diphenylmethyl having a melting point of 140-145 C (decomp.).
 EMI173.2
 



  IR (KBr) cm: vC = O 1780, 1720, 1680, 1670, 1640 NMR (d6-DMSO) g values: b 1, (3H, t, J = 7Hz, NCH2CH3) '2 3 3, (2H, ls , C2-H), 3, (2H, q, J = 7Hz,> NCHCH),
 EMI173.3
 4, 5, 00 (2H,), CH-

  <Desc / Clms Page number 174>

 
 EMI174.1
 5, 30 (1H, d, J = 5Hz, C6-H), b 6, dd, J = 5Hz, J = 9Hz, C7-H),
 EMI174.2
 6, (2H, ABq, J = 5Hz, H H
 EMI174.3
 7,),
 EMI174.4
 7, 0) x 2), 8, 64 (1H, s, N S
 EMI174.5
 8, 1020 d, J = 9 Hz, -CONH-), 1290 HCONH-) Similarly, the following compound is obtained 0.09 g (yield: 19.2%) of 7- glyoxylamido] -3- 2, 3 , 6-tetrahydropyridazinyl)] methyl) -A-cephem-4-carboxylate, diphenylmethyl.



  P. F.: 153-154 (decomp.) IR (KBr) cm: 1780, 1725, 1690, 1665 NMR (CDCl- + d-DMSO) J b 3, (2H, 15, C2-H),
 EMI174.6
 4, (3H, m, S, J-'C6-H), och2- 5, dd, J = 5Hz, J = 8Hz, C7-H), H 6,, y il: (H 1-Co:>

  <Desc / Clms Page number 175>

 
 EMI175.1
 8, 66 a * .....



  S s H
 EMI175.2
 8, s, HCO-),
209, 86 (1H, d, J = 8Hz, -CONH-) (2) To a solution of 7.0 g of 7-E2- (2-formamidothiazol-4-yl) glyoxylamido] -3- [l- ( 4-ethyl-2, 3-dioxo-1, 2,3, 4-tetrahydropyrazinyl)] methyl} - # 3-cephem-4-carboxylate of diphenylmethyl in 35 ml of N, N-dimethylacetamide, 1.7 g are added of methoxyamine hydrochloride with ice cooling and the resulting mixture is subjected to a reaction at 15-20 C for three hours.



  Once the reaction is complete, 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 'a saturated aqueous solution of sodium chloride in this order and dries it over anhydrous magnesium sulfate. The solvent is then removed 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:
 EMI175.3
 83.7%) of 7-acetamido] -3- {El- 2, 3, 4-tetrahydropyrazinyl)] methyl-diphenylmethyl-A-cephem-4-carboxylate having a melting point of 165-168 C.



  IR (KBr) cm 1780, 1720, 1680, 1640 Similarly, the following compound is obtained [2- (2-formamidothiazol-4-yl) -2- (syn) -methoxyimino-o 7- [2- (2 -formamidothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- [1- (3,6-dioxo-1, 2,3, 6-tetrahydropyridazinyl)] methyl) - # 3-cephem- Diphenylmethyl 4-carboxylate.



  P. F. 171-1730 C (decomp.).



   The same elimination reaction is carried out as above 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 Salt of trifluoroacetic acid of 7- [2- (2-amino-5-bromothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3 acid - [1- (4-ethyl- 2, 3-dioxo-1, 2,3, 4-tetrahydropyrazinyl)] - methyl] - # 3-cephem-4carboxylic, PF: 1470 C (decomp.)
IR (KBr) cm :-) 1775,1680, 1640

  <Desc / Clms Page number 176>

 TABLE 27
 EMI176.1
 N CF-COOH-H-N- 3 OCH 3 R2 R2 0 CH 3 0 0 O - N - 1 0 0 0 CH3 * 0 0 0 0 CH- * V- - \ - N- (CH2) CH \ N-.

   H \ d N 0

  <Desc / Clms Page number 177>

 TABLE 27 (continued)
 EMI177.1
 R2 -OY-- HN N 1 - CH 0 0 N -.



  1 1

  <Desc / Clms Page number 178>

 TABLE 27 (continued)
 EMI178.1
 o cil3 - N- (CH2) cCHL-N C = C-CH -, - N 2 0 Y OMO / \ <- N- (CH2) llCH3 N (o) 0 -N - OCOC '=== / 2

  <Desc / Clms Page number 179>

 
 EMI179.1
 TABLE 27 (continued) CH, .. o H / CH) - N N-N HN = CH - N 0 o H - NH "== 1 CH2CH N" M - 0 * 1 1 1 Note: Hydrochloride

  <Desc / Clms Page number 180>

 
 EMI180.1
 TABLE 28
 EMI180.2
 
 EMI180.3
 (syn-isomer)
 EMI180.4
 R2 R Zo OP NCH 2 0 0 CH3 H'1 - CH COOH-NH - C-COOH, CH3 0 0 \> -e - N NH NH --- CHCOOH "== '2 o H -N 3 0 0 C N'NN - '= d

  <Desc / Clms Page number 181>

 
 EMI181.1
 TABLE 28 (continued)
 EMI181.2
 0 "IlHN) --CH-COOH o 0 CH3 N" HCOOH. --CHCOOH 1 - 1 0 OMO - INCH C = CH-CH, -CH.



  2-2 0 0 0 0: 0 '==' 0 0 0 - OCOC --CHCOOH 2

  <Desc / Clms Page number 182>

 
 EMI182.1
 TABLE 28 (continued)
 EMI182.2
 0 0 K - COOH COOH 2 0 0 -N 2 0 0 c - 2 o --- N COOCHCH- '== "

  <Desc / Clms Page number 183>

 
 EMI183.1
 TABLE 29
 EMI183.2
 
 EMI183.3
 (syn-isomer)
 EMI183.4
 R R2 oHo W - -N 1 CH3 w - 1 CH3 0. w - N- (CH2) 1 CH3 or - CH3 CH3

  <Desc / Clms Page number 184>

 
 EMI184.1
 TABLE (continued)
 EMI184.2
 0.



  -) -CH- 1 CH3 OHO - N (CH2) 11CH3 l '= CH3 O - 0. oHo ¯ - 1 CH3 * -N - O - (CH 2 3 \ - / "'

  <Desc / Clms Page number 185>

 
 EMI185.1
 TABLE 29 (continued)
 EMI185.2
 0 0 - P -N 0 o CH3 1 - 20COR {CH3) ni - CH CH-.



  CH CH3 N - OCOC - 0 o u - h o - 0 - -N 0

  <Desc / Clms Page number 186>

 
 EMI186.1
 TABLE 29 (continued)
 EMI186.2
 f 1 N -))) 1 1 CH3 0 .. / - OCOC '= d 0
 EMI186.3
 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; and 12.

  <Desc / Clms Page number 187>

 
 EMI187.1
 



  Example 11 (1) In a mixed solvent of 37 ml of trifluoroacetic acid and 10.8 g of anisole, 7.29 g of 7- 4-yl) -2- 1, 2, 3, 4-tetrahydropyrazinyl are dissolved. )] methyl) -A-cephem-4-carboxylate of diphenylmethyl and the resulting solution is subjected to a reaction at room temperature for two hours. Once the reaction is complete, the solvent is removed by distillation under reduced pressure.

   To the resulting residue, 50 ml of diethyl ether are added and the crystals are collected by filtration, washed sufficiently with 50 ml of diethyl ether and dried to obtain 5.2 g (yield: 92.4%) of acid 7 - (syn) 2, 3, 4tetrahydropyrazinyl)] - methyl-A-cephem-4-carboxylic having a melting point of 155-158 (decomp.) IR (KBr) cm: 1775, 1710, 1675, 1640 NMR (d6 -DMSO) f-values:

   b 1, (3H, t, J = 7Hz, NCHCH-), 3, 49 (2H, 1s, 3, (2H, q, 1? 2 3 3, (3H, s,
 EMI187.2
 4, 42, 4J95 (2H, ABq, J = 15Hz, Sis), -CH-
 EMI187.3
 5, d, J = 5Hz, C6-H), 5, dd, J = 5Hz, J = 8Hz, C7-H),
 EMI187.4
 6/65 (2H, lily,), H H

  <Desc / Clms Page number 188>

 
 EMI188.1
 7, s, U), s 8, s, HCONH-), 9, d, J = 8Hz, -CONH-), 12, HCONH-) Similarly, the compounds indicated in Table 30 are obtained.

  <Desc / Clms Page number 189>

 
 EMI189.1
 TABLE 30
 EMI189.2
 NrC-CONHJ1- HCONH \ 'OCH (syn-isomer) Compound, (KBr) P. F.

   (OC) R2 0 195-198'1775, 1720, H (decamp.) 1680-1640 - = / 3 0 0 H - 1775, 1680, -N N- (CH 2 4 CH3 1640 '== 1 0 1 - 165-170 1775, 1680, "1640" == 1 1 1 1 - 195-198 1775, 1685, 1 0 0 0 H -N 155-158 1780, 1720, (decomp.) H - 144-147 1778, 1685 , = 1660, 1645

  <Desc / Clms Page number 190>

 
 EMI190.1
 TABLE 30 (continued)
 EMI190.2
 CH3 1 N 1 186-188 1775, 1710,, 1690, 1650 - 'O, 0 eV 218-221 1670, - Y o

  <Desc / Clms Page number 191>

 
 EMI191.1
 (2) To a solution of 5.63 g of - 3-dioxo- 1, 2, 3, 4-tetrahydropyrazinyl)] methyl) -A-cephem-4-carboxylic acid L cephem-4-carboxylic acid in 25 ml of N, N-dimethylacetamide, 1.52 g of 1.8-
CH NH-CH COOHdiazabicyclo [5, 4, 0] -7-undecene and 3.84 g of 1-pivaloyloxyethyl iodide with ice cooling, then the resulting mixture is subjected to a reaction for 30 minutes.

   Once the reaction is complete, the mixture is poured into a mixed solvent of 100 ml of water and 100 ml of ethyl acetate. The organic layer is then separated, washed with water and dried over anhydrous magnesium sulfate. The solvent is removed by distillation 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%) of 7- [2- (2-formamidothiazol-4-yl) -2- ( syn) - methoxyiminoacetamido] -3 - {[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl] - # 3-cephem-4-carboxylate of 1-pivaloyl-oxyethyl having a melting point of 140-142 C.



   IR (KBr) cm zoo 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 by the corresponding esters.

  <Desc / Clms Page number 192>

 



  TABLE 31
 EMI192.1
 ,) HCONH) \ '1 OCH3 COUR1 (syn-isomer) Compound --------, ------- OO Rl 0)' - N N-CH-182-188 1780, 1740, 1680 -1640 CH == 3 A -CHOCOC CH, -NN '"'" "'"' "'" "CH3-N -N -CHOCOC - 108-115 1782, 1740, 1680, 1640 CH3 (CH) -CHOCOC! '- 1780, 1740, 1680-1640 CH - N) -CH-

  <Desc / Clms Page number 193>

 TABLE 31 (continued)
 EMI193.1
 - 1 1785, 1745, 1685, 1645 CH - N) ,, J -L 0 - -H 1780, 1742, 1680, 1640 "" "-N '== i - CHOCOOCH2CH3 0 0 1 1780, 1760, 1680, 1640 UH-N NCH * 1 * 1 0 - NCH2CH3 1780, 1680-1630 &commat; 0 0 0 - -CHL) - 136-141 1780, 1720, 1680, 1640 -N NCH2CH3 bt

  <Desc / Clms Page number 194>

 
 EMI194.1
 (U 0) - -; CI} 00 zone.

   (n n: m E- <
 EMI194.2
 - Y \ H 1810, 1775, 1720, 1670, 0 0 1640 c Il 0 0 0 H -) - N 1775, 1745, 1685, 1650 (o) - f) -CH2OCOC (CH3) 3 N '"" t 1780, 1750, 1690, 1660 -N 0 1

  <Desc / Clms Page number 195>

 TABLE 31 (continued)
 EMI195.1
 3 - "'N 1780, 1740, 1680-1640 1 0 0 Note: * 1 Diastereoisomer

  <Desc / Clms Page number 196>

 (3) To a solution of 5.5 g of 7- [2- (2-formamidothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3 - {[1- (4-ethyl-2,3 -dioxo-1, 2, 3, 4tetrahydropyrazinyl)] methyl] - # 3-cephem-4-carboxylate of 1-pivaloyl-oxyethyl obtained in (2) above in 27.5 ml of methanol, 1 is added, 13 ml of concentrated hydrochloric acid and the resulting mixture is subjected to a reaction at 35 ° C. for two hours. Once the reaction is complete, the solvent is removed by distillation under reduced pressure.

   50 ml of ethyl acetate and 50 ml of water are added to the residue and the mixture is adjusted to pH 6.0 with sodium hydrogencarbonate. The organic layer is separated and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure. 45 ml of diethyl ether are added to the residue and the crystals are collected by
 EMI196.1
 filtration to obtain 4.65 g (yield: 88.1%) of 7-thiazol-4-yl) -2- 3- 3 1 dioxo-1,2,3,4-tetrahydropyrazinyl) methyl) -A-cephem- 4-carboxy- [2- (2-amino-late of 1-pivaloyloxyethyl having a melting point of 148-150 C.



   IR (KBr) cm: 1780.1740, 1680.1640
 EMI196.2
 NMR -DMSO) b 0,,
 EMI196.3
 1.52 (3H, d, J = 5Hz, -OCHO-), 1 CH
 EMI196.4
 3, (2H, ls,
 EMI196.5
 3, (2H, q, J = 7Hz, CH), 1? 1-1 2 3
 EMI196.6
 3,),
 EMI196.7
 4, 04 (2H, ABq, J = 15Hz, s) -CH-
 EMI196.8
 5, d, J = 5Hz, C6-H), 5, dd, J = 5Hz, J = 8Hz, C7-H),
 EMI196.9
 6. (2H, they,), H H

  <Desc / Clms Page number 197>

 
 EMI197.1
 678 s, N XX S H 7, q, J = 5H. iCH1
 EMI197.2
 7, 22 (2H, ls, -NH), 9, d, J = 8Hz, -CONH-) Similarly, the compounds listed in Table 32 are obtained.

  <Desc / Clms Page number 198>

 TABLE 32
 EMI198.1
 N H2N- (Il N CH -R2 "s N OCH Compound IR (KBr) P.



  Ri R2 cm 0 0 198-201 1780, 1, '' '33 - -CH, 0, -OCHO-),) CH3 1640 CH3 3 3, (3H, s,> N-CH3) '(2H, is, (3H, s, 4, (2H, ABq, J = 15Hz, S), 24 d, J = 5Hz,) C6-H), S, dd, J = 5Hz, J = 8Hz, C7-H), 6 , 60 (2H, ABq, J = 6Hz, X), HH

  <Desc / Clms Page number 199>

 TABLE 32 (continued)
 EMI199.1
 Ni 7, 07 (1H, q, J = 5Hz, -CH-), CH3 CH, 7, (2H, ls, d, J = 8Hz, -CONH-) 0, (3H, t, J = 7Hz,> N (CH) - 139-141 1783, 1, 18 (9H, s, -C), 53 1 CH - N 1680, (3H, d, J = 5Hz, -CHO-), 1640 CH3 1, 04- 1.85 (6H, m,> NCH2 (CH) 3.59 (2H, ls, C2-H), (2H, t, J = 7Hz, NCH 3.91 (3H, s, 08 (2H, ABq, J = 15Hz, S CH

  <Desc / Clms Page number 200>

 TABLE 32 (continued)
 EMI200.1
 5, d, J = 5Hz, C6-H), (1H, dd, J = 5Hz, J = 8Hz, C7-H), 6, 65 (2H, Js, s,), 6, 85 (1H, HH - 5, q, J = 5Hz, SH - d, J = 8Hz, iCH3 - 0, (3H, t, J = 7Hz,;

   ) - 145-150 1780, 118 1 (decomp.) CH-HN 1645 (3H, d, J = 5Hz, -OCHO-), CH3 un 3 3.60 (2H, ls, C2-H), 3.72 (2H, t, J = 7Hz,

  <Desc / Clms Page number 201>

 TABLE 32 (continued)
 EMI201.1
 3, (3H, s, 41, 5, 09 (2H, ABq, J = 15Hz, Sil), CH 5, d, J = 5Hz, C6-H), (1H, dd, J = 5Hz, J = 8Hz , C7-H), 6, (2H, ls, HH - s, A), 98 (1H, q, J = 5Hz, SH -OCHO-), 9, 75 (1H, d, J = 8Hz, 1 CH3 - - 170-172 1780, 0, (3H, t, J = 8Hz,> N (CH) 1 CH-N 02-143 (21H, m, -C 1640> NCH2 56 (3H, d, -.,.

  <Desc / Clms Page number 202>

 
90TABLEAU32 (continued)
 EMI202.1
 J = SHz, (4H, CH3 m,> NCH2 (CH-) ,.

   zzb J '(3H, s, -OCH), 43, 11 (2H, ABq, J = 15Hz, S), 5.28 lCH (lH, d, J = 5Hz, C6-H), 5) dd, J = 5Hz, J = 8Hz, C7-H), 6, (2H, ls, = <), 6, s, H H NJ q, J = 5Hz, S H - 15 (2H, 15, 1 CH3 9, d, J = 8Hz, -CONH-)

  <Desc / Clms Page number 203>

 TABLE 32 (continued)
 EMI203.1
 0il86 (3H, t, J = 7Hz,> N (CH2) CH), - 153-158 1780, 1, <'-C 1 (decomp.) 1745, 1, 02-1, 87 (20H, m, CH.-N' 1640 d, J = 5Hz, -OCHO-), 53 (2H, ls, CHC2-H) , 3J (2H, t, J = 7Hz,> - (2H, ABq, J = 15Hz, S 5, d, CH J = 5Hz, C6-H), dd, J = 5Hz, J = 8Hz, C7-H ), (2H, 1s, 75 HHS

  <Desc / Clms Page number 204>

 TABLE 32 (continued)
 EMI204.1
 701 1CH3 9, d, J = 8Hz, -CONH-) 1, (12H, m, -C), Q 0 NCHCH), 47 (2H, ls, C2-H), m - -NN-CHCH-145- 147 "'J = 7Hz, -N' 378), 30, 5, 01 1675, 3 $ 1640 (2H, ABq, J = 15Hz, SJ-), 5. d, J = 5Hz, C6-H), 6 , 06 (3H, m, -OCH 6.55 (2H, ls, = <), H H N-rrs, k), 12), S 9.

   d, J = 8Hz, -CONH-)

  <Desc / Clms Page number 205>

 (1H, q, J = 5Hz, -OCHO -), TABLE 32 (continued)
 EMI205.1
 23 (6H, t, J = 7Hz, NCHCH-, - 55 (3H, d, J = 5Hz, -CHOCOOCH 3, 53 (2H, ls, C2-H), 2 CH3 '== 1 Z-CH CH 3 3 1640 g NCHCH), 386), 19 (2H, q, J = 7Hz, 5.05 (2H, ABq, J = 15Hz, S.),) 521 d, J = 5Hz, C6-H), 86 ( lH, dd, J = 5Hz, J = 8Hz, C7-H), 6) '52, 6, (2H, ABq, J = 6Hz, N) HHSH 6, q, J = 5Hz, -OCHO-), iCH3

  <Desc / Clms Page number 206>

 TABLE 32 (continued)
 EMI206.1
 7.02 (2H, ls, d, J = 8Hz, -CONH-) 1, (3H, t, J = 7Hz,> NCHCH), 3, (2H, ls, C2-H), (2H, Y " "" 8 '' "J = 7Hz, 99 (3H, s, fi) K 1680" 2 1 'NCH CH 1640- - -CH2CH, 17-5, -), d, J = 5Hz, C6-H), 3 y, y 6 5, dd, J = 5Hz, J = 8Hz, CH), 6 (2H, ABq, J = 7Hz, J = \), s, HHNA), SH 0 7,).



  H - o) - H H d H H H

  <Desc / Clms Page number 207>

 TABLE 32 (continued)
 EMI207.1
 , 87 d, J = 8Hz, -CONH-) 0, m, - CH 0 0 139-144 1780, - (CH CH - <'' 2- '1640 2 CHCH 0, NCHCHg), s, -OCH-), 4, 30 (2H, t, J = 7Hz, - 39, 5, 12 (2H, ABq, J = 15Hz, Sil) ,: 5, d, J = 5Hz, C6-H), (lH, dd, J = 5Hz, J = 8Hz, C7-H), 6 ,, (2H, ls, HH - s, J), 7, 28 (2H, ls, SH 9, d, J = 8Hz, -CONH-)

  <Desc / Clms Page number 208>

 TABLE 32 (continued)
 EMI208.1
 1, (3H, t, J = 7HZ, NCHCH), 220 53 1 3 - CHC == CCH.



  2,1., Mp.) -H), 73;) / (decomp.) - L / ou, 1640 1640 o 0 J15Hz, CH (3H, m, C6-H, -OCH2C =), 87 (1H, dd, J = 5Hz, J = 8Hz, C7-H), 6, 59 = <), H H s, /), 17 (2H, ls, -NH), S H 9) '62 (1H, d, J = 8Hz, &verbar;

  <Desc / Clms Page number 209>

 TABLE 32 (continued)
 EMI209.1
 124 31 (3H, CH3 s, -CH), 40 (2H, ls, C2-H), - H 141-142 1775, 399 01, 33! - '"1 2 5, d, J = 5Hz, C6-H), 5in61-6114 (3H, m, -OCH C7-H), 6 (2H, ls, -NH), 6, SH 7/24 ( 2H, ABq, J = 10Hz, H), OH 9, d, J = 8Hz, -CONH-) i

  <Desc / Clms Page number 210>

 TABLE 32 (continued)
 EMI210.1
 119), (6H, -CH! (2H, ls, C2-H), - 2/1740, - (3H, s, -OCH), 02, S 0 1640 (2H, ABq, J = 15Hz, S) , 2 5, d, J = 5Hz, C6-H), 6J (3H, m, CH, -OCHO-), 6 ...

   (2H, S H m, -NH), 98 -H)

  <Desc / Clms Page number 211>

 TABLE 32 (continued)
 EMI211.1
 1, (9H, s, -C)), 43 * 3 (4H, ls, C: -CH (3H, s, (2H, / 1745, (decomp.) 1660 o 2 (1H, d, J = 5Hz , C6-H), 5.60-6, (3H, m, C7-H, (1H, s, N-rr-), (2H, SH ABq, J = 10Hz, JC'9, 62 d, J = 8Hz, -CONH-)

  <Desc / Clms Page number 212>

 TABLE 32 (continued)
 EMI212.1
 * 3 124)), 53 is, C2-H), 4, 06 (3H, s, 4, (2H, ABq, J = 15Hz, s S), d, J = 5Hz, - 134-137 1780, " - '"V -CH- 0 1680 S (5H, m, 1650 - 88 (1H, s, NX)' 7, (2H, SH ABq, J = 5Hz, <H), H> -H), 59 d, J = 8Hz, - (measured

  <Desc / Clms Page number 213>

 TABLE 32 (continued)
 EMI213.1
 * 3 18) d, J = 6Hz, -OCHO-), (3H, s, 1 CH3 chug - 143-145 1780, - 47 1 '-NH), (3H, s, 3 "tr- 5, 29 ( 2H, ABq, J = 15Hz, S), lCH 5, 22 d, J = 5Hz, C6-H), 5, dd, J = CH), 92 s, NX) 'SH 6 ,, (2H, ABq, J = 10Hz, HX q, J = 6Hz, -OCHO-), 1 CH, 9.

   d, J = 8Hz, -CONH-)

  <Desc / Clms Page number 214>

 
1TABLE 32 (continued)
 EMI214.1
 1, (9H, s, -C), 3, 65 (2H, 15, C2-H), 0 0 41P44, (2H, ABq, J = 15Hz, H -CH d, J = 5Hz, 2 (0) -CH- 1650 C6-H), 5, - 89 s, HH - J), 36 (2H, 1s, NH-), S 0 7, 27 (5H, m, '- \))' 981 d, J = 8Hz, -CONH-) Note: * 1 Diastereoisomer
 EMI214.2
 1 * 2 Hydrochloride (the salt is prepared in the usual way) * 3 The desired compound is obtained by reacting the salt of trifluoroacetic acid with a halide in the presence of 1, 8-diazabicycloL5, 4, OJ-7-undecene at a temperature of -5 to 0 C.

   

  <Desc / Clms Page number 215>

 
 EMI215.1
 (4) To a solution of 1.05 g of 7- - (2, 3-dimethyl-6-oxoA 3 l, cephem-4-carboxylic acid obtained in (1) above in 10 ml of methanol, 0.38 ml of concentrated hydrochloric acid are added and the resulting mixture is reacted at 35 for two hours, after the reaction is completed, the solvent is distilled off under reduced pressure and 10 ml of diethyl ether, then the crystals are collected by filtration and 0.43 g (yield: 84.8%) of acid hydrochloride 7- - (2,3-dimethyl-6-oxoA 3 l, 6-dihydropyrazinyl) is obtained. ] methylt-Z3-cephem-4-carboxylic acid having a melting point of 250 C or more.



  IR (KBr) cm *: o 1765, 1660, 1620 NMR (d6-DMSO) b 2 values, (6H, is, -CH-x 2), 3, (2H, ls, C2-H), 3190 4, (2H, ABq, J = 15Hz, H- 5, d, jazz C.-H), '"b 578 dd, J = 5Hz, J = 8Hz, C7-H), 6, s, 5 S'TH) 7.979 dd, J = 8Hz, -CONH-)

  <Desc / Clms Page number 216>

 
 EMI216.1
 Example 12 (1) In a similar manner to that of Example 7 - the compounds listed in Table 33 are obtained from the starting materials indicated below.
 EMI216.2
 



  N (H OCHCOOR (starting material, syn-isomer) NH: 01- 0 0 2 o JN --- CHN \ t COOCH (o)) 2 / CN (&commat;) \ 'OCHCOOR COOCH ze 2 (required compound, syn-isomer)

  <Desc / Clms Page number 217>

 
 EMI217.1
 TABLE 33
 EMI217.2
 1 Compound P.



  1! 1780, 1720, - 1, 1780, 1720, g 1 150-152 1780, 1720, 1 d 1645 1 1
 EMI217.3
 (2) The compounds of Table 34 are obtained by reacting the above-mentioned compounds in a similar manner as in Example 7- (2)

  <Desc / Clms Page number 218>

 TABLE 34
 EMI218.1
 D1 HCOOH. H.



  S-ii N N-CH \, OC 2 (syn-isomer) P. .



  Compound - l (3H, t, J = 7 3) (2H, ls, C2-H), 3 "- / 012 '"' (2H, / 1680, 1670, (2H, m, 1630 S), 20 d , J = 5Hz, 2 C6-H), 5, dd, J = 5Hz, J = 9Hz, C7-H), 6. (2H, s, = 98 HH (1H, s, T), 730 S

  <Desc / Clms Page number 219>

 TABLE 34 (continued)
 EMI219.1
 8, s, HCOOH), 80 (1H, d, J = 9Hz, -CONH-) 1, (3H, t, J = 7Hz,> NCH H 2, 80 (4H, m, 2, 00 (2H, \ ", 80 125-128 -TC)) p.) 0 '1635 3, 1635 HH 3, (2H, q, J = 7Hz, NCHCH), 5, 4, 50-5, 00 (2H, m, Sua) , 25 (1H, d, 2 J = 5Hz, C dd, J = 5Hz, J = 9Hz, C7-H), 6, (2H, s,,), 96 HHSH 1

  <Desc / Clms Page number 220>

 TABLE 34 (continued)
 EMI220.1
 7 7/30 (3H, m, H),) HH 8, 9, d, J = 9Hz, -CONH-) 1) (6H, t, J = 7Hz, NCHCH, - -CH 122-123 1770, 3 , (2H, q, J = 7Hz, NCHCH), "1670, 18 (2H, q, J = 7Hz, 1640 477 (2H, m, S 24 (1H, d, CH, J = 5Hz, C6-H) , 5, 91 (1H, dd, J = 5Hz, J = 9Hz, C7-H), 69 (2H, s, 1

  <Desc / Clms Page number 221>

 TABLE 34 (continued)

   
 EMI221.1
 '\), s, N H H S 8 s, HCOOH), d, J = 9Hz, -CONH-) L-1 m 1

  <Desc / Clms Page number 222>

 Example 13 (1) To a solution of 2.72 g of 2- (2-t-amyloxycarboxamidothothol-4-yl) acetic acid in 40 ml of anhydrous methylene chloride, 1.06 g of N- is added. methylmorpholine, and the mixture is cooled to -35 C. 1.12 g of ethyl chlorocarbonate are then added and the mixture is subjected to a reaction at a temperature of -35 to -25 C for 1.5 hours, after which 5.18 g are added
 EMI222.1
 of 7-amino-3-l-2, 3, 4-tetrahydropyrazinyl)] - -A-cephem-4-carboxylate of diphenylmethyl, and the mixture is subjected to reaction for one hour at a temperature of - 30 to - 20 C and then for one hour at a temperature of - 10 to + 10 C.

   Once the reaction is complete, the solvent is removed by distillation under reduced pressure. The residue is dissolved in 40 ml of ethyl acetate and 30 ml of water. The organic layer is separated and again 30 ml of water are added. The mixture is adjusted to pH 7.0 with sodium hydrogencarbonate with ice cooling. The organic layer is separated, washed with 30 ml of water and 30 ml of a saturated aqueous solution of sodium chloride in this order, then dried over anhydrous magnesium sulfate.



  The solvent is removed by distillation under reduced pressure and 35 ml of diethyl ether are added to the residue, then the crystals are collected by filtration to obtain 3.62 g (yield: 90.5%) of 7- [2- (2 -t-amiyloxycarboxamidothiazol-4-yl) acetamido] -3 - {[1- (4-ethyl-2, 3-dioxo-1, 2,3, 4-tetrahydropyrazinyl] methyl-A-cephem-4-carboxylate diphenylmethyl having a melting point of 152-154 C (decomp.).
 EMI222.2
 



  IR (KBr) cm-1 '' 'Similarly, the following compound is obtained: 6, g (yield: 82.7%) of 7-acetamido] -3- 2, 3, 6-tetrahydropyridazinyl)] methyl - cephem-4-carboxylatedediphenylmethyl.



  P. F.: 136-139 (decomp.) IR (KBr) cm: 1780, 1720, 1665
The compounds of Table 35 are obtained by subjecting the compounds obtained above (1) to a reaction in the same manner as in Example 6- (3).

  <Desc / Clms Page number 223>

 TABLE35
 EMI223.1
 
 EMI223.2
 Compound-j. KRr P. 'NMR R2 1, (3H, t, J = 7Hz, NCH2CH3)' 3.

   (2H, Ir 1-1 2 3 1 109-115 81 (4H, NCHCH-, - - '(decomp.) 1690, - 1630 N - CH2-), 47, (2H, ABq, J = 15Hz, s S), d, J = 5Hz, C6-H), S), - CH \ 5, (3H, m, C7-H, H). 81 7 H H s, N 9, 24 (1H, d, J = 8Hz, -CONH-) S

  <Desc / Clms Page number 224>

 TABLE 35 (continued)
 EMI224.1
 343 (2H, 1s, Nn-CH-), o 1770, S HN> 200 1710, 5, (2H, ls,), 5. d, J = 5Hz, 1 1670, \ - 0 C6-H), 5 , dd, J = 5Hz, J = 8Hz, C7-H), 6, s, NJC), (2H, ABq, s HS JlOHz,) d, J = 8Hz, -CONH-) -

  <Desc / Clms Page number 225>

 Example 14
6.82 g are dissolved in 48 ml of N, N-dimethylacetamide
 EMI225.1
 of 7- (4-bromo-3-oxobutylamido) -3-ï 2, 3, 4tetrapydropyrazinyl)] - methyl-A-cephem-4-carboxylate of diphenylmethyl and 1 g of thiourea, and the mixture is subjected to a reaction room temperature for two hours.

   When 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 hydrogen carbonate. The organic layer is separated and dried over anhydrous magnesium sulfate, then the solvent is removed by distillation under reduced pressure.



  Subsequently, the residue is dissolved in 33 ml of trifluoroacetic acid and 8 ml of anisole and the mixture is reacted at room temperature for one hour. Once the reaction is complete, the solvent is removed by distillation under reduced pressure. To the residue is added 40 ml of diethyl ether and the crystals are collected by filtration to obtain 4.50 g (yield: 74.1%) of acid trifluoroacetic acid salt 7- [2- 2-
 EMI225.2
 aminothiazol-4-yl) acetamido] -3- 2, 3, 4tetrahydropyrazinyl)] methyl} -A-cephem-4-carboxylic acid having a melting point of 109-1150 C (dec.).



  Similarly, the following compound is obtained: salt of trifluoroacetic acid 7- [2- (2-aminothiazol-4-yl) acetamido] -3 - {[1- (3,6-dioxo-1,2) , 3, 6-tetrahydropyridazinylmethyl) - # 3-cephem-4-carboxylic, PF: 200 C or more.



   The physical properties (IR values, NMR) of this compound are identical to those of Example 13- (2).

  <Desc / Clms Page number 226>

 



  Preparation example 1
An aqueous sodium salt solution of 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamidoJ-3- l [1- (2, 3-dioxo-1, 2,3, 4-tetrahydropyrazinyl)] methyl} - # 3-cephem - 4-carboxylic, conventionally to obtain a lyophilized and sterilized sodium salt. 1 gram (active amount) of the sodium salt is dissolved in 20 ml of physiological saline solution to obtain a solution for injection.



  Preparation example 2
1 gram (active amount) of the lyophilized product obtained in Preparation Example 1 is dissolved in 4 ml of an aqueous solution at 0.5% (w / v) of lidocaine hydrochloride to obtain a solution for injection which can be diluted.



  Preparation example 3
1 gram (active amount) of the lyophilized product obtained in Preparation Example 1 is dissolved in 20 ml of a 5% glucose solution to obtain a solution for injection.



   In addition, the other compounds of formula (I) can also be converted into corresponding lyophilized products (sodium salts) or solutions for injection by treating them in the same manner as in Preparation Examples 1 to 3.


    

Claims (1)

o CLAIMS 1. Cephalosporin derivative represented by the formula below, or salt thereof:  EMI227.1  formula in which R1 represents a hydrogen atom  EMI227.2  2 or a protecting group for the carboxyl function; represents a group of formula:  EMI227.3  o 0 0 N - '\ = 1 R9 1 0 1 1 R14 or j,. - .- \ - N oU -N R1S o R2 where R represents a hydrogen atom, a hydroxyl, nitro, carbamoyl or thiocarbamoyl group, an alkyl, alkenyl, alkynyl, alkadienyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl, aralkyl, acyl, alkoxy, alkylthio, acyloxyalkyloxy radical , alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocycle-sulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl,  dialkylthio-  <Desc / Clms Page number 228>  carbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonylthiocarbamoyl, arylsulfonylthiocarbamoyl, sulfamoyl, alkylsulfamoyl, methoxyalkyl, alkylaminoalkyl, alkylaminoalkyl, alkylaminoalkyl, alkylaminoalkyl, alkylaminoalkyl, alkylaminoalkyl, alkylaminoalkyl, alkylaminoalkyl, alkylaminoalkyl, alkylaminoalkyl, alkylaminoalkyl, alkylaminoalkyl, alkylaminoalkyl,)  EMI228.1  optionally substituted, or else a group of formula  EMI228.2  Rib - R17  EMI228.3  may be the same or different, a hydrogen atom 17 or an alkyl radical, or else form a ring with the nitrogen atom adjacent to them,, 7 8 9 10 11 12 14 each of the substituents R, R, R, R,,, R 15 and which may be the same or different, represents a hydrogen or halogen atom or an alkyl, aralkyl or aryl radical.  substituted, 13 R13 represents a hydrogen or halogen atom, a carboxyl, sulfo, carbamoyl or thiocarbamoyl group, or an alkyl, aralkyl, aryl, alkoxy, alkthio, alkylthio, acyl, alkoxycarbonyl, cycloalkyloxycarbonyl, acyl- radical.  EMI228.4  alkyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclic sulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, acylcarbamoyle, acylthiocarbamoyle, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonylthiocarbamoyle or arylsulfonylthiocarbamoyle, optionally substituted; R represents a hydrogen atom or an alkoxy radical; R4 represents a hydrogen or halogen atom; RR represents a hydrogen atom or an optionally protected amino group;  A represents a group of formula -CHL-, or a group of formula  EMI228.5    <Desc / Clms Page number 229>  in which R represents a hydrogen atom, an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl or heterocyclic radical, optionally substituted, or else a group protecting the function  EMI229.1  0 R19 hydroxyl, or a group of formula P19 each of the substituents R and R, which may be the same or different, represents a hydroxyl group or an alkyl, aralkyl, aryl, alkoxy, aralkyloxy or aryloxy radical, and the bond means that the compound may be a syn isomer or an anti isomer or a mixture of the two.  2. A cephalosporin derivative or a salt thereof according to claim 1, in the formula of which R3 is a hydrogen atom.  3. Cephalosporin derivative or salt thereof according to claim 1 or 2, in the formula of which  EMI229.2  4 R is a hydrogen atom.  4. Cephalosporin derivative or salt thereof according to any one of claims 1 to 3, in the formula of which R5 is an amino group.  5. Cephalosporin derivative or salt thereof  EMI229.3  according to any one of claims 1 to 4, in the formula of which A is a group of formula  EMI229.4  - - N in which R and the bond have the f 18 OR  EMI229.5  same definitions as in claim 1. 6. A cephalosporin derivative or a salt thereof 1 R according to claim 5, in the formula of which is an optionally substituted alkyl radical.  7. Cephalosporin derivative or salt thereof according to any one of claims 1 to 6, in the  <Desc / Clms Page number 230>    EMI230.1  - formula of which A is a group of formula N "" 'OCH 3  EMI230.2  -i-uj-c yn /. 8. Cephalosporin derivative or salt thereof according to any one of claims 1 to 6, in  EMI230.3  - It the formula of which A is a group of formula N 1 OC (syn isomer) in which R has the same definition as  EMI230.4  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  EMI230.5    EMI230.6  (syn isomer) in which has the same definition as in claim 1. 10. Cephalosporin derivative or salt thereof according to any one of claims 1 to 9, in the  EMI230.7  0 C) 2 HO formula 6 '== 1 which R has the same definition as in claim  EMI230.8  1. 11. Cephalosporin derivative or salt thereof according to claim 10, in the formula of which is a hydrogen atom, a heterocyclic radical, an alkyl, aralkyl or cycloalkyl radical. or  EMI230.9  R16 a group of formula-N '"  EMI230.10  and have the same definitions as in claim 1.  <Desc / Clms Page number 231>    EMI231.1   12. Cephalosporin derivative or salt thereof according to claim 10, in the formula of which is a hydrogen atom, a substituted alkyl, aralkyl or cycloalkyl radical, or else a group  EMI231.2  R of which R and have the \  EMI231.3  same definitions as in claim 1. 13. Cephalosporin derivative or salt thereof according to any one of claims 1 to 9, in 2 the formula of which R is a group of formula  EMI231.4  RD R L \ "N - R9 N R9 78 N R in which R, have the same definitions  EMI231.5  as in claim 1. 14. A cephalosporin derivative or a salt thereof according to claim 13, in the formula of which each of the substituents R and R, which may be identical or different, is a hydrogen atom or an alkyl radical. 15. Cephalosporin derivative or salt thereof according to any one of claims 1 to 9, in 2 the formula of which R is a group formula  EMI231.6    EMI231.7  d l il 1 IU 1 IL. l ^ d'f '.. wherein R, R and R have the same definitions as in claim 1. 16. A cephalosporin derivative or salt thereof according to claim 15, in the formula of which each d b. 10 11 12. t ^ t of R and which may be the same or different, is a hydrogen atom or  <Desc / Clms Page number 232>    EMI232.1  halogen or an alkyl radical. 17. A cephalosporin derivative or a salt thereof according to any one of claims 1 to 9, in the  EMI232.2  formula of which R a grouping of noses -? zo 1314 in which R, the same definitions  EMI232.3  as in claim 1. 1 Cephalosporin derivative or salt thereof according to claim 17, in the formula of which each d b. 13 14 15.. d. R and which may be the same or different, is a hydrogen atom or an alkyl radical. 19. 7-Methoxyiminoacetamido acid-3- {[1- (2, 3-dioxo-1, 2, 3, 4-tetrahydropyrazinyl) methyl} -A-cephem-4-carboxylic acid, ester thereof or salt thereof this one. 20. 7-Carboxymethoxyiminoacetamido] -3- 3-dioxo-1, 2, 3, 4tetrahydropyrazinyl) methyl} -A-cephem-4-carboxylic acid, ester thereof or salt thereof. 21. 7-Methoxyiminoacetamido acid] -3- (4-methyl-2, 3-dioxo-1, 2, 3, 4tetrahydropyrazinyl)] methyl-A-cephem-4-carboxylic acid, ester thereof or salt thereof this. 22. 7-Carboxymethoxyiminoacetamido] -3- {(4-methyl-2, 3-dioxo- 1, 2, 3, 4-tetrahydropyrazinyl) methyl} -A-cephem-4carboxylic acid, ester thereof or salt thereof -this. 23. 7- [2- methoxyiminoacetamido] -3- (4-ethyl-2, 3-dioxo-1, 2, 3, 4tetrahydropyrazinyl) methyl} -A-cephem-4-carboxylic acid, ester thereof or salt of it. 24. Acid 7-  <Desc / Clms Page number 233>    EMI233.1  carboxymethoxyiminoacetamido] -3- {(4-ethyl-2, 3-dioxo- 1, 2, 3, 4-tetrahydropyrazinyl) methyl} -A-cephem-4carboxylic acid, ester thereof or salt thereof. 25. 7-methoxyiminoacetamido] -3- (4-isopropyl-2, 3-dioxo- 1, 2, 3, 4-tetrahydropyrazinyl) methyl} -A3-cephem-4carboxylic acid, ester thereof or salt thereof this. 26. 7-methoxyiminoacetamido] -3- (4-dimethylamino-2, 3dioxo-1, 2, 3, 4, tetrahydropyrazinyl) methyl} -A-cephem-4carboxylic acid, ester thereof or salt thereof. 27. 7-12-Carboxymethoxyiminoacetamido acid] -3- 2, 3-dioxo-1, 2, 3, carboxylic acid, ester thereof or salt thereof. 28. 7-Methoxyiminoacetamido] -3- {[1-methyl} -A-cephem-4-carboxylic acid, ester thereof or salt thereof. 29. 7-Methoxyiminoacetamido acid-3- {(3, 6-dioxo-1, 2, 3, 6-tetrahydropyridazinyl) methyl) -A3-cephem-4-carboxylic acid, ester thereof or salt thereof . 30. 7-Carboxymethoxyiminoacetamido] -3- 6-dioxo-1, 2, 3, 6tetrahydropyridazinyl) -céphem-4-carboxylic acid, ester thereof or salt thereof. 31. 7-Methoxyiminoacetamido] -3- {[1- 6-dihydropyridazinyl) methyl} -A3-cephem-4-carboxylic acid, ester thereof or salt thereof. 32. 7-Carboxymethoxyiminoacetamido] -3- 6dihydropyridazinyl) methyl} -A3-cephem-4-carboxylic acid, ester thereof or salt thereof.  <Desc / Clms Page number 234>    EMI234.1   NOT A WORD. for the preparation of a represented by the following formula, or of a salt of  EMI234.2  this: R3 R3 N N N-CH S R4 0 1 R  EMI234.3  formula in which R represents a hydrogen atom 2 or a group protecting the carboxyl function; represents a group of formula  EMI234.4    EMI234.5  where represents a hydrogen atom, a hydroxyl, nitro, carbamoyl, thiocarbamoyl or sulfamoyl group, or an alkyl, alkenyl, alkynyl, alkadienyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl, aralkyl, acyl, alkoxy, alkylthio radical cyoalkyloxy, aryloxy, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl,  <Desc / Clms Page number 235>    EMI235.1  heterocycle-sulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl,  dialkylthiocarbamoyl, acylcarbamoyl, oacylthiocarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonylthiocarbamoyl, arylsulfonylthiocarbamoyethyl, hino-alkylaminoalkyl, cycloalkyl, alkylkulfonoyl, alkyl  EMI235.2  click, optionally substituted, or a group of  EMI235.3  , 16 formula-N of the substituents R16 and 1-7 R17  EMI235.4  which may be the same or different, represents a hydrogen atom or an alkyl radical, or else and can form a ring with the nitrogen atom which 7 R is adjacent to them;  substituents R, R 9 10 11 12 14 15. ^ "of R, R, R, R and which may be the same or different, represents a hydrogen or halogen atom or an alkyl, aralkyl or aryl radical optionally substituted RR represents a hydrogen or halogen atom, a carboxyl, sulfo, carbamoyl or thiocarbamoyl group, or else an alkyl, aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfon radical cycloalkylsulfonyl, arylsulfonyl, heterocycle-sulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkylsulfonylcarbamoylylbyloylbyloylbyloyl  EMI235.5  a hydrogen atom or an alkoxy radical;  R psprésauriabcmed'hogae cu e ésgrteuatEn ogaO gtTOLpems possibly protected; A represents a group of formula -CH-, a group of formula  <Desc / Clms Page number 236>    EMI236.1  Il N in which R represents a hydrogen atom, e 18 6R18 or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl or heterocyclic radical, optionally substituted, or a group protecting the hydroxyl function, or a group of formula  EMI236.2  O / R 19 it - each of the substituents R and R, which '"  EMI236.3  may be the same or different, represents a hydroxyl group or an alkyl, aralkyl, aryl, alkoxy, aralkyloxy or aryloxy radical;  and the bond means that the compound can be a syn isomer or an anti isomer or a mixture of the two, characterized in that it consists in reacting a compound corresponding to the following formula, or else  EMI236.4  a salt thereof: R3 R3 R28 J - N "-CH '1 0 COOR  EMI236.5  formula in which represents an amino group  EMI236.6  or a group of formula R31 '"C = C-NH- 32 f Razz R R  EMI236.7  31 32 33 in which each of the substituents R, R and R, which may be identical or different, represents a hydrogen atom or an organic residue not participating in the reaction, or else a group of formula  EMI236.8    <Desc / Clms Page number 237>    34 35 in which each of the substituents R and R, which may be identical or different,  represents a hydrogen atom or an organic residue not participating in the 1 2 3 reaction, and R, R and R have the same definitions as above, with a compound represented by the formula  EMI237.1  next, or with a reactive derivative thereof at the  EMI237.2  carboxyl group:  R5 N- (N-r S  EMI237.3  45 formula in which R, R and A have the same definitions as above, or [B] to react a compound corresponding to the formula  EMI237.4  following, or a salt thereof:  EMI237.5    EMI237.6  j-u-mu-Lt-ud. mj-ë L 123 R, and A have the same definitions as above, with a compound represented by the formula:  EMI237.7  in which R5 has the same definition as above, or [C] to react a compound corresponding to the following formula, or a salt thereof:  EMI237.8    <Desc / Clms Page number 238>    EMI238.1  1 2 3 4 5 ^ formula in which R, R and have the same definitions as above, with a compound represented by the following formula, or one with a salt thereof:   HONOR  EMI238.2  2 formula in which R18 has the same definition as above, and, where appropriate, after step [A], [B] or [C], to remove the protective group, to protect the carboxyl group or to transform the product into a salt of it.  34. Method according to claim 33, characterized in that it consists in reacting a compound corresponding to the following formula, or a salt thereof:  EMI238.3    EMI238.4  1 2 3 28 formula in which 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 thereof at  EMI238.5    EMI238.6  45 formula in which R, R and A have the same definitions as in claim 33, then, if necessary, to remove the protective group, to protect the carboxyl group or to transform the product into a salt thereof.  35. Method according to claim 34,  <Desc / Clms Page number 239>    EMI239.1  characterized in that A represents a group of  EMI239.2  - H formula in which R18 formula N OR  EMI239.3  have the same definition as in claim 33. 36. Process according to claim 34 or 35, characterized in that the reaction takes place at a temperature of -50 C to + 400C. 37. Process according to claim 33, characterized in that it consists in reacting a compound represented by the following formula, or a salt thereof.  EMI239.4  ci R 1 XCHCO-A-CONH ---- S --N-CHR 011 COOR  EMI239.5  1 formula in which R, R, R, A and X have the same definitions as in claim 33, with a compound represented by the formula:  EMI239.6    EMI239.7  in which has the same definition as in claim 33, then, if appropriate, in removing the protective group, in protecting the carboxyl group or in transforming the product into a salt thereof. 38. Method according to claim 37, characterized in that A represents a group of  EMI239.8  - it formulates which R and the bond formula N in OR  EMI239.9  have the same definitions as in claim 33.  <Desc / Clms Page number 240>    39. Process according to claim 37 or 38, characterized in that the reaction is carried out at a temperature of 00 to 100 C.  40. Process according to claim 33, for the preparation of a compound represented by the following formula,  EMI240.1  or a salt thereof: R3 R s 5 N-n --- CCONH ----- R 4 R OR COORl  EMI240.2  1 2 3 4 5 18 formula in which R, R, R, R, R, R and the bond have the same definitions as in claim 33, characterized in that it consists in reacting a compound represented by the following formula ,  EMI240.3  or a salt thereof:  R3 1 1 R ¯ <l 1 2 S - L i-N! / "'I COOR  EMI240.4  1,234 5 formula in which R, R, R, R and R have the R4 same definitions as in claim 33, with a compound represented by the following formula, or with a salt thereof: HONOR  EMI240.5  2 formula in which R has the same definition as in claim 33, then, if necessary, eliminating the protective group, protecting the carboxyl group or transforming the product into a salt thereof.  <Desc / Clms Page number 241>    41. Process according to claim 40, characterized in that the reaction is carried out at a temperature of 00 to 1000C.  42. 7- (optionally substituted amino) - 3-methyl substituted-ss3-cephem-4-carboxylic acid represented by the following formula, or salt thereof:  EMI241.1  formula in which RI represents a hydrogen atom or a group protecting the carboxyl function; R2  EMI241.2  represents a group of formula:  EMI241.3  0 0. HG "'" y. ""' Y. o - NiR9 -R12 -N 15 b R R8 0 RR14 where RE represents a hydrogen atom, a hydroxyl, nitro, carbamoyl, thiocarbamoyl or sulfamoyl group, or else an alkyl, alkenyl, alkynyl, alkadienyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl, aralkyl, acyl, alkoxy radical , acyloxy, cycloalkyloxy, aroxy, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, alkylcarbamoyl, alkylkrybyl, carboyl, carboxycarbon  EMI241.4  arylsulfonylcarbamoyl, alkylsulfonylthiocarbamoyl, arylsulfonylthiocarbamoyie, sulfamoyl, alkylsulfamoyl, dialkylsulfamoyl, alkoxythiocarbonyl, alkylideneamino, cycloalkylmethyleneamino,    arylmethyleneamino, heterocyclemethyleneamino or heterocyclic, optionally  <Desc / Clms Page number 242>    EMI242.1  Substituted R16, or a group of formula-N R17  EMI242.2  h d b'1 bl 1. ^ each R and R, may be the same or different, represents a hydrogen atom or an alkyl radical or else R16 and R17 can form a ring with the nitrogen atom which is adjacent to them;  EMI242.3  . 7 8 9 10 11 12 each of the substituents R, R, R, Ruz Ruz Riz 14 16, ^ 'd'd'ff' R and R, may be the same or different, represents a hydrogen or halogen atom or a radical 1 3 alkyl, aralkyl or aryl. optionally substituted;  R represents a hydrogen or halogen atom, a carboxyl, sulfo, carbamoyl or thiocarbamoyl group, or else an alkyl, aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxy- radical.  EMI242.4  carbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocycle-sulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, acylcarbamoyloybyloybylonylcarbylonylcarbyloyl,  EMI242.5  optionally R represents a hydrogen atom 7 R or an alkoxy radical;  R represents a  EMI242.6  amino group, a group of formula R31 C-C-NHR "R 31 32 33 in which each of the substituents R, R and R, which may be identical or different, represents an atom  EMI242.7  of hydrogen or an organic residue, or else a group of  EMI242.8  R34 formula which each of the substituents ruz R  <Desc / Clms Page number 243>   R34 R and R which may be the same or different, represent a hydrogen atom or an organic residue.  43. 7- (optionally substituted amino) - 3-methyl-substituted-A-cephem-4-carboxylic acid or salt thereof according to claim 42, in the formula of which R3 is a hydrogen atom.  44. Acid 7- (optionally substituted amino) -3-  EMI243.1  methyl or a salt thereof according to claim 43, in the formula of which 28. R is an amino group. 45. Acid 7- optionally substituted) -3methyl or a salt thereof according to claim 44, in the formula of which R is  EMI243.2  a group of formula 0 0 H -  EMI243.3  in which has the same definition as in claim 42.  46. 7- (optionally substituted amino) -3methyl substituted- # 3-cephem-4-carboxylic acid or salt thereof according to claim 45, in the formula of which  EMI243.4  is a hydrogen atom, a heterocyclic radical or an alkyl, aralkyl or cycloalkyl radical)  EMI243.5  Substituted R16, or a group of formula-N "" -  EMI243.6  in which R have the same definitions as in claim 42.  47. Acid 7- (optionally substituted amino) -3-  EMI243.7  methyl or a salt thereof according to claim 46, in the formula of which is a dialkylamino radical or a hydrogen atom, or else an alkyl, aralkyl or cycloalkyl radical optionally substituted by an alkanoyloxy group or  <Desc / Clms Page number 244>    EMI244.1  ¯ carboxyl or a group of formula '\ Y 24 0 in which R24 represents an alkyl radical  EMI244.2  48. Acid 7- optionally substituted) -3methyl 3-cephem-4-carboxylic or salt thereof according to claim 45, in the formula of which is a hydrogen atom or an alkyl, aralkyl or cycloalkyl radical, substituted, or a  EMI244.3  R group of formula 7  EMI244.4  the same definitions as in claim 42. 49. Acid 7- optionally substituted) -3methyl or salt thereof according to claim 48, in the formula of which is a dialkylamino group or a hydrogen atom, or an alkyl, aralkyl or cycloalkyl radical optionally substituted by an acyloxy radical. 50. Acid (optionally substituted 7-aminoE9-3methyl or salt thereof according to claim 44, in the formula of which R is  EMI244.5  R7 a group of formula 'o o n  EMI244.6  the same definitions as in claim 42. 51. Acid 7- optionally substituted) -3methyl or a salt thereof according to claim 50, in the formula of which each - substituents R and R, which may be identical or different, is a hydrogen atom or an alkyl radical. 52. Acid 7- optionally substituted) -3methyl or a salt thereof according to claim 44, in the formula of which R2  <Desc / Clms Page number 245>    EMI245.1  U is a group of formula RIO-N \ o  EMI245.2  d l 11 10 R11 t R12 l d'f '"in have the same definitions as in claim 42. 53. Acid 7- optionally substituted) -3methyl or a salt thereof according to claim 52, in the formula of which h d b. 10 11 t R12. , RetR, may be the same or different, is a hydrogen or halogen atom or an alkyl radical. 54. Acid 7- optionally substituted) -3methyl or a salt thereof according to claim 44, in the formula of which  EMI245.3  R2 is a group of formula R NrR l = R14 -N R "o  EMI245.4  13 14 15 wherein and have the same definitions as in claim 42. 55. Acid 7- optionally substituted) -3methyl or a salt thereof according to claim 54, in the formula of which h d b. 13 R14 R1S. ^ and R, may be the same or different, is a hydrogen atom or an alkyl radical. 56. Process for the preparation of an optionally carboxylic acid 7- represented by the following formula, or of a salt thereof:  <Desc / Clms Page number 246>    EMI246.1    EMI246.2  formula in which a hydrogen atom or a protecting group for the carboxyl function; R2 represents a group of formula:  EMI246.3  0 HG VN -N N-R, 10- '==' - N9 1 12 OU - Y., - "- r o l 0;  Ê-Nl CR'5 0  EMI246.4  where represents a hydrogen atom, a hydroxyl, nitro, carbamoyl, thiocarbamoyl or sulfamoyl group, or an alkyl, alkenyl, alkynyl, alkadienyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl, aralkyl, acyl, alkoxy, alkylthio radical cycloalkyloxy, aryloxy, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclic sulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, acylcarbamoyl, acylthiocarbamoyle, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, alkylsulfonylthiocarbamoyle, arylsulfonylthiocarbamoyle, alkylsulfamoyl, dialkylsulfamoyl, alkoxythiocarbonyl, amino, arylmethyleneamino, heterocycle-methyleneamino or heterocyclic, optionally substituted,  or a  EMI246.5  R group of formula-N where each of the substituents  EMI246.6  16-1 / zo and which may be identical or different, represents a hydrogen atom or an alkyl radical, or 1 C 1'7 well R16 and R17 can form a ring with the atom  <Desc / Clms Page number 247>    EMI247.1  nitrogen adjacent to them; each of the substituents 7 8 9 10 11 12 14 15. ^ R, R, R, R, R, R, and R, which may be the same or different, represents a hydrogen or halogen atom or an alkyl radical , aralkyl or optionally substituted aryl;  R13 represents a hydrogen or halogen atom, a carboxyl, sulfo, carbamoyl or thiocarbamoyl group, or else an alkyl, aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, arylyloxycarbonyl, alkylsulfonyl radical arylsulfonyl, heterocycle-sulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoyl, acylcarbamoyl, acylthiocarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyylylsulfonyl  EMI247.2  optionally substituted; represents a hydrogen atom or an alkoxy radical;  R28 represents a  EMI247.3  amino group, a group of formula 31 C = C-NHR33 R  EMI247.4  31 32 33 in which each of the substituents and R33, which may be identical or different, represents a hydrogen atom or an organic residue not participating in the reaction, or else a group of formula  EMI247.5  R34 - which each of the substituents R34 and R35  EMI247.6  R, which may be identical 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 of this one :  <Desc / Clms Page number 248>    EMI248.1  formula in which R3 and R28 have the same definitions as above;  R29 represents an acyloxy radical or  EMI248.2  carbamoyloxy, substituted; and Z represents 1- / S with a compound of formula:  EMI248.3    EMI248.4  1 z li 14 1 1-) where R,, have the same definitions as above, or with a salt thereof, in the presence of an acid or an acid complex compound, then, if applicable if necessary, to remove the protective group, to protect the carboxyl group or to transform the product into a salt thereof.  57. Process for the preparation of a 7- (optionally substituted amino) -3-methylsubstituted-A-cephem-4-carboxylic acid or a salt thereof according to claim 56, characterized in that R3 is an atom hydrogen.  58. Process for the preparation of a 7- (optionally substituted amino) -3-methyl-substituted 3- # cephem-4-carboxylic acid or a salt thereof according to claim 57, characterized in that said acid or said complex acid compound is a Lewis acid or a complex compound of a Lewis acid.  59. Process for the preparation of an acid 7-  EMI248.5  (optionally substituted amino) -3-methyl-substituted-3-cephem-4-carboxylic or a salt thereof according to claim 58, characterized in that said Lewis acid or said complex complex of Lewis acid is boron trifluoride or a complex compound of this  <Desc / Clms Page number 249>    EMI249.1  latest. 60. Process for the preparation of an optionally cephem-4-carboxylic acid 7- or a salt thereof according to any one of claims 56 to 59, characterized in that the reaction is carried out in the presence of an organic solvent.  EMI249.2   61. Process for preparing an optionally carboxylic acid 7- or a salt thereof according to claim 60, characterized in that said organic solvent is an organic carboxylic acid, an ester, a nitroalkane or a sulfolane.  62. Process for the preparation of an acid 7-  EMI249.3  (optionally substituted amino) -3-methyl-substituted-cephem-4-carboxylic or a salt thereof according to any one of claims 56 to 61, characterized 29 in that R is a radical 63. Process for preparation of a 7- (optionally substituted amino) -3-methyl-substituted acid or a salt thereof according to acetoxy.Any of claims 56 to 62, characterized in that the reaction is carried out at a temperature from OOC to 80 C.  64. Pharmaceutical composition which can be used for the treatment of bacterial infections in humans and animals, characterized in that it comprises an antibacterial amount of a cephalosporin or of a pharmaceutically acceptable salt thereof according to the any of claims 1 to 32, in association with an inert diluent or a pharmaceutically acceptable carrier.