NL8303955A - NEW CEPHALOSPORINES, METHODS FOR PREPARING THEM, ANTIBACTERIALS CONTAINING THEM, THEIR INTERMEDIATES AND METHOD FOR PREPARING THE INTERMEDIATES. - Google Patents

Description

- 1 -

Reg.No.120.030 / Bnt / JvdB

Novel cephalosporins, methods of preparation thereof, antibacterial agents containing them, intermediates thereof and method of preparation of the intermediates.

The invention relates to new cephalosporins, methods of preparing said cephalosporins, an antibacterial agent containing said cephalosporins, intermediates for preparing said cephalosporins and a method of preparing said intermediates.

The present inventors have conducted investigations to find compounds with a broad anti-bacterial spectrum, which exhibit excellent anti-bacterial activity with respect to gram-positive and gram-negative bacteria, which are stable against 0-lactase produced by bacteria, have a low toxicity, and at the same time are well absorbable by oral or parenteral route of administration and which have an excellent therapeutic effect on human and animal diseases. As a result, new cephalosporins were found to be characterized in that an unsubstituted or substituted 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl, 2-oxo 1,2-dihydropyrazinyl, 3,6-dioxo 1,2, 3,6-tetrahydropyridazinyl or 6-oxo 1,6-dihydropyridazinyl 20 is attached to the exomethylene group at the 3-position of the W ring by a carbon nitrogen bond and the group of the formula 20 wherein A, R and having the meaning mentioned below associated with the amino group in the 7-position have the above excellent properties.

It is an object of the invention to provide new cephalosporins with the above chemical structural characteristics and with a broad antibacterial spectrum, which are stable against 0-lactamase produced by bacteria, have a low toxicity, and are well absorbed at oral or parenteral administration, and which have an excellent therapeutic effect on the diseases 83 0 3 95 5

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- 2 - of humans and animals.

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

It is a further object of the invention to provide an antibacterial agent containing said cephalosporins.

It is a still further object of the invention to provide intermediates for the preparation of said new cephalosporins and to provide a process for the preparation of said intermediates.

Other objects and advantages of the invention will become apparent from the following

i J

scraping.

According to the invention there is provided a new cephalosporin, in particular a cephalosporin represented by the formula 1 or a salt thereof, wherein R 1 represents a hydrogen atom or a carboxyl protecting group and a group of the formulas 23-26 wherein 20 Rg a hydrogen atom, a hydroxyl group, a nitro group, a carbamyl group, a thiocarbamyl group, a sulfamyl group or an unsubstituted or substituted alkyl, alkenyl, alkynyl, alka-dienyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl, aralkyl, acyl, alkoxy, alkylthio, acylthio , cycloalkyloxy, 25, aryloxy, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycar- v ~ y carbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclic sulfonyl, alkylcarbamoyl, dialkylcarbamoyl, alkylthiocarbamoyl, dialkylthiocarbamoy1, acylcarbamoyl, acylthiocarbamoyl, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl 30, alkylsulfonylthiocarbamoyl, arylsulfo- of CH₃CN , alkylsulfamoyl, dialkylsulfamoyl, alko xythiocarbonyl, alkylideneamino, cycloalkylmethyleneamino, arylmethyleneamino, heterocyclic methyleneamino or heterocyclic group, or a group of formula 27 (wherein R ^ g 35 and R17, which may be the same or different, represent a hydrogen atom or an alkyl group or together with their adjacent 8303955

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9 t-3-sending nitrogen atom may form a ring) and each of the groups R7-12, R14 and Risf or may be different, a hydrogen atom, a halogen atom or an unsubstituted or substituted alkyl, aralkyl or aryl group; R13 a hydrogen atom, halogen atom, a carboxyl, sulfo, carbamyl or thiocarbamyl group, or an unsubstituted or substituted alkyl, aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxycarbonyl, cycloalkyl loxycarbonyl, acyloxycarbonyl, aralkyloxyl carbonyl, alkyl , arylsulfonyl, heterocyclic sulfonyl, alkylcarbamoyl, dialkylcarbamyl, alkylthiocarbamyl, dialkylthiocarbamyl, acylcarbamyl, acylthiocarbamyl, alkylsulfonylcarbamyl, arylsulfonylcarbamyl, alkylsulfonylthylsulfonyl R-, a hydrogen-

O

atom or an alkoxy group; R ^ a hydrogen atom or a halogen atom; R_ a hydrogen atom or an optionally protected amino group; and A represents a group of the formula -Cf ^ - or a group of the formula 21, wherein R ^ g is hydrogen, an unsubstituted or substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, heterocyclic group, or 20 a hydroxyl protecting group; or a group of formula 22 (wherein R Ώ and R _, which may be the same or different, xy zu represent a hydroxy, alkyl, aralkyl, aryl, alkoxy, aralkyloxy or aryloxy group) and the bond means that the compound is a syn isomer or an anti isomer or a mixture thereof.

The invention also provides an "o?" a method of preparing said cephalosporins or salts thereof, an antibacterial agent containing said cephalosporins, intermediates for preparing said cephalosporins, and a method of preparing said intermediates.

The invention will be further illustrated in detail below.

Unless otherwise indicated, the term "alkyl" is taken to mean a straight or branched chain alkyl group including, for example, methyl, ethyl, n-propyl, 8303955

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t - 4 - isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, hexyl, heptyl, octyl, dodecyl, lauryl and the like; under the term "alkoxy" the -O-alkyl group, wherein the alkyl is as defined above? the term "lower alkyl" is a straight or branched chain alkyl including, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, pentyl and the like; under the term "lower alkoxy" the -O-lower alkyl group, wherein the lower alkyl is as defined above, the term "acyl" a formyl-10 group, a 2-5 alkanoyl group including, for example, acetyl, propionyl, isovaleryl, pivaloyl, pentanecarbonyl and the like; a C 1-4 cycloalkanecarbonyl group including, for example, cyclopentylcarbonyl, cyclohexylcarbonyl and the like; an aroyl group including, for example, benzoyl, toluyl, 2-naphthyl and the like; and a heterocyclic carbonyl group including, for example, thenyl, 3-furoyl, nicotinyl and the like, the term "acyloxy" the -O-acyl group, wherein the acyl has the meaning previously given; the term "alkylthio" means the -S-alkyl group, wherein the alkyl has the previously given meaning; the term "alkenyl" means an alkenyl including, for example, vinyl, allyl, isopropenyl, 2-pentenyl, butenyl and the like; the term "alkynyl" means the alkynyl group including, for example, ethynyl, 2-propynyl and the like; the term "cycloalkyl" means a 7 cycloalkyl including, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl) and the like; the term "alkadienyl" means an alkadienyl including, for example, 1,3-butadienyl, 1,4-hexadienyl and the like; the term "cycloalkenyl" means a C 1-7 cycloalkenyl group including, for example, cyclopentenyl, cyclohexenyl and the like; the term "cycloalkadienyl" means a C 1-4, cycloalkadienyl including, for example, cyclopentadienyl, cyclohexadienyl and the like; the term "aryl", for example, phenyl, naphthyl, indanyl and the like; the term "aralkyl" for example benzyl, phenethyl, 4-methylbenzyl, naphthylmethyl and the like; the term "hetero-35 cyclic group" means a heterocyclic with at least one heteroatom selected from oxygen, nitrogen and sulfur including at 83u 3 9 5 5

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- 5 - example furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazoly1, oxadiazolyl, thiatriazolyl, oxatriazolyl, triazolyl, tetrazolyl, pyridyl, 5- (5-methyl) 4- (2-pyrrolinyl), 5 N-methylpiperidinyl, quinolyl, phenazinyl, 1,3-benzodioxalanyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, phthalydyl, cumarinyl and the like; the term "heterocyclic alkyl" means a group consisting of the above-mentioned heterocyclic group and the above-defined alkyl group, and the term "halogen atom" means, for example, fluorine, chlorine, bromine or iodine.

The symbol in the formulas in this description represents a hydrogen atom or a carboxyl protecting group, including those commonly used in the field of the penicillins and cephalosporins, for example an ester-forming group, which may be removed by a catalytic hydrogenation, chemical reduction, or treatment under other mild conditions; an ester-forming group that can be easily removed in the living body; or an organic silyl-containing group, an organic phosphorus-containing group, or an organic tin-containing group and the like, which can be easily removed when treated with water or an alcohol; and other various well-known ester-forming groups.

These protecting groups preferably include groups as follows; (a) alkyl groups, for example, C 1-4 alkyl, (b) substituted lower alkyl groups, wherein at least one of the substituents is selected from a halogen atom or a nitro, acyl, alkoxy, oxo, cyano, hydroxyl, cycloalkyl, aryl, alkylthio, alkylsulfinyl , alkylsulfony1, alkoxycarbonyl, 5-alkyl-2-oxo-1,3-dioxol-4-yl, 1-indanyl, 2-indanyl, furyl, pyridyl, 4-imidazolyl, phthalimido, succinimido, azethidino, aziridino, pyrrolidino, piperidino , 35 morpholino, thiomorpholino, N-lower-alkylpiperazino, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 8 3 0 3 9 5 5

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* - 6 - thiadiazolyl, oxadiazolyl, thiatriazolyl, oxatriazolyl, triazolyl, tetrazolyl, quinolyl, phenazinyl, benzofuryl, benzothienyl, benzoxazoly1, benzothiazolyl, cumarinyl, 2,5-dimethylpyrrolidino, 1,4,5,6-methyl-tetrahydropyrimino , 2,6-dimethylpiperidino, 4- (5-methyl-2-pyrrolinyl), 4- (2-pyrrolinyl), N-methylpiperidinyl, 1,3-ben-zodioxolanyl, alkylamino, dialkylamino, acyloxy, acylthio, acylamino, dialkylaminocarbony1 , alkoxycarbonylamino, alkenyloxy, aryloxy, aralkyloxy, cycloalkyloxy, cycloalkenyl-10-oxy, heterocyclic oxy, alkoxycarbonyloxy, alkenyloxycarbonyl alkylcarbonyloxy, aryloxycarbonyloxy, aralkyloxycarbonyl, heterocyclic oxycarbonyloxy, alkenyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxy-carbonyl, heterocyclic oxycarbonyl or alkylanilinogroep 15 or an alkyl anilino group substituted by a halogen atom, a lower alkyl or lower alkoxy group, (c) cycloalkyl group; lower alkyl substituted cycloalkyl group or (2,2-di-lower alkyl 1,3-dioxol-4-yl) methyl groups, 20 (d) alkenyl groups; (e) alkynyl groups; (f) phenyl group; sili-substituted phenyl groups in which at least one of the substituents is selected from the substituents specifically mentioned under (b); or aryl groups such as groups represented by the formula 28, wherein -CH = CH-O-, -CH = CH-S-, -CH 2 CH 2 S-.

—CH = N — CH = N—, —CH = CH — CH = CH—, -CO-CH = CH-CO- or -CO-CO-CH = CH-, or a substituted derivative thereof, wherein the substituents are selected are those specifically mentioned under (b) 30 or groups represented by the formula 29, wherein "^ 2" is a lower alkylene group such as either - (CK ^) ^ - or a substituted derivative thereof, wherein the substituents are selected from those specifically mentioned under (b), (g) aralkyl groups such as benzyl 35 or substituted benzyl groups in which at least one of the substituents are selected from those specifically named 83 1) 3 95 5

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- 7 - ff are under (b) above, (h) heterocyclic group or substituted heterocyclic groups, wherein at least one of the substituents is selected from those specifically mentioned under (b) above, (i) indanyl or phthalidyl groups or substituted derivatives thereof, wherein the substituents are methyl or halogen; tetrahydronaphthyl groups or substituted derivatives thereof, wherein the substituents are methyl groups or halogens; trityl, cholesteryl, bicyclo / 4,4,0_7decyl and the like, (j} phthalidylidene-lower alkyl group)

Cpen or substituted derivatives thereof, wherein the substituents are halogens or lower alkyl groups. The above carboxyl protecting groups are typical examples, and the carboxyl protecting group may also be selected from the other protecting groups described in the following literature; U.S. Patents 3,499,909, 3,573,296 and 3,641,018; German patents 2,301,014, 2,253,287 and 2,337,105.

These carboxyl protecting groups preferably include diphenylmethyl, 5-lower alkyl 2-oxo 1,3-dioxol-4-yl lower alkyl groups, acyloxyalkyl groups, acylthioalkyl groups, phthalidyl group, the indanyl group, phenyl-25 group, substituted or unsubstituted phthalidylidene lower alkyl - groups or those groups which can be easily removed in a living body, such as groups represented by formulas 30, 31 and 32, wherein a known substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group; a hydrogen atom or a known unsubstituted or substituted alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group; R22 is a hydrogen atom, a halogen atom, or a known unsubstituted or substituted alkyl, cycloalkyl, aryl, or heterocyclic group, or - (C 1 ^) nC00R2 ^ (where R22 has the same meaning as previously given, and n represents 0, 1, or 2) and m 0, 1 or 2 8 3 υ 3 9 5 5

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* - 8 -% represents.

More specifically, one can use 5-lower alkyl 2-oxo 1,3-dioxol-4-yl-methyl groups such as 5-methyl 2-oxo 1,3-dioxol-4-yl-methyl, 5-ethyl 2-oxo 1, 3-di-5-oxol-4-yl-methyl, 5-propyl-2-oxo-1,3-dioxol-4-yl-methyl and the like; acyloxyalkyl groups such as acetoxymethyl, pivaloyl oxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryl oxymethyl, valeryloxymethyl, 1-acetoxyethyl, 1-acetoxy n-propyl, 1-pivaloyloxyethyl, 1-pivaloyloxy n-propyl and the like; Acylthioalkyl groups such as acetylthiomethyl, pivaloylthioethyl, benzoylthiomethyl, p-chlorobenzoylthiomethyl, 1-acetylthioethyl, 1-pivaloylthioethyl, 1-benzoylthioethyl, 1- (p-chlorobenzoylthio) ethyl and the like; alkoxymethyl groups such as methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxy-15 methyl, n-butyloxymethyl and the like; alkoxycarbonyloxyalkyl groups such as methoxycarbonyloxymethyl, ethoxycarbonyl-oxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxy-methyl, n-butoxycarbonyloxymethyl, tert-butoxycarbonyloxy-methyl, 1-methoxycarbonyloxyloxy-1-oxoxloxy-methyl, 1-methoxycarbonyloxyethyl, 1 tert-butoxycarbonyloxyethyl, 1-n-butoxycarbonyloxyethyl and the like; alkoxycarbonylmethyl groups such as methoxycarbonylmethyl, ethoxycarbonylmethyl and the like; phalidyl group; indanyl group; phenyl group; phthalidylidene-25 alkyl groups such as 2- (phthalidylidene) ethyl, 2- (5-fluorophthalidylidene) ethyl, 2- (6-chlorophthalidylidene) ethyl, 2- (6-methoxy-phthalidylidene) ethyl and the like, etc.

1 * 2 represents a group of formulas 23-26, wherein represents a hydrogen atom, a hydroxyl group, nitro group, carbamoyl group, thiocarbamyl group, sulfamyl group, or an unsubstituted or substituted alkyl, alkenyl, alkynyl, alkadienyl, cycloalkyl, cycloalkenyl , cycloalkadienyl, aryl, aralkyl, acyl, alkoxy, alkylthio, acyloxy, cycloalkyloxy, aryloxy, alkoxycarbonyl, cycloalkyloxycarbonyl, 35 acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, OR3alkylsulfonyl, heterocyclicl - carbamyl, dialkylcarbamyl, alkylthiocarbamyl, dialkylthio-carbamyl, acylcarbamyl, acylthiocarbamyl, alkylsulfonyl-carbamyl, arylsulfonylcarbamyl, alkylsulfonylthiocarbamy1, arylsulfonylthiocarbamyl, alkylsulfamyl, dialkylsulfamyl, 5 alkoxythiocarbonyl, alkylideenamino, cycloalkylmethyleenamino, arylmethyleneamino, heterocyclic methyleneamino or heterocyclic group; a group of formula 27 (wherein each of the groups R ^ g and R ^, which may be the same or different, represent a hydrogen atom or an alkyl group, or Rj.g and form a ring together with their adjacent nitrogen atom), each of the groups R7-12 * ^ and ^ 5 »which may be the same or different, a hydrogen atom, a halogen atom, or an unsubstituted or substituted alkyl, aralkyl or aryl group; R ^ a hydrogen atom, a halogen atom, a carboxyl group, a sulfo group, a carbamyl group, a thio-carbamyl group, or an unsubstituted or substituted alkyl, aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxycarbonyl, cycloalkylcarbonyl, acyloxycarbonyl, aralkyloxycarbonyl , alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclic sulfonyl, alkylcarbamyl, dialkylcarbamyl, alkylthiocarbamyl, dialkylthiocarbamyl, acylcarbamylsulfonylcarbamyl, arylsulfonyl, arylsulfyl, arylsulfyl In each of the groups

for R. and R. mentioned above, the term o means IJ

"Cycloalkyloxy" the group -O-cycloalkyl, the term "aryloxy" means -O-aryl, the term "alkoxycarbonyl" has the formula 33, the term "cycloalkyloxycarbonyl" has the formula 34, the term "acyloxycarbonyl" has formula 35, the term "aralkyloxycarbonyl" has the formula 36, the term "alkylsulfonyl" means -SO 2 ~ alkyl, the term "cycloalkylsulfonyl" means -SO 2 ~ cycloalkyl, the term "arylsulfonyl" means -SO 2 ~ aryl, the term "heterocyclic sulfonyl" means -SC 1 -heterocyclic ring, the term "alkylcarbamyl" has the formula 37, the term "dialkylcarbamyl" has the formula 38, the term "alkylthio-35 carbamyl" has the formula 39, the the term "dialkylthiocarbamyl" has the formula 40, the term "acylcarbamyl" has the formula 8303955

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- 10 - 41, the term "acylthiocarbamyl" has the formula 42, the term "alkylsulfonylcarbamyl" has the formula 43, the term "aryl-sulfonylcarbamyl" has the formula 44, the term "alkylsulfonyl-thiocarbamyl" has the formula 45, the term "arylsulfonylthio-5 carbamyl" has the formula 46, the term "alkylsulfamyl" has the formula -SO 2 -NH-alkyl, the term "dialkylsulfamyl" has the formula 47, the term "alkoxythiocarbonyl" has the formula 48, the term "alkylideneamino" means -N = CH-alkyl, the term "cycloalkylmethyleneamino" means -N = CH-cycloalkyl, the term "arylmethyleneamino" means -N = CH-aryl, and the term "heterocyclic methyleneamino" means - N = CH heterocyclic ring.

The groups of formula 27, wherein Rg and Rg have the meanings given previously, include the amino group, alkylamino groups represented by -NH-alkyl, dialkylamino groups represented by the formula 49, and groups represented by the formulas 50-63 .

The substituents for the various groups mentioned above include halogen atoms, alkyl-20 groups, aralkyl groups, aryl groups, alkenyl groups, hydroxy groups, oxo groups, alkoxy groups, alkylthio groups, the nitro group, cyano group, amino group, acyl groups, acyloxy groups, the carboxyl group, carbamyl group, sulfo group , sulfa-myl group, alkylamino groups represented by -NH-alkyl, dialkylamino groups represented by formula 49, acyl amino groups represented by -NH-acyl, alkoxycarbonyl groups represented by formula 33, acylalkyl groups such as acetylmethyl, propionylmethyl and the like, aminoalkyl groups such as aminomethyl, aminoethyl and the like, N-alkyΙ-ΒΟ aminoalkyl groups such as N-methylaminomethyl, N-methylaminoethyl and the like, Ν, dial-dialkylaminoalkyl groups such as N, N-dimethylaminomethyl, Ν, Ν-dimethylaminoethyl and the like, hydroxyalkyl groups such as hydroxymethyl, hydroxyethyl and the like, hydroxyiminoalkyl groups such as hydroxyiminomethyl, hydroxyi minoethyl and the like, alkoxyalkyl groups such as methoxymethyl, raethoxyethyl, ethoxymethyl, ethoxyethyl and the like, carboxyalkyl groups such as carboxymethyl, carboxyethyl 83 9 5 5

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3-such, alkoxycarbonylalkyl groups such as methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl and the like, aralkyloxycarbonylalkyl groups such as benzyloxycarbonylmethyl, benzyloxycarbonyl-5-ethyl, sulfoethyl, sulfethyl, sulfylethyl, such as sulfomethyl such carbamylalkyl groups such as carbamylmethyl, carbamylethyl and the like, carbamylalkenyl groups such as carbamylallyl and the like, N-hydroxy-10 carbamylalkyl groups such as N-hydroxycarbamylmethyl, N-hydroxycarbamylethyl and the like, a group of the formula 64 wherein R 1 has a lower alkyl radical etc. The above-mentioned different groups Rg-g may be substituted by at least one of the above substituents. Among the above substituents, the hydroxyl group, the amino group and the carbonyl group may be protected by a suitable protecting group, which is usually available in the art. The hydroxyl protecting groups include all the hydroxyl protecting groups, which can usually be used, such as easily removable acyl groups, eg benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzzyloxycarbonyl, 4-methoxybenzyloxycarbonyl> 3,4-dimethoxy-benzyloxycarbonyl, 4- ( phenylazo) benzyloxycarbonyl, 4- (4-methoxy-phenylazo) benzyloxycarbonyl, tert.-butoxycarbony1, 1,1-dimethyl-25 propoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, (^) 2,2,2-trichloroethoxycarbonyl, 2,2,2- tribromoethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, 1-cyclopropyl-ethoxycarbonyl, 8-quinolyloxycarbonyl, formyl, acetyl, chloroacetyl, benzoyl, trifluoroacetyl and the like; alkyl sulfonyl groups, for example, methanesulfonyl, ethanesulfonyl and the like; arylsulfonyl groups, for example phenylsulfonyl, toluene sulfonyl and the like; benzyl group; diphenylmethyl group; trityl group; methoxymethyl group; tetrahydropyranyl group; tetrahydrofuranyl group; 2-nitrophenylthio group; 2,4-dinitrophenylthio-35 group; and such.

In addition, it falls under amino-8303955

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protecting groups all commonly used amino protecting groups such as easily removable acyl groups e.g. 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxy-carbonyl, benzyloxycarbony1, p-toluenesulfonyl, 4-nitro-5-benzyloxycarbonyl, 2 bromobenzzyloxycarbonyl, acetyl, (mono-, di-tri) -chloroacetyl, trifluoroacetyl, formyl, tert-amyloxy-carbonyl, tert-butoxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) -benzyloxycarbonyl 4- (4-methoxyphenylazo) benzyloxycarbonyl, pyridin-1-oxide-10 2-yl-methoxycarbonyl, 2-furyloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 1-cyclopropylethoxycarbonyl, phthaloyl, succinyl, 1-adamant oxycarbonyl, 8-quinolyloxycarbonyl and the like; further readily removable groups, for example, trityl, 15-nitrophenylsulfonyl, 2,4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy 1-naphthylmethylene, 3-hydroxy 4-pyridylmethylene, 1- methoxycarbonyl 2-propylidene, 1-ethoxycarbonyl 2-propylidene, 3-ethoxycarbonyl-2-butylidene, 1-acetyl 2-propylidene, 1-benzoyl 2-propylidene, 20 1- / N - (2-methoxyphenyl) carbamyl / 2- propylidene, 1- / N- (4-methoxyphenyl) carbamyl-2-propylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl 5-oxocyclohexylidene, 4-nitrofurfurylidene and of such; di- or tri-alkylsilyl group; and the like. Then the carboxyl protecting groups include all commonly used carbonyl protecting groups and there are cases where the carboxyl group is protected by such a group as methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, benzyl, diphenylmethyl, trilyl, 4-nitro-30 benzyl, 4-methoxybenzyl, benzoylmethyl, acetylmethyl, 4-nitro-benzoylmethyl, p-bromobenzoylmethyl1,4-methanesulfonylbenzoyl-methyl, phthalimidomethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2 -propenyl, 1,1-dimethylpropy1, acetoxymethyl, propionyloxy-methyl, pivaloyloxymethyl, 3-methyl 3-butynyl, succinimido-35 methyl, 1-cyclopropylethyl, methylthiomethyl, phenylthiomethyl, dimethylaminomethyl, quinoline-1-oxide, 2-ylmethyl 1-oxide-2-ylmethyl, bis (p-methoxyphenyl) methyl and the like, 8303955

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12a / r in which the carboxyl group is protected by a non-metal compound, such as titanium tetrachloride, and in which the carboxyl group is protected by a silyl group such as dimethylchlorosilane as described in Japanese patent application no.

5 7073/71 and Dutch patent application 71.05259.

Rj represents a hydrogen atom or an amino group protected or unprotected, and such amino protecting groups include many groups commonly used in the field of the penicillins and cephalo-10 sporines, specifically all of the amino protecting groups mentioned above for A represents a group of the fromule -CEL- or a group of the formula 21, wherein R is a hydrogen atom, an unsubstituted or substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, heterocyclic group or a hydroxyl protecting group, or a group of the formula (wherein each of the groups Rg and which may be the same or different is a hydroxyl, alkyl, aralkyl, aryl, alkoxy, aralkyloxy or aryloxy group) and the bond means that the compound may be a syn isomer or an anti isomer or a mixture thereof. The said hydroxyl protecting group includes the hydroxyl protecting groups mentioned for R1. In addition, the above different groups for R 1 may be substituted by at least one substituent selected from halogen atoms, the oxo group, O cyano group, hydroxyl group, alkoxy groups, amino group, alkyl amino groups, dialkylamino groups, heterocyclic groups and groups of the formulas 65-67 wherein has the same meaning as defined above and any of the groups R25-27 '30 which may be the same or different represent a hydrogen atom, an alkyl group, an aralkyl group or an aryl group. Among these substituents, the hydroxyl group, the amino group, and the carboxyl group may be protected by the carboxyl protecting group and the amino protecting group designated for R 1 and the carboxyl protecting group designated for R 1, respectively.

8303955

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v.

V

- 13 -

The oximes of the formula 21 include syn and anti isomers and mixtures thereof.

Formula 68 includes tautomers, as shown in Scheme A, in which a protected or unprotected amino group is included, and such tautomers are also included in this invention, wherein R 4 and R 1 have the same meanings as defined above and R , -a represents an optionally protected imino group. In these formulas, the imino protecting group for Rα includes those groups used in the penicillins and cephalosporins field, and specifically the same groups as the monovalent groups among the amino protecting groups mentioned above for Θ v

When the -CH2R2_group in formula 1 is a group of formula 69 or 70, where R ^, R ^ q, R ^ and R have the meanings given previously, there are tautomers as shown in schemes B and C, wherein Rg and Rg are hydrogen atoms, and these tautomers are also included in the invention.

The salts of formula 1 include salts to the basic group and the acid group, which are well known in the art of the penicillins and cephalosporins. The basic group salts include salts with mineral acids such as hydrochloric, nitric, sulfuric and the like; Salts with organic carboxylic acids, such as oxalic acid, hamstone; acid, formic acid, trichloroacetic acid, trifluoroacetic acid and the like; and salts with sulfuric acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluene 2-sulfonic acid, toluene 4-sulfonic acid, mesitylene sulfonic acid (2,4,6-trimethyl-30 benzenesulfonic acid), naphthalene 1-sulfonic acid, naphthalene 2-sulfonic acid, phenylmethanesulfonic acid, benzene 1,3-disulfonic acid, toluene 3,5-disulfonic acid, naphthalene 1,5-disulfonic acid, naphthalene 2,6-disulfonic acid, naphthalene 2,7-disulfonic acid, benzene-1,3,5-trisulfonic acid, benzene 1,2,4 trisulfonic acid, naphthalene 1,3,5,5-trisulfonic acid and the like. The salts on the acid group include salts with alkali metals, such as with sodium, 8303955

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J

- 14 - t potassium and the like; salts with alkaline earth metals, such as calcium, magnesium and the like; ammonium salts; and salts with nitrogen-containing organic bases, such as procaine, dibenzylamine, N-benzyl β-phenethylamine, 1-ephenamine, 5 Ν, Ν-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, Ν, Ν-dimethylaminiline, N-methyl N-methylmorpholine, diethylamine, dicyclohexylamine and the like.

This invention also includes all optical isomers and the racemic compounds of cephalosporins of the formula 1 and their salts, and also all crystal forms and hydrates of said compounds. More specifically, preferred examples of the compounds represented by the formula 1 are oximes, wherein A is a group of the formula 21, especially its syn isomers, wherein R 1 is preferably an alkyl group, especially methyl, ethyl or a substituted alkyl group, especially -CH 2 COOR 2 or of the formula 71 (wherein R 2 has the same meaning as defined above).

Preferred examples of R 2 are groups of the formula 23, wherein R 1 is a hydrogen atom, an unsubstituted or substituted alkyl group or a group of the formula 27 (wherein R 1 and R have the same meanings as given previously); groups of the formula 24, wherein each of the 25 groups R, which may be the same or different, represent a hydrogen atom or an alkyl group; groups of the formula 25, wherein each of the groups r ^ q_ ^ 2 'which may be the same or different represents a hydrogen atom, a halogen atom or an alkyl group; and groups of the formula * 26 wherein each of the substituents R 2 which may be the same or different represent a hydrogen atom or an alkyl group.

Next, pharmacological effects of some typical compounds represented by the formula 1 will be shown.

1) Antibacterial activity (Table A) 83 Ü 3 9 5 5

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Η - 15 -

According to the standard method of Japan Society of Chemotherapy / "Chemotherapy", Vol. 23, pp. 1-2 (1975), a bacterial solution obtained by cultivation in heart infusion broth (manufactured by 5 Oak Kagaku) at 37 ° C for 20 hours is inoculated. on a cardiac infusion agar containing a drug and cultivated at 37 ° C for 20 hours after which the growth of the bacteria is observed to determine the minimum concentration inhibiting the growth of the bacteria as MIC (ig / ml) The amount of the inoculated bacteria is 10 ^ cells per plate 6 (10 cells per ml) The MIC values of the following test compounds are as shown in Table A: ^ (A) trifluoroacetic acid salt of 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamido / 3- {/ 1-15 (2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) 7methyl} A3-cephem-4- carboxylic acid, (B) trifluoroacetic acid salt of 7- / 2— (2-aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamido / 3- {/ 1— (4-methyl 2,3-dioxo-1,2,3 , 4-tetrahydropyrazinyl) / methyl} Δ3-20 cefem 4-carboxylic acid, (C) trifluoroacetic acid salt of 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamido_ / 3- {/ 1— (4-ethyl 2,3) -dioxo 1,2,3,4-tetrahydropyrazinyl) _7methyl} Δ3-cephem 4-carboxylic acid, 25 (D) trifluoroacetic acid salt of 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamido / 3 - {_ / 1 - (4-isopropyl 2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) _ / methyl} -Δ3-cephem 4-carboxylic acid, (E) trifluoroacetic acid salt of 7- / 2— (2 - 30 aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamido / 3- {/ 1- (4-dimethylamino 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) / methyl} -Δ3-cephem 4- carboxylic acid, (F) 7- / 2- (2-aminothiazol-4-yl) 2- (syn) - carboxymethoxyiminoacetamido ^ / 3- {/ 1- (2,3-dioxo 1,2,3,4-tetrahydropyrazinyl_) / methyl} A3-ce'f em 4-carboxylic acid, (G) trifluoroacetic acid salt of 7- / 2- (2- 8303955

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/ - 16 - aminothiazol-4-yl) 2- (syn) -carboxymethoxyiminoacetamido 7 3 - {/ 1- (4-methyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) 7-methyl} Δ3-cephem 4-carboxylic acid, (H) trifluoroacetic acid salt of 7- / ~ 2- (2-aminothiazol-4-yl) 2- (syn) -carboxymethoxyiminoacetamido / 3- {/ 1- (4-ethyl-2,3-dioxo) -1,2,3,4-tetrahydropyrazinyl) / -methyl} Δ3-cephem 4-carboxylic acid, (I) trifluoroacetic acid salt of 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -carboxymethoxyiminoacetamido _ / - 10 3- {/ 1- (4-dimethylamino 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) _7methyl} Δ3-cephem 4-carboxylic acid, (J) trifluoroacetic acid salt of 7- / 2- 9 (2- aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamido_7 3- {/ 1- (2-oxo-1,2-dihydropyrazinyl) _ / methyl} Δ3-cephem 4-carboxylic acid, 15 (K) trifluoroacetic acid salt of 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamido / 3- {/ 1- (3,6-dioxo-1,2,3,6-tetrahydropyridazinyl) _ / methyl} Δ3-cephem-4 -carboxylic acid, (L) Formic acid salt of 7- / 2- (2-amino-thiazol-4-yl) 2- (syn) -carboxymethoxyiminoacetamido / 3- {/ 1- (3,6-diox o 1,2,3,6-tetrahydropyridazinyl) 7methyl} Δ3-cephem 4-carboxylic acid, (M) trifluoroacetic acid salt of 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamido 7—3— {/ 1-25 (3-methyl-6-oxo-1,6-dihydropyridazinyl) _7methyl} Δ3-cephem 4-carboxylic acid and (N) Formic acid salt of 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -carboxymethoxyiminoacetamido 7 3- {/ 1- (3-30 methyl 6-oxo 1,6-dihydropyridazinyl) 7methyl} Δ3-cephem 4-carboxylic acid.

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v - 19 - 2) Recovery from the urine.

A test compound is administered orally to mice (ICR, male, 4 weeks old) at 1 mg per mouse and determine what is found in the urine. The results obtained are shown in Table B.

In test compounds No. 1 and No. 2, the ester group is easily removed in the living body, whereby the compounds are converted into the corresponding free carboxylic acids. Therefore, what is found in the urine is determined by quantitatively measuring the free carboxylic acids, which are excreted with the urine.

Method of administration: A test compound suspended in 0.5% CMC (carboxymethyl cellulose) is administered orally.

Quantitative Measurement Method: The amount of free carboxylic acid is measured by a bioassay (a paper disc method) using the test organism listed in Table B.

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•] t> - 21 - 3) Acute toxicity.

The LD ^ q values of the following test compounds were 3 g per kg or more when the compounds were administered intravenously to mice (ICR, 5 male, 20-24 g body weight).

Test connections:

Sodium 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -methoxyimino-acetamido / 3- {/ 1- (2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) / -methyl } A3-cephem 4-carboxylate, 10 Sodium 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamido_ / 3- {/ 1- (4-methyl 2,3-dioxo 1) 2,3,4-tetrahydropyrazinyl) / methyl} A3-cephem 4-carboxylate,

Sodium 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -methoxyimino-acetamido / 3- {/ 1- (3,6-dioxo 1,2,3,6-tetrahydropyridazinyl) / - Methyl} Δ3-cephem 4-carboxylate and

Sodium 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -methoxyimino-acetamido / 3- {/ 1- (3-methyl 6-oxo 1,6-dihydropyridazinyl) / -methyl} Δ3- cefem 4-carboxylate.

Next, an explanation will be given below of the production processes.

The compounds of the invention can be prepared according to product routes I and II of the formula sheet.

In the above formulas, Rjg, A and the bond ----- have the same meanings as defined above; R ^ g & represents the group for R ^ g except a hydrogen atom; R represents an amino group, or a group of formula 72, in which any Rg ^ gg, which may be the same or different, represent a hydrogen atom or an organic residue which does not participate in the reaction, or a group of formula 73 wherein each of the Rg4 and Rgg, which may be the same or different, represents a hydrogen atom or an organic residue that does not participate in the reaction; R 1 g represents an unsubstituted or substituted acyloxy or carbamyloxy group; R benzyl, phenoxymethyl or a group of the formula 100, wherein R ^, Rg and A are the previously given 8303955

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- 22 - have meaning, X represents a halogen atom,> Z> S.or> S-> 0; and the dotted line in the ring represents a double bond between the 2 and 3 position or the 3 and 4 position.

A further detailed explanation 5 will be given below. Rg represents an amino group, a group of the formula 72 or a group of the formula 73, and the group of the formula 72 includes the group of the formula 74, which is its isomer. The organic residues not participating in the reaction for ^ 5 include those well known in the art, especially substituted or unsubstituted the aliphatic radicals, alicyclic radicals, aromatic radicals, aromatic-aliphatic radicals, heterocyclic radicals, acyl groups and the like . More specifically, the following I 3 groups are included: 1) aliphatic radicals: alkyl groups? alkenyl groups; 2) alicyclic radicals: cycloalkyl groups; cycloalkenyl groups; 3) aromatic radicals: aryl groups; 4) aromatic-aliphatic radicals: aralkyl groups; 5) heterocyclic radicals: hetero cyclic groups; 6) acyl groups: acyl groups which may be derived from organic carboxylic acids, which include aliphatic carboxylic acids, alicyclic carboxylic acids and alicycloaliphatic carboxylic acids, including aromatic aliphatic carboxylic acids, aromatic oxyaliphatic carboxylic acids, aromatic thioaliphatic carboxylic acids, heterocyclic aliphatic carboxylic acids carboxylic acids, heterocyclic oxyaliphatic carboxylic acids and heterocyclic thioaliphatic carboxylic acids, wherein an aromatic moiety or a heterocyclic group is attached directly or via an oxygen or sulfur atom to an aliphatic carboxylic acid; organic carboxylic acids, in which an aromatic radical, an aliphatic group or an alicyclic group is connected to the carbonyl group via an oxygen, nitrogen or 8303955

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- 23 - * sulfur atom; aromatic carboxylic acids; heterocyclic carboxylic acids and the like.

The above aliphatic carboxylic acids include formic, acetic, propionic, butyric, isobutyric, pentanoic, methoxyacetic, methylthioacetic, acrylic, crotonic and the like, the above alicyclic carboxylic acids include cyclohexanoic acid and the like, and the above alicycloaliphatic carboxylic acids include cyclopentanoic acid cyclohexane acetic acid, 10 cyclohexane propionic acid, cyclohexadiene acetic acid and the like.

The aromatic radicals in the above organic carboxylic acids include phenyl, naphthyl and the like.

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Each of the groups that form these organic carboxylic acids can be further substituted by a substituent such as a halogen atom, a hydroxyl group, a protected hydroxyl group, an alkyl group, an alkoxy group, acyl group, nitro group, amino group, a protected amino group, a carboxyl group, or a protected carboxyl group.

The substituted or unsubstituted acyloxy and carbamyloxy groups for R also include alkanoyl oxy groups such as acetoxy, propionyloxy, butyryloxy and the like; alkenoyloxy groups such as acryloyloxy and the like; aryloxy groups such as benzoyloxy, naphthoyloxy and the like and carbamoyloxy group. These groups can be substituted by one or more substituents, such as halogen, nitro, amino, alkyl, alkoxy, alkylthio, acyloxy, acylamino, hydroxyl, carboxyl, sulfamyl, carbamyl, alkoxycarbonylcarbamyl groups, arylcarbamyl groups, alkoxycarbonylsulfarayl groups, aryl-30 groups, carbamylolo groups .

In the above substituents for R 8, the hydroxyl group, amino group, carboxyl group and the like may be protected with protecting groups commonly used, and specifically include the hydroxyl protecting, amino protecting and carboxyl protecting groups mentioned above for R 6.

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- 24 - ë a) Conversion reaction at the 3-position.

7- unsubstituted or substituted amino 3-substituted methyl cephemcarboxylic acid of formula 4 or a salt thereof can be obtained in high yield with high purity using an industrially easy procedure by a 2,3-dioxo 1,2, 3,4-tetrahydro-pyrazine of the formula 3a, a 2-oxo 1,2-dihydropyrazine of the formula 3b, a 3,6-dioxo 1,2,3,6-tetrahydropyridazine of the formula 3c or a 6-oxo 1,6-dihydropyridazine of the formula 3d or a salt thereof to react with a cephalosporanoic acid of the formula 2 or a salt thereof, in the presence of an acid or a complex compound of an acid, after which, if desired, the protecting group , protects the carboxyl group or converts the resulting compound into a salt thereof. Furthermore, the above-mentioned 2,3-dioxo 1,2,3,4-tetrahydropyrazine can be prepared according to the method described in Journal of Chemical Society, Perkin I, p.

1888-1890 (1975).

Furthermore, if necessary, one can remove the substituent of the amino group at the 7 position in a conventional manner to obtain a 7-unsubstituted amino compound. According to this procedure, not only Δ3-cefem compounds but also L · 2-cefem compounds can be used as starting compounds, and when using the Δ * -cephem compounds as the starting compounds, the reaction product can be further added the Δ2-cefem compounds convert into Δ3 -cephem compounds.

Also, not only compounds in which> 2 is> S, but also compounds in which> Z is> SK) can be used as the starting materials, and in the latter case> SK) can be converted to> S during the reaction or in the post-treatment step. .

When the 2,3-dioxo 1,2,3,4-tetrahydropyrazine of the formula 3a, the 2-oxo 1,2-dihydro-pyrazine of the formula 3b, the 3,6-dioxo 1,2,3, 6-tetrahydro pyridazine of the formula 3c and 6-oxo-1,6-dihydropyrida- 8303955

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4 - 25 - zines of the formula 3d, which are used as reagents in the reaction, having basic or acidic groups as substituents, these compounds can be used as necessary in the form of the corresponding salt in the reaction. In this case, the salts on the basic groups and the salts on the acid groups are those referred to as the salts of the compounds of the formula 1.

Also included among the salts of the compounds of formulas 2 and 4 are the salts to the basic groups and to the acidic groups, and these salts include those listed above as the salts of the compounds of formula 1. The salts of the compounds of the formula ^ 2 can be isolated beforehand and then used, or

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can be prepared in situ.

As the acids or the complex compounds of acids used in the reaction, mention can be made, for example, protonic acids, Lewis acids or complex compounds of Lewis acids. The protonic acids include sulfuric acids, sulfonic acids and superacids (superacids means 20 acids stronger than 100% sulfuric acid and this includes some of the above sulfuric and sulfonic acids). More specifically, the protonic acids include sulfuric acids such as sulfuric acid, chlorosulfuric acid, fluorosulfuric acid, and the like, sulfonic acids, for example, alkyl (mono- or di) sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, and the like

O) aryl (mono-, di- or tri) sulfonic acids such as p-toluene sulfonic acid and the like, superacids such as perchloric acid, magic acid (FSC> 3H-SbF5), FSC> 3H-AsF5, CF3S03H-SbF5, HF —BF3, H2SO4 ~ SO3 and the like.

The Lewis acids include, for example, boron trifluoride, and the complex compounds of Lewis acids include complex compounds of boron trifluoride with dialkyl ethers such as diethyl ether, di-n-propyl ether, di-n-butyl ether and the like; with amines such as ethylamine, n-propylamine, n-butylamine, triethanolamine and the like, with carboxylates such as ethyl formate, ethyl acetate and the like 8303955

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- 26 - * body; with aliphatic acids such as acetic acid, propionic acid and the like; and with nitriles such as acetonitrile, propionitrile and the like.

The reaction is preferably conducted in the presence of an organic solvent. Organic solvents used include any organic solvents that are inert to the reaction, for example nitroalkenes such as nitromethane, nitroethane, nitropropane and the like; organic carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, dichloroacetic acid, propionic acid and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; ethers such as diethyl ether; diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, anisole, dimethyl cellosolve and the like; esters such as ethyl formate, diethyl carbonate, methyl acetate, ethyl acetate, ethyl chloroacetate, butyl acetate and the like, nitriles such as sulfonitrile; These solvent chins are used mixed with two or more In addition, one can use complex compounds formed from these organic solvents and Lewis acids as the solvent It is sufficient that the amount of the acid or the complex compound of the acid is at least equimolar the amount of the compound represented by the formula 2 or 25 is a salt thereof, and the amount may vary depending on the respective cases, in particular it is preferred to use an amount of 2-10 moles per mole of the compound of formula 2 or a salt thereof When the complex compound collection of the acid, it can be used as such as a solvent, and two or more of the complex compounds can be mixed.

It is sufficient that the amount of the 2,3-dioxo 1,2,3,4-tetrahydropyrazine of the formula 3a, the 2-oxo 1,2-dihydropyrazine of the formula 3b, the 3,6-dioxo 1, 2,3,6-tetrahydropyridazine of the formula 3c or the 6-oxo 1,6-dihydropyridazine of the formula 3d or a salt 8303955

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\ - 27 -

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its at least equimolar to the amount of the compound represented by the formula 2 or a salt thereof, and in particular the use in an amount of from 1.0 to 5.0 moles per mole is preferred.

This reaction is usually carried out at 0-80 ° C and completed in 10 minutes to 30 hours. The presence of water in the reaction system can cause undesired side reactions such as lactonization of the starting material or products and cleavage of the β-lactam ring, so that it is desirable to keep the system under anhydrous conditions. To meet this requirement, it is sufficient to add to the reaction system a suitable dehydrating agent, for example, a phosphorus compound such as phosphorus pentoxide, polyphosphoric acid, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, and the like; an organic silylating agent such as N, O-bis (trimethylsilyl) acetamide, trimethylsilylacetamide, trimethylchlorosilan, dimethyl dichlorosilan and the like; an organic acid chloride such as acetyl chloride, p-toluenesulfonyl chloride and the like; an acid anhydride such as acetic anhydride, trifluoroacetic anhydride and the like; an inorganic dehydrating agent such as anhydrous magnesium sulfate, anhydrous calcium chloride, a molecular sieve, calcium carbide and the like.

When a compound represented by the formula 2, in which R 1 represents a carboxyl protecting group, is used as starting material, a compound represented by the formula 4, wherein R 1 is a hydrogen atom, can in some cases be obtained by the reaction , or by removing the protecting group in a conventional manner.

Now, the 3-reaction reaction described in production route II will be explained.

The halogenated compound represented by the formula 16 'can be prepared according to the method described in Tetrahedron Letters, No. 46, pp. 3991-3994 (1974) and Tetrahedron Letters No. 40, pp. 3915-3918 (1981).

bath original 8303955 - 28 - /

The compound represented by the formula 27, or a salt thereof, can be prepared by reacting a halogenated compound represented by the formula 16 or a salt thereof, with a 2,3-dioxo 1,2,3,4-tetrahydro-5 pyrazine of the formula 3a or a salt thereof in the presence of a base. The base includes alkali carbonates (e.g. sodium carbonate and the like), alkali hydrogen carbonates (e.g. sodium hydrogen carbonate, potassium hydrogen carbonate and the like), alkali hydroxides (e.g. -10 hydroxide, potassium hydroxide and the like), nitrogen-containing organic bases, e.g. triethylamine, pyridine Ν, Ν-dimethylaniline and the like.

The conversion in the 3-place becomes

O

V-? generally carried out in a suitable solvent. The solvent includes halogenated hydrocarbons such as chloroform, methylene chloride and the like; ethers such as tetrahydrofuran, dioxane and the like; N, N-dimethylformamide; Ν, Ν-dimethylacetamide; acetone; water and mixtures thereof.

In this case, the compound 20 represented by the formula 3a or a salt thereof is preferably used in an amount of about 1.0-2.0 moles per mole of the compound represented by the formula 16 or a salt thereof. The reaction is generally run at a temperature of 0-50 ° C for 30 minutes to 10 hours.

The mixture of a Δ2 and Δ3 cephem compound thus obtained, ie a compound represented by the formula 17 or a salt thereof, can easily be converted into the Δ3 cephem compound to form the compound of the formula 18 or a salt to obtain it, which is then converted into the compound of formula 19 or a salt thereof by deacylation. Such conversion reaction and deacylation are known in the field of penicillins and cephalosporins and are specifically described in

Journal of Organic Chemistry, Volume 35, No. 7, pp. 2430-2433 35 (1970) and "Cephalosporins and Penicillins" (by Flynn,

Academy Press), pp. 56-64.

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- 29 - \

When the substituents of the 2,3-dioxo 1,2,3,4-tetrahydropyrazine of the formula 3a, the 2-oxo 1,2-dihydropyrazine of the formula 3b, the 3,6-dioxo 1,2,3, 6-tetrahydropyridazine of the formula 3c or the 6-oxo 5 1,6-dihydropyridazine of the formula 3d or its salt, which are used as the reagents in the reaction, are substituted by a hydroxy group, an amino group, a carboxyl group and the like , these groups can be protected by the above protecting groups before reacting and subjected to a conventional removal reaction upon completion of the reaction to obtain a desired compound.

Also, the compound represented by the formula 4 or 19 may be protected, if necessary, at the carboxy group or converted to the salt by a conventional method to obtain the intended compound. Alternatively, the compound of formula 4, wherein R represents "an amino group 4.", may be converted into a reactive derivative on the amino group or the compound represented by the formula 19, as set forth below, in a conventional method, b ) Acylation.

When the compound represented by the formula 5, 6, 7, 8 or 1¾ or a salt thereof or a reactive derivative thereof is reacted with a compound represented by the formula 4 or a salt thereof or a reactive (/) derivative to the amino group, a compound of the formulas 1, 9, 10, 11 and 11 is obtained. 14 or a salt thereof.

The salts of the compound represented by formulas 5, 6, 7, 8 or 13 include salts to the basic group or the acid group, which specifically include those listed as the salts of the compound represented by the formula 1.

The reactive derivatives on the amino group of the compound represented by the formula 4 include all derivatives often used in acylation, for example an isocyanate, a Schiff base produced by the 8 3 3 S 5 5

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Reaction of the compound represented by the formula 4 or a salt thereof, with a carbonyl compound such as an aldehyde, a ketone and the like (ketimine type or its isomer, namely enamine type); a silyl derivative, a phosphorus derivative or a tin derivative, produced by the reaction of a compound represented by the formula 4 or a salt thereof with a silyl compound, such as bis (trimethylsilyl) acetamine, trimethylsilylacetamine, trimethylsilyl chloride and the like, a phosphorus compound such as phosphorus trichloride, or of the formula 75, 76 or 77, (CH 3 CH 2 O) 2PCl, (CH-1CH 2 PCl and the like, or a tin compound such as (C 1 H 2 J 2 SnCl and the like).

The reactive derivatives of the compounds represented by formulas 5, 6, 7, 8 and 13 specifically include acid halogenies, acid anhydrides, mixed acid anhydrides, active acid amides, active esters, reactive derivatives obtained by reaction of the compounds represented by formulas 5, 6, 7, 8 and 13 with a Vilsmeier reagent. The mixed acid anhydrides include a mixed acid anhydride with a monoalkyl carbonate such as monoethyl carbonate, monoisobutyl carbonate and the like, a mixed acid anhydride with a lower alkanoic acid which may be substituted by a halogen such as pivalic acid, trichloroacetic acid and the like. The active acid amide includes N-acyl saccharin, N-acyl imidazole, N-acyl benzoylamide, Ν, Ν'-dicyclohexyl N-acyl-urea, N-acyl sulfonamide and the like. The active ester includes cyanomethyl ester, substituted phenyl esters, substituted benzyl esters, substituted thienyl esters and the like.

The reactive derivatives obtained by reaction with a Vilsmeier reagent include those obtained by reaction with a Vilsmeier reagent obtained by reaction of an acid amide, such as Ν, Ν-dimethylformamide, N, N-dimethyl-acetamide and the like with a halogenating agent, such as phosgene, thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, phosphorus pentachloride, trichloromethyl chloroformate, oxalyl chloride and the like.

8 3 0 3 9 5 5

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V

- 31 -

If any of the compounds represented by formulas 5, 6, 7, 8 and 13 are used in the form of a free acid or a salt, a suitable condensing agent is used. The condensing agent includes 5 Ν, Ν'-disubstituted carbodilmides, such as Ν, Ν'-dicyclohexylcarbodilmide; azolide compounds, such as Ν, Ν'-thionyl dilmidazole; dehydrating agents such as -N-ethoxycarbonyl 2-ethoxy 1,2-dihydroquinoline, phosphorus oxychloride, alkoxyacylenes and the like; 2-halo-pyridinium salts such as 2-chloropyridinin-methyl iodide and 2-fluoropyridinium-methyl iodide and the like.

This acylation reaction is usually carried out in a suitable solvent in the presence or absence of a base. As the solvent, a solvent inert to the reaction can be used, for example, a halogenated hydrocarbon such as chloroform, methylene chloride and the like; an ether such as tetrahydrofuran, dioxane and the like; Ν, Ν-dimethylformamide; N, N-dimethyl acetamide; acetone, water or a mixture thereof. As the base, an inorganic base such as an alkali metal hydroxide, an alkali metal hydrogen carbonate, an alkali metal carbonate, an alkali metal acetate and the like can be used; a tertiary amine such as trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine, N-methylmorpholine, lutidine, collidine and the like or a secondary amine such as dicyclohexylamine, diethylamine and (^) the like.

The compound represented by the formula 9 and a salt thereof, which can be converted into the compounds represented by the formulas 1a and 1b and salts thereof can be produced by the following procedure:

To obtain the compound represented by the formula 9 or a salt thereof using the compound represented by the formula 4 or a salt thereof, one may use a 4-halo 3-oxo butyryl halide which is obtained by the reaction of a diketene with a halogen, such as chlorine or bromine / Journal of the Chemical 83 03 95 5

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J

- 32 - /

Society, 97, 1987 (1910) / react with the compound represented by the formula 4 or a salt thereof by a conventional method. The reaction conditions and procedures known in the art can be applied to this reaction. The salt of the compound represented by the formula 9 can be easily prepared by a conventional method, and the salt comprises the same salts as stated for the salts of the compounds represented by the formula 1. Although the compound represented by the formula 10 9 or a salt can be isolated and purified, it can be used for the subsequent reaction without isolation.

In addition, the compounds represented by formulas 5, 6, 7, 8 or 13 or a salt thereof or a reactive derivative thereof may preferably be used in an amount from about 1 mole to several moles per mole of the compound represented by the formula 4 or a salt thereof or a reactive derivative thereof to the amino group. The reaction is usually carried out at a temperature from -50 ° C to 40 ° C. The reaction time is usually 10 minutes to 48 hours.

Furthermore, one can convert the compounds represented by formulas 1, 9, 10, 11 and 14, which is a carboxyl protecting group, to the compounds represented by formulas 1, 9, 10, 11 and 14, wherein R 1 is a hydrogen atom, or their salts by the usual method? and likewise one can convert the compounds represented by the general formulas 1, 9, 10, 11 and 14, wherein R 1 is a hydrogen atom, into the compounds represented by the formulas 1,9, 10, 11 and 14, wherein R 1 carboxyl protecting group or salts thereof; and the salts of the compounds represented by formulas 1, 9, 10, 11 and 14 can be converted into the respective corresponding free acid forms.

If R 3, R 3, and R 5 contain groups that are active for the reaction, these groups can also be suitably protected in this acylation reaction with con- 83 03 9 5 5

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V

- 33 - protective groups before reacting, and the protecting groups can also be removed by a usual post-reaction method.

The compound represented by the formula 1 and a salt thereof according to this invention obtained by the above-mentioned method can be isolated in a usual manner, c) Nitrosation.

To obtain the compound represented by Formula 10 or a salt thereof from the compound represented by Formula 9 or a salt thereof, a nitrosating agent can then be reacted with the compound represented by Formula 9 or a salt thereof, u De reaction is usually carried out in a solvent, and as a solvent one can use a solvent which is inert to the reaction such as water, acetic acid, benzene, methanol, ethanol, tetrahydrofuran and the like. Preferred examples of the nitrosating agent include nitric acid and its derivatives, for example nitrosyl halides such as nitrosyl chloride, nitrosyl bromide and the like, alkali nitrites such as sodium nitrite, potassium nitrite and the like, alkyl nitrites such as butyl nitrite, pentyl nitrite and the like. When using a nitrous acid salt as the nitrosating agent, it is preferable to carry out the reaction in the presence of an inorganic or organic acid such as hydrochloric, sulfuric, formic, acetic and the like. When using an alkyl nitrite as the nitrosating agent, it is preferable to carry out the reaction in the presence of a strong base such as an alkali metal alkoxide and the like. The reaction is usually carried out at a temperature of -15 ° C to 30 ° C and the reaction time is usually from 10 minutes to 10 hours. The salt of the compound represented by the formula 10 can be easily prepared by a conventional method, and the salt comprises the same salts as mentioned above for the salts of the compound represented by the formula 1. Although the compound represented 8303955

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* - 34 - t can be isolated and purified by the formula 10 or a salt thereof, thus obtained, and purified by a well-known method, it can be used for the subsequent reaction without isolation.

5 d) etherification and phosphorylation.

In order to obtain the compound represented by the formula 11 or a salt thereof from the compound represented by the formula 10 or a salt thereof, the compound represented by the formula 10 or a salt thereof is subjected to an etherification or phosphorylation reaction.

The etherification reaction and the phosphorylation reaction can be carried out in a conventional O manner as described in Japanese patent applications 137,988 / 78, 105,689 / 80, 149,295 / 80 and the like.

For example, alkylation can be performed in a conventional manner. The reaction is usually carried out at a temperature from -20 ° C to 60 ° C and is completed in 5 minutes to 10 hours.

As the solvent, one can use a solvent which is inert to the reaction, for example tetrahydrofuran, dioxane, methanol, ethanol, chloroform, methylene chloride, ethyl acetate, butyl acetate, N, N-dimethyl formamide, NN-dimethyl acetamide, water or a mixture of it.

As the alkylating agent, one can use, for example, a lower alkyl halide such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide and the like, dimethyl sulfate, diethyl sulfate, diazomethane, diazoethane, methyl p-toluenesulfonate and the like. When using an alkylating agent other than diazomethane and diazoethane, the reaction is carried out in the presence of an alkali metal carbonate such as sodium carbonate, potassium carbonate and the like. an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and the like; or an organic base such as triethylamine, pyridine, Ν, Ν-dimethylaniline and the like.

Also, the salt of the compound represented by the formula 11 can be easily obtained at 8303955

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i - 35 - in a conventional manner, and this includes the same salts as mentioned above as the salts of the compound represented by the formula 1.

In addition, a protecting group can be introduced and removed in a conventional manner, whereby a compound can be changed into a corresponding target compound.

Although the compound represented by the formula 11 or a salt thereof, thus obtained, can be isolated and purified in a conventional manner, they can be used for the subsequent reaction without isolation, e) Ring closure reaction.

The compound represented by the formula la or lb or a salt thereof according to this invention may be obtained by the reaction of the compound represented by the formula 9, 10 or 11 or a salt thereof with the thioformamide or thiourea represented by the formula 12. This reaction is usually carried out in a solvent. As the solvent, one can use a solvent which is inert to the reaction, for example, water, methanol, ethanol, acetone, tetrahydrofuran, dioxane, Ν, Ν-dimethylformamide, N, N-dimethyl acetamide, N-methyl pyridone, only or as a mixture of two or more of them. Although it is not essential to add an acid remover, the reaction sometimes proceeds more smoothly by adding an acid remover in such an amount that the cephalosporin backbone is not affected. The acid remover used for the reaction includes inorganic and organic bases such as alkali hydroxides, alkali hydrogen carbonates, triethylamine, pyridine, Ν, Ν-dimethylaniline and the like. The reaction is usually carried out at a temperature of 0-100 ° C. Thioformamide or thiourea is usually used in an amount from about 1 mole to several moles per mole of the compound represented by the formula 9, 10 or 11 or a salt thereof. The reaction time is 1-48 hours, preferably 1-10 hours.

8303955

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) - 36 ->

Furthermore, in the compound represented by the formula la or lb, the protection and removal of the carboxyl group or the conversion of a product into a salt thereof can be carried out in a conventional manner to convert the compound into the corresponding target compound. If R 1, and R 1 in formula 1a or 1b contain groups that are active for the reaction, these groups can be suitably protected by a conventional protecting group before reacting and the protecting group can be removed in a usual manner after The reaction. The intended compound represented by the formula la or lb or the salt thereof obtained in this way can be isolated in a conventional manner.

f) Oximation.

The compound represented by the formula Ib or a salt thereof is obtained by reaction of the compound represented by the formula 14 or a salt thereof with the compound represented by the formula 15 or a salt thereof. The salt of the compound represented by the formula 20 includes hydrochlorides, hydrobromides, sulfates and the like.

This reaction is usually carried out not only in a solvent such as water, an alcohol, N, N-dimethylacetamide and the like, but also in other solvents inert to the reaction or a mixed solvent thereof. The reaction is carried out at a temperature of 0-100 ° C, preferably (10-50 ° C. The reaction time is usually 10 minutes to 48 hours.

The compound represented by the formula 15 or a salt thereof is used in an amount from about 1 mole to several moles per mole of the compound represented by the formula 14 or a salt thereof. Although the salt of the compound represented by the formula 15 can be used by itself for the reaction, it can also be reacted in the presence of a base, for example an inorganic base such as an alkali metal hydroxide (eg sodium hydroxide, potassium hydroxide and the like), an alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide and the like), 8303955

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37 - an alkali carbonate (e.g. sodium carbonate, potassium carbonate and the like), an alkaline earth carbonate (e.g. magnesium carbonate, calcium carbonate and the like), an alkali hydrogen carbonate (e.g. sodium hydrogen carbonate, potassium hydrogen carbonate and the like), an alkaline earth phosphate (e.g. magnesium phosphate) -phosphate and the like), an alkali hydrogen phosphate (e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate) or an alkali acetate (e.g. sodium acetate, potassium acetate), an organic base such as a trialkylamine (e.g. trimethylamine, triethylamine and the like), methylpyrolidine and the like) -methylmorpholine, 1,5-diazabicyclo- / 4,3,0 / 5-nonene, 1,4-diazabicyclo / 2,2,2 / octane, 1,5-1 diazabicyclo / 5,4,0-7 7-undecene and such. The compound represented by the formula Ib or a salt thereof of this invention, thus obtained, can undergo conversion of Rj in a conventional manner, and can also be isolated by a conventional method, g) Alkoxylation.

The compound represented by the formula 4, wherein R 1 is an alkoxy group, can be synthesized from the compound represented by the formula 4, wherein a hydrogen is in a manner known per se, for example, according to the method described in Journal of 25 Synthetic Organic Chemistry, Japan, 35 / (7), 563-574 (1977).

Furthermore, one can synthesize the compounds represented by formulas 1, 1a, 1b, 9, 10, 11 and 14, wherein R 1 is an alkoxy group, from the respective compounds represented by formulas 1, 1a, 1b, 9, 10, 11 and 14, wherein R 1 is a hydrogen atom in a manner known per se, for example, according to the method described in Japanese patent applications 24,888 / 79 and 103,889 / 79.

The compound represented by the formula 1 or a salt thereof, thus obtained, can be administered to humans and animals in the form of a free acid or in the form of a pharmaceutically acceptable salt or ester 8 3 3 9 5 5

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i - 38 -> for the purpose of treating or 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 that case, it is sufficient that the compound be formed into a dosage form commonly used with cephalosporin medicaments, for example, tablets, capsules, powders, fine grains, granules, syrups, injections (including droplets), suppositories and the like . When the above drug is formed into a dosage form, diluents and / or additives may be used, for example, carriers such as starch, lactose, sugar, calcium phosphate, calcium carbonate and the like; adhesives such as gum arabic, starch, microcrystalline cellulose, carboxymethyl cellulose, hydroxypropyl cellulose and the like; lubricants such as talc, magnesium stearate and the like; disintegrants such as carboxymethyl calcium, talc and the like.

When the compound represented by the formula 1 or a salt thereof is administered, the dosage, the duration of administration and the route of administration can be varied depending on the symptoms of the patient, and generally it is sufficient to administer orally or parenterally to a adult at a dose of about 50-5000 mg in 1-4 25 servings per day.

The invention will now be elucidated hereinbelow by reference examples and examples, which are illustrative only and in no way limit.

Reference Example 1 (1) To a solution of 20.0 g of ethyl N- (2,2-diethoxyethyl) oxamate in 60 ml of ethanol, 6.1 ml of a 70% by weight ethylamine solution in water is added and subjected to the mixture reacted at room temperature for 1 hour.

After the completion of the reaction, the precipitated crystals are collected by filtration and recrystallized from ethanol to 8303955

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V

39 obtaining 17.0 g (yield 85.1%) of N-ethyl N '- (2,2-diethoxyethyl) oxamide, m.p. 131-132 ° C.

IR (KBr) cm Vq-q ^ 50.

In such a manner, the 5 compounds shown in Table C are obtained.

> 4 h 8303955

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ί '

r Table C

c (CH3CH2O) 2CHCH2NHCOCONHR6

Solvent. Mp. IR (KBr) cm - for recrystallization (° C) v__0 R6 tallization. -H Ethyl 141-142 1650, 1635 Acetate -CH3 Ethanol 135-136 1645 - (CH2) 2CH3 Acetone 84-85 1645 Q -CH-.

-CH ^ 3 Acetone 145-146 1650, 1635 \ CH n-Hexane - (CH2) 3CH3 n-Hexane 111-112 1645 - (CH2) 4CH3 n-Hexane 92-93 1650 - (CH2) 5CH3 n-Hexane 87- 88 1650 - (CH2) 7CH3 n-Hexane 110-111 1645 - (CH ^ J ^ CH. N-Hexane 83-84 1645

Δ XX J

-; -----

Ethanol 154-155 1640 -CHj— (O) n-Hexane 113-114 1655 -CH2CH2OH Ethanol 118-119

CH

-N 3 Ethanol 157-158 1645-CH 3

0CH

Xi-v - 128-129 1655 -CH2- <g) -OCH3 8303955

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- 41 - (2) To a solution of 17.0 g of N-ethyl Ν '- (2,2-diethoxyethyl) oxamide obtained as under (1) in 85 ml of acetic acid, 0.05 ml of concentrated hydrochloric acid are added. The mixture is refluxed for 30 minutes. After the completion of the reaction, the solvent is removed by distillation under reduced pressure, 70 ml of acetone is added to the residue, and the crystals are collected by filtration. The crystals are recrystallized from methanol to give 6.8 g (yield 61.8%) of 4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazine, mp 173-174 ° C.

IR (KBr) cm -1: v 1680-1620 CO

In such a manner, the compounds shown in Table D are obtained.

15 1 8303955

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• Solvent Mp. IR (KBr) cm "1; - ~ - for recris- (° r \ u

R6 tallization 1 'C = O

r \

- 42 - Table D

(W »·.

HN N-R6 w -H -. > 280 1680-1640 -CH3 Ethanol 220-231 1690-1635 - (CH2) 2CH3 Acetone 182-183 1680-1640 ^ 13 CH-5 -CH ^ 3 Acetone 215-219 1680, 1625 ^ CH3 ___ - (CH2) 3CH3 Acetone 149-150 1680, 1640 - {CH.) 4CH, Acetone 171-172 1685, 1660, J 1620 - (CH2) 5CH3 Acetone. 141-142 1520 '1660, - (CH2) ^ CH3 Acetone 145-146 1670, 1635 - (ch2) hCH3 Ethanol 145-146 1660, 1625 - (e) Acetone 254-255 1670, 1635 -O1® Acetic acid 225 1665, 1635 -CH2CH2OCOCH3 Methanol 178-180 ^ 5 '1675'

CH

-N <3 Ethanol 229-230 1700-1625 ^ CH3 1 -. - ------- -— - -------. .. ........

OCH 3 - 175-176 1740-1620 -ch2- {o) -och3 8303955

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t - 43 - (3) To a suspension of 5.2 g of 4- (2,4-dimethoxybenzyl) 2,3-dioxo 1,2,3,4-tetrahydropyrazine obtained as under (2) in 26 ml Ν, Ν -dimethylformamide, 4.1 g of potassium carbonate are added, and the mixture is stirred at room temperature for 30 minutes. 5.8 g of 4-bromoethyl 5-methyl-1,3-dioxol-2-one are then added and the mixture is reacted at 50-60 ° C for 3 hours. The reaction mixture is placed in a mixed solvent of 2 ml of ethyl acetate and 200 ml of water, the organic layer is separated, washed with 100 ml of water and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue is purified by column chromatography (Wako silica gel C-200, eluent chloroform) to obtain 4.9 g (66.0%) 1- (2,4-dimethoxy) 15-benzyl) 4- (5-methyl-2-oxo-1,3-dioxol-4-yl) -methyl-2,3-oxo-1,2,3,4-tetrahydropyrazine, mp 154-156 ° C. IR (KBr) cm -1: vc_Q 1820, 1675, 1630.

In such a manner, the compounds shown in Table E are obtained.

20 8303955

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- 44 - (r

K Table E

QCH «j OO / - (3 CH3OH ^ Q ^ - ch2- / n-r6 __Smpt. (° C) IR (KBr) cm" 1: \> c = 0 Rö - (V = 0 188-190 1775, 1700 , 1650 ^ <g> .7 _______ -CH-OCOC (CH _) - 100-101 1750, 1690, 1660, * * Δ 1640 -CH2COOC (CH3) 3 105-106 1740, 1690, 1650 rn w '8303955

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1 - 45 -

V

(4) 3.7 g of 1- (2,4-dimethoxybenzyl) 4- (5-methyl-2-oxo-1,3-dioxol-4-yl) are dissolved in a mixed solvent of 37 ml of trifluoroacetic acid and 10.8 g of anisole. methyl 2-dioxo 1,2,3,4-tetrahydropyrazine obtained under 5 (3) and let the mixture react at 50-60 ° C for 2 hours. The solvent is then removed by distillation under reduced pressure. 30 ml of diethyl ether are added to the residue and the crystals are collected by filtration to obtain 2.0 g (90.9%) of 4- (5-methyl 2-oxo 1,3-dioxol-4-yl) -10 methyl 2 1,3-dioxo 1,2,3,4-tetrahydropyrazine, mp T 225-226 ° C.

! IR (KBr) cm -1: vc_Q 1825, 1805, 1725, 1690, 1670.

Q In such a manner, the compounds shown in Table F are obtained.

15 0 8 3 0 3 S 5 5

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- 46 -

Table F CD P

VK 6 HN N-R6 W '! j -: - Mpv (° C) IR (KBr) cm ”1: v___ R6 c = 0

kV

V- (> 270 1790, 1775, 1730, Q (O / 1690 -CH2OCOC (CH3) 3 166-167 1740, 1700, 1660 -CH-COOH, 282., 17 30, 1670-1630 2 (decomposition) 8 3 ü 3 9 5 5

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% - 47 - 1 (5) To a solution of 2.6 g of 1-carboxymethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazine in 13 ml Ν, Ν-dimethylacetamide, 3.9 g of diphenyldiazo-methane are added at room temperature and allow the mixture to react for 10 minutes. The reaction mixture is placed in a mixed solvent of 25 ml of ethyl acetate and 25 ml of water and the mixture is stirred for 15 minutes. The precipitated crystals are collected by filtration and washed with 10 ml of ethyl acetate and 10 ml of diethyl ether in this order to give 2.9 g. (80.4%) 1-diphenylmethyloxycarbonylmethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazine, m.p. 97-98 ° C.

IR (KBr) cm ** 1: vc = 0 1750, 1675, 1645.

-W

Example I

(1) To a solution of 10 ml of ethyl acetate containing 2.71 g of boron trifluoride, 2.72 g of 7-aminocepaiosporanoic acid (hereinafter referred to as 7-ACA) and 1.54 g of 4-ethyl 2,3-dioxo 1 are added. 2,3,4-tetrahydropyrazine and react the mixture at room temperature for 16 hours. After the completion of the reaction, the reaction mixture is placed in 50 ml of methanol under cooling and then 3.16 g of pyridine is added dropwise. The precipitated crystals are collected by filtration, washed sufficiently with 30 ml of methanol, 25 and then dried to obtain 3.10 g (88.1%).

Qj 7-amino 3- {/ ** 1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) / methy1} A3-cephem 4-carboxylic acid, melting point 191-195 ° C (under decomposition).

IR (KBr) cm "1: u Λ 1795, 1670, 1620 C = 0 30 NMR (CF3COOD) 6 values: 1.44 (3H, t, J = 7Hz, ^ NCH2CH3), 3.69 (2H, bs, C2-H), 4.08 (2H, q, J = 7Hz,? NCH2CH3), 5.14, 5.51 (2H, ABq, J = 15Hz,),

35 * I

> CH 2 “5.48 (2H, s, Cg-H, C? -H),

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8303955 4 - 48 - 6.74, 7.00 (2H, ABq, J-6Hz, formula 78.

(2) The conversion reaction at the 3-position mentioned under (1) above is performed under the reaction conditions shown in Table G to obtain 5 7-amino 3- {/ 1- (4-ethyl 2,3-dioxo 1). , 2,3,4-tetrahydropyrazinyl) / methyl} Δ3-cephem 4-carboxylic acid in the yields shown in Table G.

10 © 8303955

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λ 1.

- 49 - Table G

Starting material Acid or .. Reaction- How much-

No. ——-—— solution complex conditions 7-ACA%? medium compound (opflx * -CH2CH3 Of ACID yield) i <) 7, "V c". sulfo Boring Chamber- 2.6 g 1 2.72 g 1.54 g Ian._ tri-tempera- (73.9 *) 10 ml fluoride ture 2.71 g 2 hours - 2 2 72 σ 1 54 er Nitro- Drill- Chamber- 2.85 g 9 9? y methane tri-tempera- (81.0%) 14 ml fluoride acid diethyl 16 hours ether complex ___ 5.7 g__ (3) In a manner as under (1) above, the compounds shown in Table H are obtained. In this case, the intended compounds are obtained by pouring the reaction mixture at the 5 3 position in ice water after the completion of the reaction and adjusting the pH to 3.5 with 28% ammonia under ice cooling.

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- 53 - (4) The conversion reaction at the 3-position mentioned under (1) above is carried out under the reaction conditions shown in Table J to obtain 7-amino 3- {/ 1- (3,6-dioxo 1, 2,3,6-tetrahydropyridazinyl) J-5 methyl} Δ3-cephem 4-carboxylic acid in the yields shown in Table I.

Table I

No. Starting Solution- Acid or com- Reaction- Amount of material__ agent plex compound condition 7-ACA Maleation of ties (hydric acid yield) ___ide .____________________

Tri- Boron Tri- Chamber- 1.72 g r '' '} Fluorofluoride temperature 1 2.0 g 0.91 g vinegar diethyl acid (72.3%) acid ether 16 hours 10 ml complex 4.17 g

Sulfo-Boron Tri-Chamber- 2.75 g 2 2.72 g 1.23 g Lan Fluoride Temperature 10 ml 2.71 g rature (84.9%) 3 hours (5) In such a manner as under (1) above, the crude crystals shown in table j are obtained.

83 ü 3 9 5 5

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- 57 -

Note: The compounds in No. 10, 11, 12, 13, 14 and 15 were obtained by the reaction with sulfolan as a solvent.

* 1: This compound was obtained by placing in methanol, filtering out the insolubles and adding pyridine to the filtrate.

* 2: The proposals were made because it has not been confirmed whether the chlorine atom is in the 4- or 5-position, and whether the product consists of a single compound or a mixture (such representations in later tables have the same meaning).

* 3: The representation means that the product is a mixture of a 4-substituted compound and a 5-substituted compound (such representations in later tables have the same meaning).

Example II

To a suspension of 3.0 g 7-amino 3- {/ 1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazyl-20-nyl) </ methyl} A3-cephem 4-carboxylic acid obtained according to Example I-1) in 30 ml of methanol, 1.62 g of p-toluenesulfonic acid monohydrate is added to form a solution, then 5.0 g of diphenyldiazomethane are slowly added to the solution and the obtained mixture reacts at room temperature for 15 minutes. After the completion of the reaction, the solvent is removed by filtration under reduced pressure and the residue thus obtained is dissolved in a mixed solvent of 20 ml of ethyl acetate and 20 ml of water. The solution is adjusted to pH 7.0 with sodium hydrogen carbonate. The organic layer is then separated and dried over anhydrous magnesium sulfate and the solvent is removed by distillation under reduced pressure. The residue is purified by column chromatography (Wako silica gel C-200, eluent benzene: ethyl acetate = 1: 4 by volume) to give 3.1 g (70.3%) 7-amino 3- {/ 1- (4) -ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) -7methyl} Δ3-cephem 4-carboxylate with a 1, V'f.

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- 58 - melting point of 183-186 ° C (with decomposition).

IR (KBr) cm -1: vc = Q 1765, 1730, 1680, 1630.

In such a manner, the compounds shown in Table K are obtained.

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Table K: (continued)

___Smpt. (° C) IR (KBr) cnT1: vc_Q

R2

O O

170-174 1765, 1730, -N N (CHL), -CH- (decomposition) 1685, 1635 \ - / 25 3

O. O.

J-K 186-188 1765, 1730, NJ (CH2) 7CH3 (decomposition) 1685, 1635 o-o. O y- \ 164-172 1765, 1730, -N N (CH2) i; 1CH3 (decomposition) 1685, 1635

O. O.

ï — X / -y 165-168 1765, 1725, -N, N ~ \ H / (decomposition) 1680, 1625

O O

^ - \ / v. 155-160 1770, 1725, ~ N N-CI ^^ Oy (decomposition) 1680, 1630

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146-148 1770, 1725, -N NCH2CH2OCOCH3 (decomposition) 1678, 1623

O O

7 ~~ \ CH_ 172-175 1760, 1720, -N N-nC J 1680, 1630 ch3 e'i 82-85 1775, 1720, (decomposition) 1650

O

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Table K (continued) - 61 -, (

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HlTp (decomposition) 1665 Ύ Q o HIl Si 17 8-181 17 80, 1730, - ^ (decomposition) 1660

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Example III

In a mixed solvent of 25 ml of trifluoroacetic acid and 10 ml of anisole, 4.9 g of diphenylmethyl 7-amino 3- / 1- (2,3-dioxo 1,2,3,4-tetrahydro-5-pyrazinyl_7 Δ3-cephem 4-) are dissolved carboxylate and allow the solution to react at room temperature for 2 hours After completion of the reaction, the solvent is removed by distillation under reduced pressure and 50 ml of diethyl ether are added to the residue and the crystals are collected by filtration. sufficiently washed with 40 ml diethyl ether and then dried to obtain 4.25 g (97.0%) trifluoroacetic acid salt of 7-amino 3- {/ 1- (2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) _ ? methyl1} Δ3-cephem 4-carboxylic acid, m.p. 105-106 ° C (with decomposition).

15 IR (KBr) cm-1: vc_Q 1780, 1700-1630 NMR (CF ^ COOD) δ values: 3.72 (2H, bs, C2-H), 5.14, 5.52 (2H, ABq, H = 15Hz, formula 79), 5.44 (2H, s, Cg-H, C7-H), 6.78, 6.98 (2H, ABq, H = 6Hz, formula 78).

In such a manner, the compounds shown in Table L are obtained.

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Example IV

To a suspension of 5.0 g 7-amino 3- {/ 1- (3-methyl 6-oxo 1,6-dihydropyridazinyl) 7methyl} Δ3-cephem 4-carboxylic acid in 15 ml acetone is added 2.36 g 5 1 8-diazabicyclo / 5,4,0 / -7-undecene and 4.51 g of pivaloyloxy-methyl iodide at 10-15 ° C and let the mixture react for 30 minutes. After the completion of the reaction, the reaction mixture is placed in a mixed solvent of 50 ml of water and 50 ml of ethyl acetate, and the organic layer is separated, washed with water and then dried over anhydrous magnesium sulfate.

Then 10 ml of an ethyl acetate solution containing 1.40 g of oxalic acid is added and the crystals precipitated are collected by filtration and washed with ethyl acetate to obtain 4.59 g (56.2%) oxalic acid salt of pivaloyloxy -15 methyl 7-amino 3 - {/ 1- (3-methyl 6-oxo 1,6-dihydropyridazinyl) -1 / methyl} Δ3-cephem 4-carboxylate, mp 145-157 ° C (decomposition).

IR (KBr) cm "1: vc = o 1790, 1750, 1660 NMR (d_-DMS0) δ values: 6 20 1.21 (9H, s, -CH3x3), 2.29 (3H, s,> -ch3 ), 3.52 (2H, bs, C2-H), 4.94, 5.33 (2H, ABq, J = 15Hz, formula 79), 5.14 (1H, d, J = 5Hz, Cg-H ), 5.76-6.23 (3H, m, C 1 -H, -OCH 2 O-), O 7.01, 7.53 (2H, ABq, J = 10Hz, formula 78), 7.44 ( 3H, bs, -NH3).

Example V

(1) To a solution of 2.69 g of 30 l- (5-methyl 2-oxo 1,3-dioxol-4-yl) methyl 2,3-dioxo 1,2,3,4-tetrahydropyrazine in 27 ml Ν 1.52 g of potassium carbonate are added and the resulting mixture is stirred at room temperature for 20 minutes. Then one adds. add 4.67 g of tert-butyl 7-phenylacetamido 3-bromomethyl Δ * -cephem 35 4-carboxylate under ice cooling, and let the mixture react at room temperature for 2 hours. It is brought to 303955

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reaction mixture in a mixed solvent of 200 ml ethyl acetate and 150 ml water, separating the organic layer, washing with 150 ml water and then drying over anhydrous magnesium sulfate. The solvent is then removed by distillation under reduced pressure and the resulting residue is dissolved in 100 ml of chloroform. 2.45 g (70% pure) m-chloroperbenzoic acid are added to the solution and the mixture is allowed to react at room temperature for 1 hour. The solvent is removed by distillation under reduced pressure and 100 ml of ethyl acetate and 100 ml of water are added to the residue. The organic layer is separated, washed with 100 ml of water and then dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is purified by column chromatography (Wako silica gel 15 C-200, eluent chloroform) to obtain 2.70 g (43.2%) 7-phenylacetamido 3- {/ 1- / 4- (5-methyl 2-oxo 1,3-di-oxol-4-yl) methyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl / _7 methyl} Δ3-cephem 4-carboxylate 1-oxide mp 135-136 ° C (with decomposition).

20 IR (KBr) cm -1, 1820, 1790, 1720, 1685, 1650.

Vrf "You"

(2) In a mixed solvent of I.

12 ml of Ν, Ν-dimethylformamide and 6 ml of acetonitrile are dissolved 3.0 g of I.

tert.-butyl 7-phenylacetamido-3- {/ 1- / 4- (5-methyl 2-oxo I

1,3-dioxol-4-yl) methyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl7-7

25 methyl} Δ3-cephem 4-carboxylate-1-oxide. To the solution

1.0 g of stannous chloride and 1.58 g of acetyl chloride are added

in this order under ice-cooling, and let the mixture react

run at room temperature for 30 minutes. H is removed

the solvent by distillation under reduced pressure and H

30 adds 50 ml of ethyl acetate and 50 ml of water to the residue, H

then the resulting mixture is adjusted to pH 6.0 with sodium H

hydrogen carbonate. The organic layer is then separated, washed with 50 ml of water and then dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue is purified by column chromatography (Wako silica gel C-200, eluent toluene / ethyl).

8303955 I

BAD ORIGINAL I

acetate = 3: 2 by volume) to obtain 2.12 g of I.

(72.4%) tert-butyl 7-phenylacetamido 3 - {/ 1- / 4- (5-methyl I

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

pyrazinyl / 7methyl} A3-cephem 4-carboxylate, melting point I.

120-122 ° C with decomposition. I

IR (KBr) cm 1: VC = Q 1820, 1775, 1715, 1685, 1645 NMR (CDCl 3) δ values: 1.58 (9H, s, -C (CH 3) 3), 2.28 (3H, s, -CH3) 3.17, 3.61 (2H, ABq, J = 18Hz, C2-H).

3.77 (2H, s, formula 80), 4.53, 5.13 (2H, ABq, J = 15Hz, formula 79), 4.71 (2H, s,> NCH -), & - 15 5.03 ( 1H, d, J = 5Hz, C.-H),

O

5.93 (1H, dd, J = 5Hz, J = 8Hz, C? -H), 6.53, 6.89 (2H, ABq, J = 6Hz, formula 78), 7.32-7.51 (5H, m, formula 81), 7.57 (1H, d, J = 8Hz, -C0NH-) In such a manner as under (1) and (2), the compounds shown in Table M are obtained.

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¥ - 78 - ((3) 2.0 g of tert-butyl 7-phenylacetamido 3- {/ 1- / 4- (5-methyl-2-oxo-1,3-dioxol-) are dissolved in 30 ml of anhydrous methylene chloride. 4-yl) methyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl 7 7-ethyl} Δ3-cephem 4-carboxylate.

To this solution, 1.59 g of Ν, Ν-dimethylaniline and 0.57 g of trimethylsilyl chloride are added in this order, and the resulting mixture is stirred at room temperature for 1 hour.

The reaction mixture is cooled to -40 ° C and 0.89 g of phosphorus pentachloride is added and the mixture is reacted at 10 -30 ° C to -20 ° C for 2.5 hours. The reaction mixture is then cooled to -40 ° C and 5.2 g of anhydrous methanol is added thereto, and the reaction is continued under ice-cooling for 1 hour. 20 ml of water are added to the reaction mixture and stirring is continued for an additional 30 minutes. The reaction mixture is then adjusted to pH 0.5 with 6 N hydrochloric acid, and the aqueous layer is then separated. 50 ml of ethyl acetate are added to this aqueous layer and the mixture is adjusted to pH 6.5 with sodium hydrogen carbonate. The organic layer is separated, washed with 50 ml of water and then 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 to obtain 1.05 g (64.8%) of tert-butyl 7-amino 3- {/ 1- / 4- (5-methyl 2-oxo 1,3-dioxol-4-yl) methyl 2,3-dioxo 1,2,3,4-tetra-25'-hydropyrazinyl / methyl} Δ3-cephem 4-carboxylate, mp 185-188 ° C with decomposition.

IR (KBr) cm -1: v 1820, 1786, 1705, 1690, 1635

v “U

NMR (CDCl_-d -DMSO) δ values: 3 6 1.52 (9H, s, -C (CH3) 3), 2.24 (3H, s, -CI ^), 3.46 (2H, bs , C2 ~ H), 4.35, 5.08 (2H, ABq, J = 15Hz, formula 79), 4.76-5.09 (4H, m,> NCH2 ~, C ^ -H, C? - H), 6.74 (2H, s, formula 78).

In such a manner, the compounds shown in Table N are obtained.

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8303955 '- 81 - ♦

Example VI

(1) 2.29 ml of N, N-dimethylacetamide and 4.58 ml of acetonitrile are dissolved in 2.29 g of 2- (2-formamidothiazol-4-yl) 2- (syn) -raethoxyiminoacetic acid and added to the 5, solution was added dropwise 1.62 g of phosphorus oxychloride, and the mixture was then reacted at -5 ° C to 0 ° C for 1 hour. Then 5.18 g of diphenylmethyl 7-amino 3 - {/ 1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) -1 / methyl} A3-cephem 4-carboxylate are added to the reaction mixture and react at -5 ° C to 0 ° C for 1 hour. After the completion of the reaction, the reaction mixture is poured into a mixed solvent of 80 ml of water and 80 ml of ethyl acetate, and the pH of the resulting solution is adjusted to 6.5 with sodium hydrogen carbonate. The organic layer is then 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. The crystals are then collected by filtration to obtain 6.05 g (83.0%) of diphenylmethyl 7- / ~ 2- (2-formamidothiazol-4-yl) 2- (syn) -methoxy-20 iminoacetamido / 3 - {/ 1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) -1 / methyl} Δ3-cefera 4-carboxylate, mp 165-168 ° C.

IR (KBr) cm ”1: vc = Q 1780, 1720, 1680, 1640 NMR (d-DMSO) 8 values: 6 25 1.18 (3H, t, J = 7Hz,> N-CH2CH3), Q 3, 59 (2H, bs, C2-H), 3.72 (2H, q, J = 7Hz,> N-CH2CH3), 3.97 (3H, s, -OCH3), 4.42, 5.04 (2H , ABq, J = 15Hz, formula 79), 5.30 (1H, d, J = 5Hz, Cg-H), 6.02 (1H, dd, J = 5Hz, J = 8Hz, C ^ H), 6.50, 6.62 (2H, ABq, J = 6Hz, formula 78) 7.04 (1H, s, -CH <), 7.17-7.82 (11H, m, x2,), 35 8.63 (1H, s, HCO-), S - 9.89 (1H, d, J = 8Hz, -C0NH-),

BAD ORIGINAL

8303955 5 * - 82 - / 12.68 (1H, bs, HCONH-).

In such a manner, the compounds shown in Tables 0, P and Q are obtained.

O

O

8303955

BAD ORIGINAL

, <r Table 0- Ν-π-C-CONH — ΓΊΓ "δΊ w n2 HCONH— ^ 4 | i SRN \ och3 COOCH (<o)) 2 (syn-isom®i3 - β ^, and IR (KBr ) cm "1:

_R2__R4 Mp. (° C) __ yc = Q

120-125 1780, 1720 / -NN-CH (decomposition) 1680-1640 x = / 3 Q nn _ 154-156 1785, 1720, (decomposition) 1685, 1645 -n_n- <ch2) 4ch3 „n _ 131-136 1783, 1725, // (decomposition) 1680, 1645 -NN (CHO) .CH_.

V— / Δ 3 O

n n - 180-182 1780, 1720, (decomposition) 1680-1640 -N_N (CH2) 7CH3, ^ _; n n w 158-166 1780, 1725, y_ ^ (decomposition) 1675, 1640 yp H 126-138. nil: ieso '-s_n-ch2- @ 8303955

BAD ORIGINAL

r ^ ï - 84 - ^ Table O (continued) 0 o Br 142 1780r 1720, y ~ l {(decomposition) 1675, 1640 -N N-CH2CH3 0 H 171-173 1780, 1720, ij (decomposition) 1690-1650 v

1 i T

H 148-151 1780, 1730,

Cjj (decomposition) 1690, 1660

V

O

H 191-195 1775, 1720, (decomposition) 1670 CH3 (Λ CH3x 'V'

O

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Table PI

fH3 N — π — C-CONH - (- t ^ Svj I

CH 3 CH 2 -? - COTHHU I CH, H2

CH3 \ O 'T I

or18 COOCHI (q), 2 l

(syn isomer) I

-3 --- 1-rs-, ™, *. CC) IR (KBr) c * '1' I

R2 r18 Mp. I w vc = 0 I

% P 176-179 1780, 1720, N NH 3 (decomposition) 1680, 1640 = 5 '- nn rTT 152-155 1780, 1720, yy 3 (decomposition) 1680, 1640 - ^ JI- (CH2 > 2CH3 Ο Ο · -ΓΤΤ 158-160 1780, 1720, ^^ Qlj 3 (decomposition) 1680, 1640 -N NCH ^ 3 ^ xch3 n 0 _rw 166-167 1780, 1720, 4 ft 3 (decomposition) 1685 »1645 -NN- (CH2) 3CH3 "\ nn _rw 162-165 1780, 1720, ^^ 3 (decomposition) 1680, 1640

- \ j- {D

n 0 r_ 145-147 1780, 1720, 3 (decomposition) 1682, 1640 -N N-CHoCHo0C0CH_ V = / 2 2 3 83 0 3 95 5

BAD ORIGINAL

t - 86 - C Table P (continued) 0 Q rH 138-144 1780, 1715, 3 (decomposition) 1690, 1620 -N> =; = n- (ch2) 7ch3 nn 88-90 1780, 1720, J y CH 3 1690-1620 -N NN ^ 3 v == y nch3 O -: ---- OO -CH CH 131 1786, 1723 'CH2CH3 (decomposition) 1684, 1645 -N N-CH2CH3 118-120 1780, 1720, | 2 3 3 (decomposition) 1660 0

II

o o _r „190-192 1780, 1720, Q) II 3 (decomposition) 1665 yy HN 2 s, 1 -Cl

"V

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Table P (continued)

CH 183-185 1780, 1720, I.

O 3 (decomposition) 1670 I

HN ^ VCH,

V

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. 128-131 1780, 1720, N 3 (decomposition) 1680, 1660

V

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v 8303955

BAD ORIGINAL

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- 88 - \ f

f Table Q

^ CHT c {N -] - C - CONH 1 f "'') ch3ch2c-oconh- <sJ II I ch2r2 \ 1CH3 COOC (CH3) 3 (syn-isomeei) - = - emnf IR (KBr> cm-1 : R2 Mp · (C) vc = 0 h 141-143 1815, 1775, -NN — CHr-r ^ CH, (decomposition) 1710, 1680, W o0 1640

Y.

o _0___ 154-156 1775, 1710, M / PV0 (decomposition) 1700, 1680, 0 0 85-88 1785, 1730, ^ (decomposition) 1715, 1660 -N N-CHo0C0C (CH,),> == / 2 3'3 O 144-146 1775, 1745, 9/9 (decomposition) 1715, 1690, M ~ 1650 -N_N-CH9C00CH {(ö)) 2 8303955

BAD ORIGINAL

- 89 - Η (2) To a solution of 6.05 g

diphenylmethyl 7- / 2- (2-formamidothiazol-4-yl) 2- (syn) - I

methoxyiminoacetamido / 3 - {/ 1- (4-ethyl 2,3-dioxo 1,2,3,4-

tetrahydropyrazinyl) / methyl} Δ3 -cephem 4-carboxylate in 31 ml I.

Methanol is added 0.5 ml of concentrated hydrochloric acid, and 1

let the mixture react at 35 ° C for 2 hours. After vol- I

After completion of the reaction, the solvent is removed by I.

distillation under reduced pressure. I. Is added to the residue

Add 100 ml ethyl acetate and 100 ml water and adjust the pH of the I.

10 solution in 6.0 with sodium hydrogen carbonate.

The organic layer is then 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 to obtain 5.1 g (87.7%) diphenylmethyl 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamido / 3 - (/ 1- (4 ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) / methyl} Δ3-cephem 4-carboxylate, m.p. 165-167 ° C.

IR (KBr) cm ”1: vc_Q 1780, 1720, 1680, 1640 20 NMR (d.-DMSO) δ values: 6 1.18 (3H, t, J = 7Hz,> N-CH2CH3), 3.55 ( 2H, bs, C2-H), 3.75 (2H, q, J = 7Hz,> N-CH2CH3), 3.90 (3H, s, -0CH3), 4.41, 5.02 (2H, ABq, J = 15Hz, formula 79), 5.26 (1H, d, J = 5Hz, C-H),

KjJ o 6.01 (1H, dd, J = 5Hz, J = 8Hz, C? -H), 6.52, 6.65 (2H, ABq, J = 6Hz, formula 78), 6.68 (1H, s, formula 82), 7.07 (1H, s, -CH ζ), 7.15-7.84 (10H, m, formula 81, x2), 9.81 (1H, d, J = 8Hz, -C0NH-).

In such a manner, the compounds shown in Table R are obtained.

8303955

BAD ORIGINAL

«

- 90 -Table R

c .N-r-C-CONH -] - f ^ '' ï \ jCH3 COOCHf <g>) 2 (syn isomer) --5 ---— mp. (° C) IR 0111: _Rf__R4 -__ vü = o 9 \ f „158-166 1780, 1720, -NN-CH (decomposition) 1680, 1640 3 O ---- 0 0 H 151-156 1780, 1720,) ) - ^ (decomposition) 1680, 1640 -N N- (CH-) 4CH, 'e = <' 2 4 3 nn „150-156 1780, 1720, ^^ (decomposition) 1680, 1640 -N N- (CH -) _ CH '\ = / 2 ^ 3 0 0 H 168-175 1775, 1723, y ^ (decomposition) 1685, 1640 -N N- (CH0) ,, CH- \ = / 2 11 3 O __, ____: ° .OH 161-166 lion 'illn' y. / V 1680, 1640 on 146 1780 '1720 <^^ (decomposition) 1680, 1640 -N NCH2CH3 1.

3303955 _ 1

BAD ORIGINAL

- 91 -. f

Table R (continued) 0 H 175-178 1780, 1720, y (decomposition) 1685 “1660 HIT'S,

V

0 rw „146-148 1780, 1720, 1 3 (decomposition) 1660

3 fS

. O ./ 8303955

BAD ORIGINAL

- 92 - * (3) 5.1 g of diphenylmethyl 7- / 2- (2-aminothiazol-4-yl) 2- (syn) - are dissolved in a mixed solvent of 20.5 ml of trifluoroacetic acid and 7.86 g of anisole. methoxyimino-acetamido / 3 - {/ 1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydro-5-pyrazinyl) / methyl} Δ3-cephem 4-carboxylate and let the solution react at room temperature for 2 o'clock. After the completion of the reaction, the solvent is removed by distillation under reduced pressure. 40 ml of diethyl ether are added to the residue and the crystals are collected by filtration to obtain 4.3 g (91.1%) of trifluoroacetic acid salt of 7- / 2- (2-aminothiazol-4-yl) 2- {syn). -methoxyiminoacetamido / 3- {/ 1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) -7-methyl} Δ3-cephem 4-carboxylic acid, m.p. 155-157 ° C with decomposition .

15 IR (KBr) cm ”1: vc = Q 1775, 1710-1630 NMR (d_-DMS0) δ values: 6 1.21 (3H, t, J = 7Hz,> -N-CH2CH3), 3.52 (2H, bs, C2-H), 3.73 (2H, q, J = 7Hz,> N-CH2CH3), 3.96 (3H, s, -OCH3), 4.44, 5.12 (2H, ABq, J = 15Hz, formula 79), 5.21 (1H, d, J = 5Hz, Cg-H), 5.83 (1H, dd, J = 5Hz, J = 8Hz, C7-H), 5.86 (3H, bs, -NH3 ^, 6.71 (2H, bs, formula 78), (^) 6.95 (1H, s, formula 82), 9.90 (1H, d, J = 8Hz, -CONH-) .

In such a manner, the compounds shown in Tables S and T are obtained.

30 8303955

BAD ORIGINAL

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i - 113 - (4) Dissolve 6f35 g of trifluoroacetic acid salt Vein 7- / 2- (2-aminothiazol-4-yl) 2- feyn) -methoxyiminoacetamido in 30 ml of water / 3 - {/ 1- (2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) / methyl} Δ3-cephem 4-carboxylic acid and adjust the resulting solution to pH 7.4 with sodium hydrogen carbonate. This solution is then purified by passing it through an Amberlite XAD-2 column to obtain 4.7 g (86.6%) sodium 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamido / 3 - {/ - (2,3-dioxo-1,2,3,4-tetrahydro-pyrazinyl) / methyl} Δ3-cephem 4-carboxylate, m.p. 200 ° C or more.

IR (KBr) cm -1: V 1763, 1670, 1650-1620.

In such a manner the following compounds are obtained: Sodium 7- / 2- (2-aminothiazol-4-yl) 2- (syn) methoxyiminoacetamido 7 3- {/ 1- (4-methyl 2, 3-dioxo 1,2,3,4-tetrahydro-pyrazinyl) 7methyl) Δ3-cephem 4-carboxylate.

Mp. 190-195 ° C (dec.) IR (KBr) cm @ -1 1760, 1670, 1650, 1630.

20 Sodium 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamido 7 3- {/ 1- (3,6-dioxol, 2,3,6-tetrahydropyridazinyl) _7- methyl} Δ3-cephem 4-carboxylate,

Sodium 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -methoxyimino-acetamido 7 3- {/ 1- (3-methyl 6-oxo 1,6-dihydropyridazinyl) _ / - 25 methyl} Δ3-cefem 4-carboxylate.

y Example VII

(1) To a solution of 3 g of 2- (2-tri-tylaminothiazol-4-yl) 2- (syn) -tert.-butoxycarbonylmethoxy-iminoacetic acid in 15 ml of Ν-dim-dimethylacetamide is added dropwise 0, Add 93 g of phosphorus oxychloride at -10 ° C and react the mixture at -5 ° C to 0 ° C for 1 hour. This solution is added dropwise to a solution of 19.4 ml of anhydrous methylene chloride, which contains 1.94 g of 7-amino 3- {/ "* 1- (4-ethyl 2,3-dioxo 1,2,3,4- tetrahydropyrazinyl) 35 methyl} Δ3-cephem 4-carboxylic acid and 2.25 g bis (trimethylsilyl) acetamide at -5 ° C to 0 ° C.

BAD ORIGINAL

8303955

V

114 - is added, the mixture is reacted at the same temperature for 30 minutes and then at 0-10 ° 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 saturated aqueous sodium chloride solution and 100 ml of acetonitrile is added to the residue. The organic layer is then separated and solid twice with 50 ml portions of saturated aqueous sodium chloride solution and the solvent is then removed by distillation under reduced pressure. The resulting residue is dissolved in 50 ml of methanol, then 1 g of diphenyldiazo-methane is added to the solution at 5-10 ° C and the mixture is reacted at the same temperature for 30 minutes.

After the completion of the reaction, the solvent is removed by distillation under reduced pressure. The residue is purified by column chromatography (Wako silica gel C-200, eluent benzene / ethyl acetate = 3: 1) to obtain 1.6 g (27.8%) of sidwnylmethyl 7- / 2- (2-tritylaminothiazol-4) -yl) 2- (syn) -tert.-butoxycarbonylmethoxyiminoacetaraido / 3 - {/ 1-20 (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) _7methyl} Δ3-cephem 4-carboxylate mp 98-100 ° C with decomposition.

IR (KBr) cm-1: v 1780, 1720, 1680, 1630 NMR (d_ — DMSO) δ values: 6 25 1.17 (3H, t, J = 7Hz,> NHC2CH3), O 1.44 (9H, s, -C (CH3) 3), 3.62 (2H, bs, C2-H), 3.74 (2H, q, J = 7Hz,> N-CH2CH3), 4.55 (2H, s, formula 86) , 30. 4.51, 5.16 (2H, ABq, J = 15Hz, formula 79), 5.27 (1H, d, J = 5Hz, Cg-H), 5.87 (1H, dd, J = 5Hz, J = 8Hz, C 1 -H), 6.55 (2H, bs, formula 78), 6.80 (1H, s, -CH <), 6.97 (1H, s, formula 82), 7.05-7 .67 (25H, m, formula 81, x 5),

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In such a manner, the compounds shown in Tables 4 and V are obtained.

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- 120 - (2) 1.6 g of di-phenylmethyl 7- / 2- (2-tritylaminothiazol-4-yl) 2- (syn) tert- are dissolved in a mixed solvent of 8 ml of trifluoroacetic acid and 3 ml of anisole. butoxycarbonylmethoxyiminoacetamido / 3- {/ 1- (4-ethyl 2,3-5 dioxo 1,2,3,4-tetrahydropyrazinyl) _7} Δ3-cephem 4-carboxylate and let the solution react at room temperature for 1 hour. After the reaction, the solvent is removed by distillation under reduced pressure. 10 ml of diethyl ether are added to the residue and the crystals are collected by filtration. The crystals obtained are then dissolved in 20 ml of 50% by weight aqueous formic acid and the solution is allowed to react at 45-55 ° C for 1 hour. After the reaction, 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. The crystals are then washed sufficiently with 10 ml of ethyl acetate and dried to give 0.7 g (80.7%) of 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -carboxy-methoxyiminoacetamido / 3 - {/ 1- (4-ethyl 2,3-dioxo 1,2,3,4-20 tetrahydropyrazinyl) / methyl} Δ3-cephem 4-carboxylic acid, mp 139-40 ° C with decomposition.

IR (KBr) cm-1: vq_o 1775, 1695, 1680, 1635 NMR (d -DMSO) 6 values: 6 1.22 (3H, t, J = 7Hz,> NCH2CH3), 25 3.53 (2H, bs, C2 -H), 3.74 (2H, q, J = 7Hz,> NCH2CH3>, 4.70 (2H, s, -OCH2CO-), 4.45, 5.10 (2H, ABq, J = 15Hz, formula 79), 5.23 (1H, d, J = 5Hz, Cg-H), 5.90 (1H, dd, J = 5Hz, J = 8Hz, C? -H), 6.69 (2H, bs, formula 78) , 6.94 (1H, s, formula 82), 9.70 (1H, d, J = 8Hz, -CONH-).

In such a manner, the compounds shown in Table W are obtained.

83 0 3 95 5

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8303955-129 - t

Example VIII

(1) To a solution of 1.68 g of dichloride in 8.40 ml of anhydrous methylene chloride, a solution of 2.08 g of bromine in 6.25 ml of water-5 free methylene chloride is added dropwise with stirring at -30 ° C and react the mixture at -30 ° C to -20 ° C for 30 minutes.

The reaction mixture thus obtained is added dropwise at -30 ° C or less to a solution of 50 ml of anhydrous methylene chloride, which contains 5.20 g of diphenylmethyl 7-amino 3- {/ Ι-ΙΟ (4-ethyl 2,3-dioxo 1). 2,3,4-tetrahydropyrazinyl) / methyl} Δ3-cephem 4-carboxylate and 4.08 g of bis (trimethylsilyl) acetamide.

When everything is added dropwise, the mixture is reacted at -30 ° C to -20 ° C for 30 minutes and then at 0-10 ° C for 1 hour. After the completion of the reaction, 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 then separated, washed with 40 ml of water and 40 ml of a saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate.

The solvent is removed by distillation under reduced pressure. To the residue 50 ral diisopropyl ether is added and the crystals thus obtained are collected by filtration to obtain 5.85 g (85.6%) diphenylmethyl 7- (4-bromo-3-oxobutylamido) 3- {/ 1- ( 4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) 7methyl} Δ3-cephem 4-carboxylate, mp 138-142 ° C (decomposition).

IR (KBr) cm 1: vc = Q 1778, 1720, 1680, 1640, 30 NMR (d-—DMSO) δ values; 6 1.22 (3H, t, J = 7Hz,> NCH2CH3), 3.40 (2H, bs, C2-H), 3.85 (2H, q, J = 7Hz,> NCH2CH3), 3.87 (2H, bs, BrCH ^ OC ^ ”, 35 4.18 (2H, bs, BrCH2CO -77 4.47, 4.96 (2H, ABq, J = 15Hz, formula 79),

BAD ORIGINAL

8303955 \ - 130 - t 5.04 (1H, d, J = 5Hz, Cg-H), 5.90 (1H, dd, J = 5Hz, J = 8Hz, C? -H), 6.15, 6.50 (2H, AB, J = 6Hz, formula 78), 6.98 (1H, s, -CüC.), 7.40 (10H, bs, formula 81 x 2), 8.55 (1H, d, J = 8Hz, -CONH-)

In such a manner the following compound is obtained: 4.09 g (62.6%) diphenylmethyl 7- (4-bromo-3-oxo-butylamido) 10 3- {/ 1- (3,6-dioxo 1,2,3) 6-tetrahydropyridazinyl) 7methyl} - Δ3-cephem 4-carboxylate, mp 124-126 ° C (decomposition).

IR (KBr) cm-1: vc_Q 1780, 1725, 1660, - v NMR (d- —DMSO) <5 values:) 6 3.49 (4H, bs, C 1 -H, formula 84), 15 4 , 52 (2H, s, formula 85), 5.06 (1H, bs, formula 79), 5.26 (1H, d, J <5Hz, Cg-H), 5.90 (1H, dd, J = SH 2, J = 8Hz, C? -H), 7.01, 7.25 (2H, ABq, J = 19Hz, formula 78), 7.09 (1H, s, -CH <), 7.24-7, 91 (10H, m, formula 81 x 2), 9.34 (1H, d, J = 10Hz, -C0NH-).

(2) To a solution of 5.50 g of diphenylmethyl 7- (4-bromo-3-oxobutylamido) 3 - {/ ~ 1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl} Δ3-cephem X ^ J 4-carboxylate in 30 ml of acetic acid, a solution of 5 ml of water containing 0.74 g of sodium nitrite is added dropwise under ice-cooling for 1 hour, and the resulting mixture is reacted at room temperature for 2 hours.

After the completion of the reaction, 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 then purified by column chromatography (Wako silica gel C-200, elution agent benzene / ethyl acetate = 2: 1 by volume) to obtain 3.15 g (54.9%). diphenylmethyl 7- (4-bromo 2-hydroxyimino 3-oxobutylamido) 3 - {/ 1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydro- 8303955

BAD ORIGINAL

4 - 131 → pyrazinyl) 7methyl} Δ3-cephem 4-carboxylate, m.p. 127-132 ° C (decomposition).

IR (KBr) cm ”1: v 1778, 1720, 1680, 1635 NMR (CDCl ^) δ values: 5 1.26 (3H, t, J = 7Hz,> NCH2CH3), 3.47 (2H, bs, C2 ~ H), 3.81 (2H, q, J = 7Hz,> NCH2CH3), 4.52 (2H, s, BrCH2C0-), 4.53, 4.78 (2H, ABq, J = 15Hz, formula 79 ), 10 5.11 (1H, d, J = 5Hz, C.-H), 6 5.80-6.15 (1H, m, Cy-H), 6.13, 6.52 (2H, ABq , J = 6Hz, formula 78), ^ 7.02 (1H, s, -CH <), 7.41 (10H, bs, formula 81 x 2), 9.20 (1H, d, J = 8Hz, -CONH-)

In such a manner the following compound is obtained: 4.71 g (75.1%) diphenylmethyl 7- (4-bromo-2-hydroxyimino-3-oxo-butylamido) 3- {/ 1- (3,6-dioxo 1, 2,3,6-tetrahydropyridazinyl) J-20 methyl} Δ3-cephem 4-carboxylate, mp 138-141 ° C (decomposition).

IR (KBr) cm ”1: \> C = Q 1780, 1720, 1660 NMR (d - DMSO) δ values: 6 3.46 (2H, bs, C2-H), 25 4.62 (2H, s , BrCH CO-) \ yy 4.96 (2H, bs, formula 79), 5.18 (1H, d, J = 5Hz, Cg-H), 5.93 (1H, dd, J = 5Hz, J = 8Hz, C 1 -H), 6.89, 7.13 (2H, ABq, J = 10Hz, formula 78), 6.96 (1H, s, -CH <), 7.13-7.72 ( 10H, m, formula 81 x 2), 9.45 (1H, d, J = 8Hz, -CONH-) 13.36 (1H, s, = N-OH).

(3) 3.00 g of the diphenyl 35- (4-bromo-2-hydroxyimino-3-oxobutylamido) 3 - {/ 1- (4-ethyl 2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) are dissolved ) _ / methyl} Δ3-cephem

BAD ORIGINAL

8303955% - 132 - t, 4-carboxylate, obtained under (2) above and 0.42 g of thiourea in 12 ml of N, N-dimethyl acetamide and react the resulting solution at room temperature for 3 hours. After the completion of the reaction, the reaction mixture is poured into a mixed solvent of 120 ml of water and 240 ml of ethyl acetate. The pH of the mixture is then adjusted to 7.0 with sodium hydrogen carbonate, the organic layer is separated, and washed with 50 ml of water and 50 ml of a saturated aqueous sodium chloride solution in this order. After the organic layer is 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 of diphenylmethyl 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -15 hydroxyiminoacetamido_7 3 - {/ l- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) -1 / methyl} Δ3-cephem 4-carboxylate mp 137-140 ° C (decomposition).

IR (KBr) cm ”1: V 1778, 1720, 1680, 1640, NMR (d -DMSO) 6 values: 6 20 1.19 (3H, t, J = 7Hz,> NCH2CH3), - 3.48 (2H , bs, C2-H), 3.68 (2H, q, J = 7Hz,> NCH2CH3), 4.46, 5.04 (2H, ABq, J = 15Hz, formula 79), 5.28 (1H, d, J = 5Hz, Cg-H), 5.97 (1H, dd, J = 5Hz, J = 8Hz, C? -H), 6.57, 6.75 (2H, ABq, J = 6Hz, formula 78), 6.79 (1H, s, formula 82), 7.07 (1H, s, -CH <), 7.53 (10H, bs, formula 81 x 2), 9.70 (1H, d, J = 8Hz, -CONH-).

(4) 2.00 g of the diphenylmethyl 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -hydroxyiminoacetamido_7 are dissolved in a mixed solvent of 10.0 ml of trifluoroacetic acid and 2.0 ml of anisole. 3 - {/ 1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) _7methyl} Δ3-35 cephem 4-carboxylate, obtained under (3) above and react the resulting solution at room temperature for

BAD ORIGINAL

8303955 4 - 133 - 2 hours. After the reaction, the solvent is removed by distillation under reduced pressure, 15 ml of diethyl ether are added to the residue, and the crystals are collected by filtration. The crystals were then washed sufficiently with 10 ml of diethyl ether and then dried to obtain 1.62 g (87.6%) of the trifluoroacetic acid salt of 7- / 2- (2-aminothiazol-4-yl) 2- ( syn) -hydroxyiminoacetamido / 3 - (/ 1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) _ / methyl> Δ3-cefem 4-carboxylic acid, mp 112-118 ° C (decomposition) .

10 IR (KBr) cm-1: vc_Q 1780, 1680, 1620 NMR (d_-DMS0) δ values: 6 1.19 (3H, t, J = 7Hz,> N-CH2CH3), 3.47 (2H, bs , C2-H), ^ 3.72 (2H, q, J = 7Hz,> NCH2CH3), 4.45-6.70 (4H, m, formula 79, Cc-H, C_-H), 6, 59-6.83 (3H, m, formula 78, 82).

Example IX

(1) To a solution of 7.1 g of diphenylmethyl 7- {4-bromo 2-hydroxyimino 3-oxobutylamido) 3-20 {/ 1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl methyl} Δ3-cephem 4-carboxylate in 70 ml of anhydrous methylene chloride, slowly add a solution of diazomethane in diethyl ether at -5 ° C to 0 ° C and react the resulting solution at the same temperature for 30 minutes. After the disappearance of the diazomethane has been determined, the solvent is removed by distillation under reduced pressure.

The residue obtained is then purified by column chromatography (Wako silica gel C-200, eluent, benzene: ethyl acetate = 3: 1 by volume) to obtain 2.32 g (32.0%) of diphenylmethyl 7- / 4- bromo-2- (syn) -methoxyimino 3-oxobutylami do / 3 - [/ 1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) J-methyl} Δ3-cephem 4-carboxylate mp 135-140 ° C (decompn.).

IR (KBr) cm -1: VC_Q 1778, 1720, 1682, 1638 35 NMR (CDC13) δ values: 1.25 (3H, t, J = 7Hz,> NCH2CH3),

BAD ORIGINAL

8303955 ¥ - 134 - <3.48 (2H, bs, C2-H), 3.84 (2H, q, J = 7Hz,> NCH0CH_), 4.00 (3H, s, -OCH3), 4.10 (2H s, BrCH2CO-), 4.48, 4.67 (2H, ABq, J = 15Hz, formula 79), 5.10 (1H, d, J = 5Hz, Cg-H), 6.05 (1H, dd, J = 5Hz, J = 8Hz, 6.38, 6.73 (2H, ABq, J = 6Hz, formula 78), 6.98 (1H, s, -CH <.), 10 7.32 (10H , bs, formula 81 x 2), 9.18 (1H, d, J = 8Hz, -CONH-)

In such a manner the following compound is obtained: 1.70 g (24.5%) diphenylmethyl 7- / 4-bromo-2- (syn) -methoxy-imino 3-oxobutylamido-7 3 - {/ 1- (3 6-dioxo 1,2,3,6-tetrahydro-pyridazinyl) 7methyl} Δ * -cephem 4-carboxylate, mp 145-148 ° C (decomposition).

IR (KBr) cm ”1: 1780, 1730, 1660 NMR (d.-DMSO) δ values: 6 20 3.49 (2H, bs, Ο ,, - Η), 4.03 (3H, s, -OCH3 ), 4.60 (2H, s, BrCH2CO-), 5.02 (2H, bs, formula 79), 5.30 (1H, d, J = 5Hz, Cg-H), 6.02 (1H, dd, J = 5Hz, J = 8Hz, C? -H), 6.92, 7.16 (2H, ABq, J = 10Hz, formula 78), 6.99 (1H, s, -CH <), 7 , 17-7.78 (10H, m, formula 81 x 2). 10.16 (1H, d, J = 8Hz, -CONH-) 30 (2) 2.3 g of diphenylmethyl 7- / 4-bromo 2- (syn) -methoxyimino 3-oxobutylamido 7 3 - {/ 1- are dissolved (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) 7methyl} Δ3-cephem-4-carboxylate and 0.32 g thiourea in 14 ml N, N-dimethyl acetamide and leave the resulting solution react at room temperature for 3 hours. After the reaction, the reaction mixture is poured into a mixed solvent of 50 ml of water

BAD ORIGINAL

8303955 4-135 → and 150 ml 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 further extracted twice with 100 ml portions of ethyl acetate.

The combined organic layer is washed with water and dried over anhydrous magnesium sulfate and 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 1.92 g (86.3%) of diphenylmethyl 10 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamido / - 3 - {/ 1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyDimethyl} Δ3-cephem 4-carboxylate mp 165-167 ° C.

ΘΙβ (KBr) cm "1: v 1780, 1720, 1680, 1640

CO

In such a manner the following compound is obtained:

Diphenylmethyl 7- / 2- (2-aminothiazol-4-yl 2- (syn) -methoxyiminoacetamido / 3 - {/ 1- (3,6-dioxo 1,2,3,6-tetrahydro-pyridazinyl) _ / methyl} Δ3-cefem 4-carboxylate, mp 175-178 ° C (dec.).

20 IR (KBr) cm "1: v 1780, 1720, 1685-1660 v" v

The same cyclization reaction as above and then the reaction mentioned in Example VI- (3) or Example VII- (2) are carried out to obtain the compounds shown in Tables x, Y and Z.

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\ - - / © 0 0 CH,

Vf I 3

—N_NCH? CH2 CF3 COOH-NH2 -C-C00H

CH3 0 0 ΉΓ

—N NH NH — -CH-COOH

\ - / «ώ ^" 'V 1' "—M l - l» «I ^ —I HM II Ι · ΙΙ - ^ - IM · —.1»! ..

^ O o —N_nch3 cf3cooh «nh2- -ch2cooh 0 0 M ^ CH3

-N N-N CF, C00H-NHO-CHoC00H

V = V V 3 2 2 xch3 8303955

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f - 141 - Γ Table. Y (continued) v. -! 0

HN

| HCOOH-NH-- -CH-COOH

-N ^ *

V

o CH-T3

N ^ f] HCGOH-NHO -CH-COOH

I 2 2

Θ. V

O

O / O

N '_, ΧΒ2? C'CH3 NH- -CH, COOH

V

o o o - / "Wy ° m> '-ch2cooh o w ® o o

- / Λ, CH-OCOC (CH 2) - NHO- -CHoCO 2 H 1

W / 2 33 2 2

BAD ORIGINAL

8303955 ^ Table (. (Continued) - 142 -. τ

0 O

b ~ i

- N NCH-COOH NH-- -CH-COOH

W / 2 * 2

O O

} ~ i / -λ ~ N NCH-CH, HCOOH-NH-- -CH-C00- (O> O -: --- O o J_ ^ Γ ~ η

- n ^ ich2ch3 hcooh-nh2 -CH2co <xgH

o o - t / ^ NCH2CH3 hcooh-nh, - -ch2cooch2ch3 o 8303955

BAD ORIGINAL

{· - 143 -

C Table Z

N-j-C— CONH ___ / 5 v H2N ~ \ 11 i R2

2 \ yy N - ^ ^ CH2R

^ OCH- O | 1

J COOR

(syn-isolate) R1 R2

0v P

h ~ i -CHOCOC (CH3) 3 N NCH2CH3 Θ ch3 ° H ° -CHOCOC (CH-) Ί - N NCH, | 33 \ = / 3 ch3

P

-CHOCOC (CH -) - - N N - {CH0) aCH_ | 3 3 n (2 4 3 ch3 O --- -CHOCOC (CH3) 3 —N N- (CH2) 5CH3 CH3 83 0 3 9 5 5

BAD ORIGINAL

Table Z (continued) - 144 - * .- ♦ (

0 / P

y ^ (-CHOCOC (CH_). -N N (CH0) -, CH., | J 3 - / 2 7 3 CH3

O .O

7 ^ ^ -CHOCOC (CH -) - - N N (CH -),. CH, «3 J _ y 2 11 3 CH 3 -n *. ^ J O o -CH2OCOC (CH3) 3 —N ^ JCH2CH3 O0 -CHOCOOC (CH.). —N NCH-CH- 3 3 V - / 2 3 CH3

* OO

W0 ~ - (CH2) 3CH3 -N NCH2CH3 8303955

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('·, - 145 - ζ Table Ζ (continued)! -CH C = C-CH3 ° ^ f ó h -NwNCH2CH3

Y.

f »3 -CHjOCOC (CHj) 3

Q O

CH,

ch-I

-CH-OCOC (CH-) - ff * J J —N u

T

O

O

-CH2OCOC (CH3) 3 HN ^ N

__2_ -CH-OCOC (CH -) ^ ^ Y Y -N 11

O

8303955

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Table Z (cont.) - 146 -% CH-, -CHOCOC (CH -) - I | L V ...

CH3 0

O O

H, Ow, ° 1 -CH2OCOC (CH3) 3 -N N / y 1 W © * Hydrochloride

The physical properties (melting point, infrared and nuclear magnetic resonance spectra) of the above compounds are the same as those obtained in Examples VI, VII, XI and XII.

/'-X

V

/ 8303955

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- 147 - »

Example X.

(1) To a suspension of 2.2 g of 2- (2-formamidothiazol-4-yl) glyoxylic acid in 11 ml of N, N-dimethyl acetamide, 1.8 g of phosphorus oxychloride 5 are added dropwise at -20 ° C. and react the resulting mixture at the same temperature for 2 hours. A solution of 26 ml of methylene chloride, which contains 5.2 g of diphenylmethyl 7-amino 3 - {/ 1- (4-ethyl 2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) 7-diethyl, is then added to this reaction mixture. } Δ3-cefem 4-carboxylate 10 contains at -30 ° C to -20 ° C. After completion of the dropwise addition, the mixture is allowed to react at the same temperature for 1 hour. After the 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 sodium chloride solution 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 (Wako silica gel C-200, eluent; chloroform / methanol = 20: 1 by volume) to give 1.4 g (20.0%) diphenylmethyl 7- / 2- (2- formamidothiazol-4-yl) glyoxylamido_7 3 - {/ 1- (4-ethyl 25 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) _7methyl} Δ3-cefem 4-carboxylate mp 140-145 ° C (decomposition ).

IR (KBr) cm-1: vc = Q 1780, 1720, 1680, 1670, 1640, NMR (d-DMSO) δ values: 6 1.20 (3H, t, J = 7Hz,> NCH2CH3), 30 3, 50 (29, bs, C2 ~ H), 3.69 (2H, q, J = 7Hz,> NCH2CH3), 4.40, 5.00 (2H, ABq, J = 15Hz, formula 79), 5.30 (1H, d, J = 5Hz, C - H),

O

6.00 (1H, dd, J = 5Hz, J = 9Hz, C? -H), 35 6.50, 6.62 (2H, ABq, J = 5Hz, formula 78), 7.04 (1H, s -CH <.), 8303955

BAD ORIGINAL

- 148 - t 7.30 (10H, bs, formula 81 x 2), 8.64 (1H, s, formula 82), 8.81 (1H, s, HCONH-), 10.20 (1H, d , J = 9Hz, -CONH-) 5 12.90 (1H, bs, HCONH-)

In such a manner the following compound is obtained: 0.09 g (19> 2%) diphenylmethyl 7- / 2- (2-formamidothiazol-4-yl) glyoxylamido / 3 - {/ 1- (3,6-dioxo 1 2,3,6-tetrahydropyridazinyl) 7methyl} 3-cephem 4-carboxy-10 late. Mp. 153-154 ° C (decompn.).

I IR (KBr) cm "1: vc = Q 1780, 1725, 1690, 1665 NMR (CDC1, + d-DMSO) δ values: 3 6 3.42 (2H, bs, C2-H), 4.96- 5.40 {3H, m formula 79, Cg-H), 5.95 (1H, dd, J = 5Hz, J = 8Hz, C? -H), 6.72-7.78 (13H, ra, -CH, formula 78, formula 81 x 2), 8.66 (1H, s, formula 82), 8.73 (1H, s, HCO-), 9.86 (1H, d, J = 8HZ, -CONH -) 20, (2) To a solution of 7.0 g - diphenylmethyl 7- / 2- (2-formamidothiazol-4-yl) glyoxylamido / - 3 - {/ - (4-ethyl 2,3-dioxo 1, 2,3,4-tetrahydropyrazinyl) / methyl} Δ3-cephem 4-carboxylate in 35 ml Ν, Ν-dimethylacetamide, 1.7 g of methoxyamine hydrochloride are added under ice cooling and the resulting mixture is reacted at 15-20 ° C for 3 hours After the reaction, the reaction mixture is poured into a

-ST

mixed solvent of 250 ml of water and 250 ml of ethyl acetate and separates the organic layer, washes with 250 ml of water and 250 ml of a saturated aqueous sodium chloride solution in this order, and dries over anhydrous magnesium sulfate.

The solvent is then removed by distillation under reduced pressure. 50 ml of diethyl ether are added to the residue and the crystals obtained are collected by filtration to obtain 6.1 g (83.7%) of diphenylmethyl 7- / 2- (2-form-35 amidothiazol-4-yl) 2- ( syn) -raethoxyiminoacetamido / -3 - {/ 1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) _7methyl} Δ3-8303955

BAD ORIGINAL

7 - 149 - cefem 4-carboxylate with melting point 165-168 ° C.

IR (KBr) cm -1: v 1780, 1720, 1680, 1640

In such a way the following compound is obtained: 5-diphenylmethyl 7- / 2- (2-formamidothiazol-4-yl) 2- (syn) -methoxy-iminoacetamido / 3 - {/ 1- (3,6-dioxo 1, 2,3,6-tetrahydropyridinyl) / methyl} Δ3-cephem 4-carboxylate, m.p. 171-173 ° C (decompn.).

The same oxidation reaction as above and then the reaction mentioned in Example VI- (2), (3) and / or Example VII- (2) is carried out to obtain the following compound and the compounds shown in Tables AA, BB and CC: (7% v / Trifluoroacetic acid salt of 7- / 2- (2-amino-5-bromothiazol-4-15 yl) 2- (syn) -methoxyiminoacetamido / 3 - (/ 1- (4-ethyl 2 1,3-dioxo 1,2,3,4-tetrahydropyrazinyl) 7methyl} 3-cephem 4-carboxylic acid, mp 147 ° C (decompn.).

IR (KBr) cm -1; v 1775, 1680, 1640.

20

O

8303955

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. X

- 150 -

TT

ΰ s o and • i-4

«M {I

> i Cl CM cn 3! a a ~ o o

O O CN

/ u -

/ CN CN CN

/ B «.33 K

/ “\ _ 8 V ^ ° rr« o: o --1 -! - o · B * 2 «η 0 auo 1 o _ <I / <0 = 2 η | =, <i) I l __ ___ yes 2 03 m /; Cl f * \ 8 T $ -0 ”5Λ> ° CM 2— 2 /, 4. a 1 o o.

oh you! j fe ^ α cn a u N *

CN

d 23 a cj υ - CN I | “T) Ύ) o ^ zr

«I

BAD ORIG ^ I ^ L ^ ^ ^ ^ 5 Ί - 151 - -Η »θ ι '>' Ο * t ο = \ y ° 4 = 1 <u; Λ! asf --—-----

Ent η 33 Ο η Ο 35 Ο Ο Ο Γ "« Μ -.

CM 33 CN

es. υ x ° xS 10 I ι 8303955

BAD ORIGINAL

- 152 - * \ i \ r ~

, 1 4 I

ÏJi

H

0 m> ^ s-ι m <ü tc

> and O

^ 33 -. . U O C_) S ώ - 0 \ \ 8 1 r ^ ° v® i "X): o: o

I I I

o.

n - T \ "** w / V.

jn 3 0

<N (N

53 a csj X) DÓ: Ó

1 I I

8303955

BAD ORIGINAL

f - 153 - r! ° <ί> Λ -o

s = I '»I

9 * s l — l ω

• Q

J

E-t * ----- —-- <u

• H

O

fH

• C

n cn o

33 33 mm O

OU X 33 £ \ / ου5 S3 XX / = \ *** «vs, °, Js ϋ-Γ>. * X) £). "o 1 __; ___ 8303955

BAD ORIGINAL

- 154 -

Table BB

e! N-C-CONH-i-fS> R 's I 0XX ^ CH2R2

^ OrIS COOH

(syn isomer) R2 R5 R18 V / - ir nch2ch3 nh2- -ch2cooh 1 w O O CH-, V-f I 3

CH2CH3 CF3COOH.NH2- -C-COOH

"I

ch3 o o

Vf

—N NH NH — -CH-COOH

v — J £ Z

O O

y-t

-N NCHj CF3COOH.NH2 -CHjCOOH

O O

M ^ CH3

- N N-N CF, COOH-NH-- -CH-COOH

v 3 2 2 xch3 BAD OF ^ lSl ^ ^ ® ^ c ', - 155 - C Table BB (continued)

O

A.

HN

| HCOOH-NH, -CH-COOH

"V

o CH, 13

N ^ 1 HCQOHINE -CH-COOH

I .22

° -V

o O .0

-N NCHlCl 2 -CHl 2ch, C00H

V

O

-HLv \ NV ~ CH2C00H

W © O o

-N ^ ch2ococ (CH3,3 NH2 "-CHLORINE

§303955

BAD ORIGINAL

. V

Table BB (continued) - 156 - 0 0

-N NCH-COOH NH, -CH-COOH

O O

y_ ^ - N NCH-CH- HCOOH-NH, - -CHoC00- (o) n '2 3 2 2' —f 1 __: __; __ O o y ^ s-C ~ i

-iQch, ch, · hcooh.nh2- -ch2cooXöV

• o o D {- n__ixca2ca2 hcooh-nh2- -ch2cooch2ch3 ^ - <«· 8303855

BAD ORIGINAL

- 157 - r

^ Table CC

Ν-η-C— CONH \ H2N "^ sJ 11 J ~ * ~ J ~ CS 2r2 ^ OCH, O I 1

J COOR

(syn isomer) R1 R2

Oy P

y ~ i -CHOCOC (CH3) 3 N NCH2CH3

Q I

CH3 O .0 y ~~ i -CHOCOC (CH-) - - N NCH.

I 3 3 \ / 3 CH3 0 .0 -CHOCOC (CH-) - —N N- {CH ,,) CH_ I 33 \ / 2 '4 3 “3 O ---: -: - w,, -CHOCOC (CH_), —N N- (CHn) _CH, I 3 3 N- / "5 3 ch3 3303955

BAD ORIGINAL

Table CC (continued)

V

- 158 - W * -CHOCOC (CH *) - -N N (CB-) -CH- yo J V / / / o CH3 Q, 0 -CH0C0C (CH,) - —N N (CH.,),, CH, | 3 3 n / 2 11 3 ch3 o --------

Oy -CH2OCOC (CH3) 3 -N ^ CH2CH3 o y0 -CHOCOOC (CH,) —N NCH, CH,

j 3 -> \ = ", / - J

CH3

^ ^ / P

-g / ° Ή5 - (CH,), CH, —N NCH, CH,

to O J J

8303955

BAD ORIGINAL

*

Table CC (continued) - 159 - CHo Λ —CHOCOC (CH3) 3 I j L - CH3 o

0 / O

Hy ° vo

-CH2OCOC (CH3) 3 -N_N - / _ Y

9 <ö> * Hydrochloride

The physical properties (melting point, infrared and nuclear magnetic resonance spectra) of the above compounds are the same as those obtained in Examples VI, VII, XI and XII.

O

8303955

BAD ORIGINAL

* ^ - 160 -

Example XI

(1) 7.29 g of diphenylmethyl 7- / 2- (2-formamidothiazol-4-yl) 2- (syn) -methoxy-5-iminoacetamido are dissolved in a mixed solvent of 37 ml of trifluoroacetic acid and 10.8 g of anisole. 7 3 - {/ 1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydro-pyrazinyl) 7methyl} Δ3-cephem 4-carboxylate and react the resulting solution at room temperature for 2 hours. After the reaction, the solvent is removed by distillation under reduced pressure. 50 ml of diethyl ether are added to the residue obtained and the crystals are collected by filtration, washed sufficiently with 50 ml of diethyl ether and dried to obtain 5.2 g (92.4%) of 7- / 2- (2-formamido-thiazole). -4-yl) 2- (syn) -methoxyiminoacetamido_7 3 - (/ 1- (4-ethyl-2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) _7methyl} Δ3-ce-15 fem 4-carboxylic acid mp 155-158 ° C (decomposition).

IR (KBr) cm 1: VC = Q 1775, 1710, 1675, 1640 NMR (d.-DMSO) δ values: 6 1.20 (3H, t, J = 7Hz,> NCH2CH3), 3.49 (2H, bs , C2-H), 3.73 (2H, q, J = / Hz,> NCH2CH3), 3.91 (3H, s, -0CH3), 4.42, 4.95 (2H, ABq, J = 15Hz, formula 79), 5.21 (1H, d, J = 5Hz, Cg-H), 5.89 (1H, dd, J = 5Hz, J = 8Hz, C? -H), 6.65 (2H, bs, formula 78), 7.46 (1H, s, formula 82), 8.59 (1H, s, HCONH-), 9.77 (1H, d, J = 8Hz, -CONH-), 12.58 (1H, bs, HCONH-) In such a manner, the compounds shown in Table DD are obtained.

8303955

BAD ORIGINAL

*. '' r - 161 -

Table PD

N-ir-C-CONH-1-HCONH-J] Nv ^ LCH2R2

^ OCH C00H

(syn isomer) IR (KBr) - Mp. (° c) -1

R2 _i vc = Q

O O 195-198 1775, 1720, H (dec.) 1680-1640 -N N-CH, \ == ^ 3 o ---- • on

y ~ K

-N N- (CH2) .CH, 122-125 1775, 1680, W 2 4 3 (dec.) 1640

__ I

i at: M - i -N N- (CH,),. CH- 165-170 1775, 1680,,

Ne = y 'J (dec.) 1640

O O

h-K / Ov -N N- (V-o 195-198 1775, 1685, N = 2 /} - <(dec.) 1650 W;

O O

hJi -N N (CH-) 7CH- 155-158 1780, 1720, J (dec.) 1680-1640

QO

M

-N_N- (CH2), CH ^ 144-147 1778, 1685, W (dec.) 1660, 1645 83 0 3 9 5 5 bad original *

Table PD (continued) - 162 - CH, i 3 | 186-188 1775, 1710, -N. % 1690, 1650 (dec.)

O

CH CH3

^ 1 I

-) 218-221 1775, 1670, (dec.) 1650

O

? 8303955

BAD ORIGINAL

> - 163 - (2) To a solution of 5.63 g of 7- / 2- (2-formamidothiazol-4-yl) 2- (syn) -methoxyiminoacet-amido 7 3 - {/ 1- (4-ethyl 2 1,3-dioxo 1,2,3,4-tetrahydropyrazynyl) / methyl} Δ3-cephem 4-carboxylic acid in 25 ml of N, N-dimethyl-5-acetamide, 1.52 g of 1,8-diazabicyclo / 5 are added. Add 4.0-7-7-undecene and 3.84 g of 1-pivaloyloxyethyl iodide under ice-cooling and react the resulting mixture for 30 minutes. After the reaction, the reaction 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 then dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. 50 ml of diethyl ether are added to the residue and the crystals are collected by filtration to obtain 5.5 g of 15 (79.6%) 1-pivaloyloxyethyl 7- / 2- (2-formamidothiazol-4-yl). ) 2- (syn) -methoxyiminoacetamido_7 3 - {/ 1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) _ / methyl} Δ3-cephem 4-carboxylate, melting point 140-142 ° C.

IR (KBr) cm -1: vc_0 1780, 1740, 1680, 1640. In such a manner, the compounds shown in Table EE are obtained. In this case, the compounds shown in Table EE can also be obtained in the same manner as in Example VI- (1), provided that the corresponding esters are substituted for the diphenyl-methyl esters.

O

8303955 bad original - 164 -

TT

<u e 0

ai O

• h II o o -.

1 CJ O M · «3 · o C> m · vo vo

> 1 VO Η H VO

w ·· ih, h H I -> | I o o o o S oo 00 00 00

CM O vo yj 'co VO

«Η Η H 1—1 I - CM H - -».

S 09 O O O O

CJ Ï * S m rp TT

ri ^ r · * r- r ~

J / -i 8 5 T

W 'ύ— CJ O CO CM o \ / 00 00 00 00 V — 2 f— Γ ~~ Γ "ï" I Η Η H i — t -k W O -'------

W 33 Z.

HO co <ü O 33 O oo- 'cm - in co -Q I O o OO · CM · H · VO - nj I O "" Η Η I — t I — I f — t H ·

E- * I / I - »- 1 I * +> I I H

CJ = Z * CM C o C 00 vo -P

K-P 00 0 CM O o vo C

g Η ^ H _____ Η H o CO ^ ^ z cn

V

PT * z O co and co O S X S3

S3 · O O O

,. · O, μ · m r- V »I! CO CM I CM | "” Cm ": ώ X) x) xj

I I I I

co co co co co co co co * m ** · · * · * M4 · * · ·

^ O U u O

CS U O CJ CJ

O O O O

O CJ CJ CJ

O co O co o co O co

S3. B EB SB SS

CJ-O CJ-CJ CJ-CJ o-CJ

i i i i 8303955

BAD ORIGINAL

<', - 165 - C _ m ο ο ο τρ ^ · τρ τρ

VO VO VO VO

H iH (H rH

* * * »M ο ο o oo oo oo o co vo vo vo vo

Ή rH rH VO rH

H

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Tp Tp vo co cn r- r ~ r- vo ps.

Ή rH iH iH rH

t. "j *" * <· * -

w in O O O O

00 00 GO 00 00 - »r- r * η» r ~

0v <H (H iH iH rH

Η 0> ------- 0) £

<N O CN CN rH

W cn vo in vo tp ___ W H rH H rH rH

I I I I rH

Η Γ- 00 Ο O VO + J

<1> rH in in VO M C

»9 Ή iH rH iH iH 0 (0 -

Eh m

E

YOU

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S CN U O Ü Ο E cn m cm: xi): xh ° xj: xh: x; i

1 t l I I

iH

n * «Ό -. n ns ro B U O m

= O d „B

O B \\ CJ

~ U U An. n U O O O fol -

O U O CN

U O U T B

O cn cn O cn 1 rj ^ + Ψ * ty * ** + o - o u u - α ψ

_ »_ · _ T

8303955

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r I

- 166 - I

Η

ο ο ..... I

r- ο ιο I

to ιη ιο

VO f-4 I

Η I

^ ο ιη ο <Ν 00 <Τ> r ~ ιο ιο (Η Γ— (ι — i ^ ^ ^ tn ιη ο Γ "" Τ ιη r * r- r *

s ιΗ <H ι — I

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Cn r-i TP r * 00

Yy 00 ΙΟ r- r ~>

q Η Η ι — I <—I

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.-1 Ή H · “'r-i Ή iH

Q) I YY I 4-> I + J

C m c d £ co c (0 vo o ®v O fn o

£ -1 r “i rH iH

"?" -v-y: x; i X) “O” °

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d d d d d

BBS

o ^ .ov o o li \ o u 0 = 0 o o li / u o 0 \ / o o cm ^ O ni cn

B B S

0 o o

1 I I

BAD ORIgSiiJlP 3 9 5 5 (·, - 167 - f__ o - VO »—t Ί o 00

VO

iH

o r ** 9 o 00 Γ · »711 Ή 01 r — i 0> _} -! Φ £ W ~ k 7 r — ί Λ -p 3 «.§ Λ (0 E- * O x" / Z = \ ° \> ° s Λ- * ί s **, / o

vJ <U

u 0)

+ J

- M

(0 _ · Η

Jp a m Q? u o o o

CN

M · M *

YOU

S3 0 3 9 5 5

BAD ORIGINAL

(3) To a solution of 5.5 g of 1-pivaloyloxyethyl 7- / 2- (2-formamidothiazol-4-yl) 2- (syn) -methoxyiminoacetamido / 3 - {/ 1- (4-ethyl 2,3- dioxo 1,2,3,4-

tetrahydropyrazinyl) / methyl} Δ3-cephem 4-carboxylate ver I

5 according to (2) above in 27.5 ml of methanol, I is added

1.13 ml of concentrated hydrochloric acid and leave the obtained I.

mixture at 35 ° C for 2 hours. After the reaction I

the solvent is removed by distillation under reduced pressure

the pressure. 50 ml of ethyl acetate and 50 ml of water are added to the residue and the pH of the mixture is adjusted to 6.0 with sodium hydrogen carbonate. The organic layer is then separated and dried over anhydrous magnesium sulfate, after which it is dried. solvent is removed by distillation under reduced pressure. 45 ml of diethyl ether are added to the residue and the crystals are collected by filtration to obtain 4.65 g (88.1%) of 1-pivaloyloxyethyl 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamido_7 3 - {/ 1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) _7methyl} Δ3-cephem 4-carboxylate, mp 148-150 ° C.

20 IR (KBr) cm 1: Vc_Q 1780, 1740, 1680, 1640 NMR (d-DMSO) δ values: 6 0.90-1.39 (12H, m, -CCCH ^,> NCH2CH3), 1.52 (3H , d, J = 5Hz, formula 87), 3.52 (2H, bs, C2-H), 3.76 (2H, q, J = 7Hz,> NCH2CH3), "j 3.88 (3H, s, -OCH-), 4.38, 5.04 (2H, ABq, J = 15Hz, formula 79), 5.21 (1H, d, J = 5HZ, Cg-H), 5.87 (1H, dd, J = 5HZ, J = 8HZ, CjH), 6.61 (2H, bs, formula 78), 6.78 (1H, s, formula 82), 7.04 (1H, q, J = 5HZ, formula 87), 7.22 (2H, bs, -NH2), 9.67 (1H, d, J = 8HZ, -C0NH-).

In such a manner, the compounds shown in Table FF are obtained.

BAD originKi3 Ö 3 9 5 5 · * - 169 - y * »» sc - to cn cn »«.

* · "As * n a".

a - ο ν »» <ν χ ΤΓ -2J JL, ^ Ο X ΙΓ> Ν - ι-Ι U Ό ο ίθ UÏ ι tn II χ - ω ® W | «· *« —Ι t-j mo SJ 2 »0—0 CO - II II o o 6 g - O n b *> -3« * co 0 3 m | *> «G ---- VO r- 01 a k k k vo • H‘ o m »m χ {j1 * Ό» i SB N x n ffl χ Όνο »

c - O X O - rtJrH TT

0 w m ι ->. , .χ!

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- 186 - (4) To a solution of 1.05 g of the 7- / 2- (2-formamidothiazol-4-yl) 2- (syn) -methoxyimino-acetamido 7 3 - {/ “1- (2, 3-dimethyl 6-oxo 1,6-dihydropyrazinyl) methyl} Δ3-cephem 4-carboxylic acid obtained under (1) above 5 in 10 ml of methanol 0.38 ml of concentrated hydrochloric acid are added and the resulting mixture is reacted at 35 ° C for 2 hours. After the reaction, the solvent is removed by distillation under reduced pressure. 10 ml of diethyl ether are added to the residue and the crystals are collected by filtration to obtain 0.43 g (84.8%) of the hydrochloride of 7- / 2- (2-aminothiazol-4-yl) -2. - (syn) -methoxyiminoacetamido _ / - 3 - {/ 1- (2,3-dimethyl-6-oxo-1,6-dihydropyrazinyl) _ / methyl} Δ3-cephem 4-carboxylic acid, mp 250 ° C or more.

IR (KBr) cm ”1 \> c_0 1765, 1660, 1620 15 NMR (d_ — DMSO) δ values: 6 2.20 (6H, bs, -CH3 x 2), 3.18 (2H, bs, C2- H), 3.90 (3H, s, -0CH3), 4.94, 5.24 (2H, ABq, J = 15Hz, formula 79), 20 5.10 (1H, d, J = 5Hz, Cg -H), 5.78 (1H, dd, J = 5Hz, J = 8Hz, C7 ~ H), 6.89 (1H, s, formula 82), 7.82 (1H, s, formula 88), 9.79 (1H , dd, J = 8Hz, -C0NH-).

Example XII

J (1) In such a manner as in Example VII- (1), the compounds shown in Table GG are obtained from the starting materials given in Scheme D on the formula sheet.

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Example XIII

(1) To a solution of 2.72 g of 2- (2-tert-amyloxycarboxamidothiazol-4-yl) acetic acid in 40 ml of anhydrous methylene chloride, 1.06 g of N-methylmorpholine 5 is added and the mixture is cooled to -35 ° C. 1.12 g of ethyl chlorocarbonate are then added and the mixture is allowed to react at -35 ° C to -25 ° C for 1.5 hours, after which 5.18 g of diphenylmethyl 7-amino 3 - {/ l- ( 4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) / methyl} Δ3 -cephem 4-carboxylate and add the mixture and react the mixture at -30 ° C to -20 ° C 1 hour and then at -10 ° C to 10 ° C for 1 hour.

After the reaction, 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 30 ml of water are added again. The pH of the mixture is adjusted to 7.0 with sodium hydrogen carbonate under ice cooling. The organic layer is separated, washed with 30 ml of water and 30 ml of a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. 35 ml of diethyl ether are added to the residue and the crystals are collected by filtration to obtain 3.62 g (90.5%) diphenylmethyl 7- / 2- (2-tert-amyloxycarboxamidothiazol-4-yl) acetamido_7 3 - {/ 1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl / methyl} Δ3-cephem-4-carboxylate, mp 152-154 ° C (decomposition).

IR (KBr) cm -1 vcQ 1780, 1720, 1685, 1640

In such a manner the following compound is obtained: 6.15 g (82.7%) diphenylmethyl 30- (2- (2-tert-amyloxycarboxamidothiazol-4-yl) acetamido] / 3- {/ 1- (3, 6-dioxo 1,2,3,6-tetrahydropyridazinyl) methyl / 3-cephem 4-carboxylate, m.p. 136-139 ° C (dec.) IR (KBr) cm -1: vcQ 1780, 1720, 1665.

bath οι ^ φ.3 9 5 5 * - 193 -> (2) The compounds shown in Table II were obtained by reacting the compounds obtained under (1) above in the same manner as in Example VI- (3).

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Example XIV

6.82 g of diphenylmethyl 7- (4-bromo-3-oxobutylamido) 3 - {/ 1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) _ / methyl} Δ3-cephem 4 are dissolved -carboxylate and 1 g of 5 thiourea in 48 ml of Ν, Ν-dimethylacetamide and let the mixture react at room temperature for 2 hours. After the reaction, the reaction mixture is poured into a mixed solvent of 500 ml water and 500 ml ethyl acetate, and the pH of the mixture is adjusted to 6.7 with sodium hydrogen carbonate.

The organic layer is separated and dried over anhydrous magnesium sulfate, and the solvent is then removed by distillation under reduced pressure. The residue is then dissolved in 33 ml of trifluoroacetic acid and 8 ml of anisole and the mixture is allowed to react at room temperature for 1 hour. After the reaction, the solvent is removed by distillation under reduced pressure. 40 ml of diethyl ether are added to the residue and the crystals are collected by filtration to obtain 4.50 g (74.1%) of the trifluoroacetic acid salt of 7- / 2- (2-aminothiazol-4-yl) acetamido / 3- {/ 1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) / methyl} Δ3-cephem 4-carboxylic acid, mp 109-115 ° C with decomposition.

In such a manner the following compound is obtained: trifluoroacetic acid salt of 7- / 2- (2-aminothiazol-4-yl) acetamido-y 3 - {/ 1- (3,6-dioxo 1,2,3,6-25 tetrahydropyridazinyl) / methyl} Δ3-cephem 4-carboxylic acid, m.p. 200 ° C or more.

The physical properties (infrared nuclear magnetic resonance values) of this compound are identical to those of Example XIII- (2).

* 30

Preparation example 1?

An aqueous sodium salt solution of 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -methoxy-iminoacetamido_7 3 - {/ 1- (2,3-dioxo 1,2,3) is treated 4-tetrahydropyrazinyl) 7-35 methyl} Δ3-cephem 4-carboxylic acid in a conventional manner to obtain a freeze-dried and sterilized sodium salt.

Badorig Si ^ 3 S - S

- 197 ->

1 g (potency) of the sodium salt is dissolved in 20 ml of physiological saline to obtain an injection solution.

Preparation Example 2 1 g (potency) of the freeze-dried product obtained in preparation Example 1 is dissolved in 4 ml of a 0.5% (weight / volume) aqueous lidocaine hydrochloride solution to obtain a dilutable injection solution.

10 Preparation example 3

1 g (potency) of the freeze-dried product obtained in preparation Example 1 is dissolved in 20 ml of 5% glucose solution to obtain an O injection liquid.

In addition, the other compounds of the formula I can also be formed into the corresponding freeze-dried products (sodium salts) or injection liquid f and proceeding in the same manner as in the preparation Examples 1-3.

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Claims (36)

A cephalosporin derivative of the formula 1 or a salt thereof, in which R 1 is hydrogen or a carboxoxyl protecting group, R 1 is a group of the formula 23-26, wherein R 9 is hydrogen, hydroxyl, nitro, carbamyl, thiocarbamyl, or an al or unsubstituted alkyl, alkenyl, alkynyl, alkadienyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl, aralkyl, acyl, alkoxy, alkylthio, acyloxy, cycloalkyl-10 oxy, aryloxy, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxoxycarbonyl, aralkyloxycarbonyl, aralkyl oxycarbonyl, aralkyl sulfonyl, arylsulfonyl, heterocyclic sulfonyl, alkyl-carbamyl, dialkylcarbamyl, alkylthiocarbamoyl, dialkylthio-carbamyl, acylcarbamyl, acylthiocarbamyl, alkylsulfonyl-15 carbamyl, arylsulfonylcarbamyl, alkylsulfonylthiocarbamyl, arylsulfonylthiocarbamyl, sulfamyl, alkylsulfamyl, dialkyl sulfamyl, alkoxythiocarbonyl, alkylideenamino, cycloalkyl-methylene-amino, arylmethyleneamino, heterocyclic methyleneamino or heterocyclic group or a group of the formula 20 27 (wherein R 1. and R. _, which may be the same or different, represent hydrogen or an alkyl group, or form a ring together with their adjacent nitrogen atom), each of the groups R ^ and R ^, which may be the same or different, hydrogen, halogen or an unsubstituted or substituted alkyl, aralkyl or aryl group, hydrogen, halogen, carboxyl, sulfo, carbamyl, thiocarbamyl, or an unsubstituted or substituted alkyl, aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxycarbonyl, cycloalkuloxycarbonyl, acyloxycarbony1, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, aryl-30sulfonyl, heterocyclicsulfonyl, alkylcarbamyl, dialkylcarbylcylcaramyl, alkylthiocarbamyl, dialkylthiocarylcarylcarboxyl alkylsulfonylthiocarbamyl or arylsulfonylthiocarbamyl group; R ^ hydrogen or an alkoxy group, R ^ hydrogen or halogen, 35 Rg hydrogen or an protected or unprotected amino group; 8303955 BAD ORIGINAL * - 199 - A is -CH - or a group of the formula 21, wherein R 1 'water - 1 lb substance, an unsubstituted or substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, heterocyclic group or a hydroxyl protecting group, or a group of the formula 22 (wherein Rg and R, which may be the same or different, represent hydroxyl, alkyl, aralkyl, aryl, alkoxy, aralkyloxy or aryloxy) and the bond Λ / vws means that the compound can be a syn isomer or an anti isomer or a mixture thereof. A cephalosporin derivative or a salt thereof according to claim 1, wherein R 1 is hydrogen. A cephalosporin derivative or a salt thereof according to claim 1 or 2, wherein R 1 is hydrogen. ^ '4. Cephalosporin derivative or a salt thereof according to any one of claims 1-3, characterized in that Rj. is an amino group. Cephalosporin derivative or a salt thereof according to any one of claims 1 to 4, characterized in that A is a group of the formula 21, wherein R 1 and the bond 10 20 have the same meaning as defined in claim 1. Cephalosporin derivative or a salt thereof according to claim 5, characterized in that R 1 'is a lo or unsubstituted alkyl group. Cephalosporin derivative or a salt thereof according to any one of claims 1-6, characterized in that A is a group of the formula 89 (syn isomer). Cephalosporin derivative or a salt thereof according to any one of claims 1-6, characterized in that A is a group of the formula 90 (syn isomer), wherein R 1 has the same meaning as defined in claim 1. Cephalosporin derivative or a salt thereof according to any one of claims 1-6, characterized in that A is a group of the formula 91 (syn isomer) in which R35 has the same meaning as defined in claim 1. A cephalosporin derivative or an 8303955 BAD ORIGINAL - 200 salt thereof according to any one of claims 1 to 9, characterized in that R is a group of the formula 23, wherein R has the same 20 meaning as defined in claim 1. 11. Cephalosporin derivative or a salt thereof according to claim 10, characterized in that R 9 is hydrogen, a heterocyclic group, a substituted alkyl, aralkyl or cycloalkyl group, or a grape of the formula 27, in which R 9 has the same meaning as defined in claim 1. I Cephalosporin derivative or a salt thereof according to claim 10, characterized in that R 1 is hydrogen, an unsubstituted or substituted alkyl, aralkyl or cyclo- alkyl group, or a grape of the formula 27, wherein R 1 and 16 R ^ have the same meanings as defined in claim 15 1. Cephalosporin derivative or a salt thereof according to any one of claims 1-9, characterized in that R 1 is a group of the formula 24, wherein R 1 g has the same meaning as in Example 1. 14. A cephalosporin derivative or a salt thereof according to claim 13, characterized in that R 1, g, which may be the same or different, represent hydrogen or an alkyl group. 15. Cephalosporin derivative or a salt thereof according to any one of claims 1-9, characterized in that R 2 is a group of the formula 25, wherein rjq_j2 have the same meaning as in claim 1. Cephalosporin derivative or a salt thereof according to claim 15, characterized in that R 3, which may be the same or different, represent hydrogen, halogen or an alkyl group. Cephalosporin derivative or a salt thereof according to any one of claims 1 to 9, characterized in that R 1 is a handle of the formula 26, in which R 1 has the same meaning as in claim 1. 18. Cephalosporin Derivative or a Badorig & A. ^? Its salt according to claim 17, characterized in that R13-15 /, which may be the same or different, represent hydrogen or an alkyl group. 19. 7- / 2- (2-aminothiazol-4-yl) 5 2- (syn) -methoxyiminoacetamido_ / 3- {/ l- (2,3-dioxo 1.2.3.4-tetrahydropyraziny1) _ / methy1} Δ3-cefem 4-carboxylic acid, an ester or a salt thereof. 20.7- / 2- (2-aminothiazol-4-yl) 2- (syn) -carboxymethoxyiminoacetamido_ / 3- {/ 1- (2,3-dioxo-10 1,2,3,4-tetrahydropyrazinyl) _7methyl} Δ3- cefem 4-carboxylic acid, an ester or a salt thereof. 21. 7- / 2- {2-aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamido / 3- {/ 1- (4-methyl-2,3-dioxo K1,2,3,4-tetrahydropyrazinyl) 7-methyl} Δ3-cephem 4-carboxylic acid, an ester or a salt thereof. 22. 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -carboxymethoxyiminoacetamido / 3- {/ 1- (4-methyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) / methyl} Δ3-cephem 4-carboxylic acid, an ester or a salt thereof. 20 23. 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamido_ / 3- {/ 1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) _7methyl} Δ3- cefem 4-carboxylic acid, an ester or a salt thereof. 24. 7- / 2- (2-aminothiazol-4-yl) 25 2- (syn) -carboxymethoxyiminoacetamido ^ / 3- {/ 1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl ) / methyl} Δ3-cephem 4-carboxylic acid, an ester or a salt thereof. 25. 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamido / 3- {/ 1- (4-isopropyl 2,3-di-oxo 1,2,3,4- tetrahydropyrazinyl) 7methyl} A3-cephem 4-carboxylic acid, an ester or a salt thereof. 26. 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamido_7 3- {/ 1- (4-dimethylamino 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) _7methyl} Δ3-cefem 4-car-35 carboxylic acid, an ester or a salt thereof. 27.7 / ~ 2- (2-aminothiazol-4-yl) 8303955 BAD ORIGINAL 202. I 2- (syn) -carboxymethoxyiminoacetamido_7 3- {/ 1- (4-dimethyl-1 amino 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) _7methyl} Δ3-cephem I 4-carboxylic acid, an ester or a salt of it. I 28.7 - / ^ 2- (2-aminothiazol-4-yl) 2- I 5 (syn) -methoxyiminoacetamido_7 3- {/ 1- (2-oxo 1,2-dihydropyrazinyl) __7methyl} Δ3-cephem 4-carboxylic acid, an ester or a salt thereof. 29. 7- / 2- (2-aminothiazol-2-yl) 2- (syn) -methoxyiminoacetamido / 3- {/ 1- (3,6-dioxo 1,2,3,6-10-tetrahydropyridazinyl) _7methyl} Δ3 -cephem 4-carboxylic acid, an ester or a salt thereof. 30. 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -carboxymethoxyiminoacetamido_7 3- {/ 1- (3,6-dioxo 1.2.3.6-tetrahydropyridazinyl) _7methyl} Δ3-cephem 4-carboxylic acid, 15 an ester or a salt thereof. 31.7 /. 2- (2-aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamido ^ / 3- {/ 1- (3-methyl 6-oxo 1,6-dihydropyridazinyl) _ / - methyl} Δ3-cephem 4-carboxylic acid, a ester or a salt thereof. 20 32. 7- / 2- (2-aminothiazol-4-yl) 2- (syn) -carboxymethoxyiminoacetamido 7 3- {/ 1- (3-methyl 6-oxo 1,6-dihydropyridazinyl) 7methyl} A3-cephem 4 -carboxylic acid, an ester or a salt thereof. 33. A process for preparing a cephalosporin of the formula 1 or a salt thereof, wherein j is hydrogen or a carboxyl protecting group, a group of the formula 23-26, wherein R is hydrogen, hydroxyl, nitro, carbamyl, thiocarbamyl, sulfamyl, or an unsubstituted or substituted alkyl, alkenyl, alkynyl, alkadienyl, cycloalkyl, cyclo-alkenyl, cycloalkadienyl, aryl, aralkyl, acyl, alkoxy, alkylthio, acyloxy, cycloalkyloxy, aryloxy, alkoxycarbonyl, cyclo-alkyloxycarbonyl , aralkyloxycarbonyl, alkyl-sulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclic sulfonyl, alkylcarbamyl, dialkylcarbamyl, alkylthiocarbamyl; arylsulfonylthiocarbamyl, alkylsulfamyl, dialkylsulfamyl, alkoxythiocarbonyl, alkylideneamino, cycloalkylmethyleneamino, arylmethyleneamino, heterocyclic methylene am ino or heterocyclic group or a group of the formula 27 (in which and which may be the same or different, hydrogen or an alkyl group, or form a ring together with their adjacent nitrogen atom), R 1 and Rjjf which are the same or different hydrogen, halogen or an unsubstituted or substituted alkyl, aralkyl or aryl group, R hydrogen, halogen, carboxyl, carbamyl, thiocarbamyl or an unsubstituted or substituted alkyl, aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxycarbonyl, ^ cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclic sulfonyl-15 cyclic, alkylcarbamyl, dialkylcarbamyl, alkylthio carbamyl, dialkylthiocarbamyl, acylcarbamyl, acylthiocarbamyl, alkylsulfonylcarbamyl, arylsulfonylcarbamyl, alky1sulfonyl-thiocarbamyl, or arylsulfonylthiocarbamyl group, R ^ represents hydrogen or a alkoxy group, R ^ hydrogen or a halogen, R ^ 20 hydrogen or an protected or unprotected amino group, A a group v of the formula -CH 1 - or of the formula 21, wherein R, Q is water-Z 10 substance or an unsubstituted or substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl, heterocyclic group or a hydroxyl protecting group or a group of the formula 22 (wherein R 1 and R 2 g, which may be the same or different (1, are hydroxyl, alkyl, aralkyl, aryl, alkoxy, aralkyloxy or aryloxy) and the bond means that the compound may be a syn isomer or an anti isomer or a mixture thereof, characterized in that 30 (a) is a compound of the formula 92 or a salt thereof, wherein R represents an amino group or Zo a group of the formula 72 wherein they may be the same or different represent hydrogen or an organic moiety which does not participate in the reaction or a group of the formula 73 wherein R <5> which may be the same or different is hydrogen or an the reaction participating organi- cal 8303955 BAD ORIGINAL * 4 - 204 - organic residue v earring, and have the same meanings as given previously, react with a compound of the formula 93 or a reactive derivative thereof in the carboxyl group, wherein R, Rg and A have the same meanings as given above, or (b ) reacting a compound of the formula 94 or a salt thereof, wherein X halogen and R 1 and A have the meanings given previously, with a compound of the formula 95, wherein R 9 has the previously given meaning 10, or (c) a compound of the formula * 96 or a salt thereof, wherein R ^ g has the previously given meaning, react with a compound of the formula 97 or a salt thereof, and wherein R ^ g has the previously given meaning, and optionally after steps (a), (b) or (c) remove the protecting group, protect the carboxyl group or convert the product into a salt thereof. 34. Process according to claim 33, characterized in that the compound, of the formula 92 or a salt thereof, in which R ^ g and R ^ q have the same meaning as in claim 33, is reacted with a compound of the formula 93 or a reactive derivative thereof in the carboxyl group, wherein R 1, R 5 and A have the meaning as defined in claim 33, after which, if desired, the protecting group is removed, the carboxyl group is protected or the product is converted into a salt thereof. 35. A process according to claim 34, characterized in that A is a group of the formula 21, wherein R and the bond "-wv" have the same meaning as in claim 33. 36. Process according to claim 34, or 35, characterized in that the reaction is carried out at a temperature of -50 ° C to 40 ° C. 37. A process according to claim 35, characterized in that a compound of the formula 94 or a salt thereof, wherein Rg, A and X is the orAiS / Q baths claimed in claim 33. 3 9 5 5 Jk - 205 - give meaning, react with a compound of the formula 95, wherein R 2 has the meaning given in claim 33, after which, if desired, the protective group is removed, the carboxyl group is protected or the product is converted into a salt 5 of it. A method according to claim 37, characterized in that A is a group of the formula 21, wherein R and the bond (ww have the same meaning as lo in claim 33. 39. Process according to claim 37 or 38, characterized in that the reaction is carried out at 0-100 ° C. 40. Process according to claim 33, characterized in that a compound of the formula 98 or a salt thereof is prepared in which Rg and the bond / Wwv have the same meaning as in claim 33, by a compound of reacting the formula 96 or a salt thereof, in which R 1 2 has the meaning given in claim 33, with a compound of the formula 97 or a salt thereof, wherein R 1q has the meaning given in claim 33, after which, if desired, the protecting group is removed, the carboxyl group is protected or the product is converted into a salt thereof. 41. Process according to claim 40, characterized in that the reaction is carried out at 0-100 ° C. 42. 7- (unsubstituted or substituted amino) 3-substituted methyl Δ3-cephem 4-carboxylic acid of the formula 92 or a salt thereof, wherein R 1 hydrogen or a carboxyl protecting group, R 1 a group of the formula 23-26 wherein Rg is hydrogen, hydroxyl, nitro, carbamyl, thiocarbamyl, sulfamyl, or an unsubstituted or substituted alkyl, alkenyl, alkynyl, alkadienyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl, aralkyl, acyl, alkoxy, alkylthio, acyloxy, cycloalkyl oxy, aryloxy, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxy-carbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonamyl, arylsulfonyl, alkylcarbamyl, benzylcarboxamyl, acylcarbamyl, butylcarboxamyl, 8amylcarbamyl, butylcarboxamyl, dialkylcarbamyl, dialylcarboxamyl, dialkylcarbamyl, dialkylcarbamyl, dialkylcarbamyl, dlalkylcarbamyl, dialkylcarboxamyl, dialyl , arylsulfonylcarbarayl, alkylsulfonylthiocarbamyl, arylsulfonylthio-carbamyl, sulfamyl, alkylsulfamyl, dialkylsulfamyl, alkoxythiocarbonyl, alkylideneamino, cycloalkylmethyleneamino, 5 arylmeth yleenimino, heterocyclic methyleneamino or heterocyclic group or a group of formula 27 (wherein Rc and R17, which may be the same or different, may be hydrogen or an alkyl group or form a ring together with their adjacent nitrogen atoms), R_R, and R 7, which may be the same or different, 7, 14, 10, 10, hydrogen, halogen or an unsubstituted or substituted alkyl, aralkyl, or aryl group, R 2 hydrogen, halogen, carboxyl, sulfo, carbamyl, thiocar-bamyl or an unsubstituted or substituted alkyl, aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxycarbonyl, cycloalkyl-15 oxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, alkylcarbamyl, alkylcarbamyl, dialkyl acylthiocarbamyl, alkylsulfonylcarbamyl, arylsulfonylcarbamyl, alkylsulfony1-20 thiocarbamyl or arylsulfonylthiocarbamyl group, R ^ hydrogen or an alkoxy group, R ^ g an amino group, ee n group of the formula 72 wherein R 31-33 'which may be the same or different, hydrogen or an organic radical or a group of the formula 73 wherein R34 and R35 which may be the same or different represent hydrogen or an organic radical. 43. 7- (unsubstituted or substituted amino) 3-substituted methyl Δ3-cephem 4-carboxylic acid or a salt thereof according to claim 42, characterized in that R 1 is hydrogen. 44. 7- (unsubstituted or substituted amino) 3-substituted methyl A3-cephem 4-carboxylic acid or a salt thereof according to claim 43, characterized in that R 3g is an amino group. 45. 7- (unsubstituted or substituted 35 amino) 3-substituted methyl A3-cephem 4-carboxylic acid or a salt thereof according to claim 44, characterized in that R 1 is a BAD ORIG $ yL 3 & 5 5 * - 207 - group is of the formula 23, wherein Rg has the same meaning as in claim 42. 46. 7- (unsubstituted or substituted amino) 3-substituted methyl Δ3-cephem 4-carboxylic acid or a salt thereof according to claim 45, having the characterized in that hydrogen represents a heterocyclic group or an unsubstituted or substituted alkyl, aralkyl or cycloalkyl group or a group of the formula 27 wherein Rg and Rg have the meanings given in claim 42. 47. 7- (unsubstituted or substituted amino) 3-substituted methyl Δ3-cephem 4-carboxylic acid or a salt thereof according to claim 46, characterized in that R1. an "O dialkylamino group or a hydrogen atom, or an alkyl, aralkyl or cycloalkyl group, which may be optionally substituted by an alkanoyloxy or carboxyl group, or group of the formula 64 (wherein R 1 represents a lower alkyl group). 48. 7- ( unsubstituted or substituted amino) 3-substituted methyl Δ3-cephem 4-carboxylic acid or a salt thereof according to claim 45, characterized in that R, ______ O 20 hydrogen or an unsubstituted or substituted alkyl, aralkyl or cycloalkyl group or a group of the formula 27, wherein Rg and Rg have the meaning given in claim 42. 49. 7- (unsubstituted or substituted amino) 3-substituted methyl Δ3-cephem 4-carboxylic acid or a salt thereof according to claim 48, characterized in that R 1 is an O dialkylamino group or a hydrogen atom, or an alkyl, aralkyl w or cycloalkyl group, which may be optionally substituted by acyloxy 50.7- (unsubstituted or substituted 30 amino) 3-substituted methyl Δ3-cefem 4-carboxylic acid or a salt t according to claim 44, characterized in that R 1 is a group of formula 24, wherein R has the meaning given in claim 42. 51. 7- (unsubstituted or substituted 35 amino) 3-substituted methyl Δ3-cephem 4-carboxylic acid or a salt thereof according to claim 50, characterized in that BAD ORIGINAL 8303955 * - 208 - A which may be the same or different, hydrogen or an alkyl group. 52. 7- (unsubstituted or substituted amino) 3-substituted methyl Δ3-cephem 4-carboxylic acid or a salt thereof according to claim 44, characterized in that it is a group of formula 25, wherein claim 111 is given meaning to have. 53. 7- (unsubstituted or substituted amino) 3-substituted methyl Δ3-cephem 4-carboxylic acid or a salt thereof according to claim 52, characterized in that R10 -12f, which may be the same or different, are hydrogen, halogen or a alkyl group. ^ 54. 7- (unsubstituted or substituted (J amino) 3-substituted methyl Δ3-cephem 4-carboxylic acid or a salt thereof according to claim 44, characterized in that R een is a group of the formula 26, wherein R The meaning given in claim 42. 55. 7- (unsubstituted or substituted amino) 3-substituted methyl Δ3-cephem-4-carboxylic acid or a salt thereof according to claim 54, characterized in that R is the same or different can be hydrogen or an alkyl group. 56. Process for preparing a 7- (substituted or unsubstituted amino) 3-substituted methyl 25 Δ3-cephem 4-carboxylic acid of the formula 92 or a salt thereof, (^ j wherein hydrogen or a carboxyl protecting group, R2 is a group of the formula 23-26, wherein R is hydrogen, hydroxyl, nitro, carbamyl, thiocarbamyl, sulfamyl, or an unsubstituted or substituted alkyl, alkenyl, alkynyl, alkadienyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl, aralkyl, acyl, alkoxy, alkylthio, acyloxy, cycloalkoxy, aryloxy, alkoxycarbonyl, cycloalkyloxycarbonyl, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclic sulfonyl, alkylcarbamyl, dialkylcarbamyl, alkylthio 35 carbamyl, dialkylthiocarbamyl, acylcarbamyl, acylthiocarbamyl, alkylsulfonylcarbamyl, arylsulfonylcarbamyl, alkylsulfonyl, 8,303,955 BAD ORIGINAL - 4 4 - 209 - thiocarbamyl, aryl sulfonyl thiocarbamyl, alkyl sulfamyl, dialkyl sulfamyl, alkoxy thiocarbonyl, alkylideneamino, cycloalkylmethyl an amino, arylmethyleneamino, heterocyclic methyleneamino or heterocyclic group, or a group of 5 formula 27 (wherein R ^ g and R ^, which may be the same or different, are hydrogen or an alkyl group, or form a ring together with their adjacent nitrogen atom), R 7-12 14 and 15 'or may be different, hydrogen, halogen or an unsubstituted or substituted alkyl, aralkyl or aryl group, R 7 hydrogen, halogen, carboxyl, sulfo, carbamyl, thiocarbamyl, or an unsubstituted or substituted alkyl, aralkyl, aryl, alkoxy, alkylthio, acyl, alkoxycarbonyl, cycloalkyloxycarbonyl _, acyloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclic sulfonyl-15 cyclic, alkylcarbamyl, dialkylcarbamyl, thiocarbamyl alkyl, dialkylthiocarbamyl, acylcarbamyl, acylthiocarba-myl, alkylsulfonylcarbamyl, arylsulfonylcarbamyl, alkylsulfonylamino -nylthiocarbamyl or arylsulfonylthiocarbamyl group, R3 hydrogen or an alkoxy group, R ^ g an amino group, a group of the '20 formula 72, wherein R3 ^ _23 »which may be the same or different, hydrogen or an organic moiety, which does not participate in the reaction, represent or a group of the formula 73, wherein R3 ^ and which may be the same or different, hydrogen or an organic residue which does not participate in the reaction, characterized in that a cephalosporanic acid of the formula 99 or a salt thereof, in which R 1 and R 8 have the meaning given previously, ROQ may or may not be -substituted acyloxy or carbamyloxy group, and Z represent> S or> SK) reacts with a compound of formula 23-26, wherein R have the meanings given previously, o ** 15 or a salt thereof, in the presence of an acid or a complex compound of the acid, after which, if desired, the protecting group is removed, the carboxyl group is protected or the product is converted into a salt thereof. 57. Process for preparing a 7- (substituted or unsubstituted amino) 3-substituted methyl BAD ORIGINAL 8303955 * * - 210 - Δ3-cephem 4-carboxylic acid or a salt thereof according to claim 56, characterized in that it is hydrogen. 58. A process for preparing a 7- (substituted or unsubstituted amino) 3-substituted 5 methyl Δ3-cephem 4 -carboxylic acid or a salt thereof according to claim 57, characterized in that said acid or complex compound of the acid is a Lewis acid or a complex compound thereof. 59. Process for preparing a 7- (substituted or unsubstituted amino) 3-substituted methyl Δ3-cephem 4-carboxylic acid or a salt thereof according to claim 58, characterized in that said Lewis acid or its complex compound is boron trifluoride or a complex connection is ^ j * of it. 60. Process for preparing a 7- (substituted or unsubstituted amino) 3-substituted methyl A3-cephem 4-carboxylic acid or a salt thereof according to claims 56-59, characterized in that the reaction is carried out in the presence of an organic solvent. A process for preparing a 7- (substituted or unsubstituted amino) 3-substituted methyl Δ3-cephem 4-carboxylic acid 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 sulfolan. f ~~>. A process for preparing a 7- (unsubstituted or substituted amino) 3-substituted methyl Δ3-cephem 4-carboxylic acid or a salt thereof according to any one of claims 56-61, characterized in that it is an acetoxy group. 63. Process for preparing a 7- (substituted or unsubstituted amino) 3-substituted methyl Δ3-cephem 4-carboxylic acid or a salt thereof according to any one of claims 56-62, characterized in that the reaction is carried out at 0- 80 ° C. 64. Pharmaceutical composition useful for treating bacterial infections in humans and animals, 8303955 BAD ORIGINAL * - 211 - characterized in that it consists of an antibacterially effective amount of a cephalosporin or a pharmaceutically acceptable salt thereof according to any one of claims 1- 32, in combination with a pharmaceutically acceptable inert diluent or carrier. —N, 4 O BAD ORIGINAL 8303955