NL192792C - Cephalosporin derivatives, process for their preparation and pharmaceutical preparations containing such a preparation. - Google Patents

Description

1 192792

Cephalosporin derivatives, process for their preparation and pharmaceutical preparations containing such a preparation

The present invention relates to cephalosporin derivatives of the formula 1 on the formula sheet, wherein R 1 represents a hydrogen atom or a carboxil protecting group, R 2 represents a heterocyclic group, R 5 represents a protective or non-amino group and A represents a group of formula 21, wherein R18 represents a methyl or ethyl group, and salts thereof.

Such cephalosporin derivatives are known from German Offenlegungsschrift 3,137,854. This literature site describes, inter alia, compounds of formula 1 wherein R 2 is an unsubstituted or substituted triazolyl or tetrazolyl group, which is bonded to the exometholene group at the 3-position of the cephem ring via a ring carbon atom. This Literature Site further relates to the use of these cephalosporins or salts thereof as an antibacterial agent.

It has now been found that cephalosporin derivatives with a heterocyclic group at 3-position of the cephem ring to be described further below have a higher antibacterial activity than the known compounds.

Thus, the present invention provides cephalosporin derivatives as defined in the preamble, characterized in that R 2 represents a group of formula 23 wherein R 6 represents a hydrogen atom or a C 1 -C 8 alkyl group.

The compounds of the invention have a broad anti-bacterial spectrum, exhibit excellent anti-bacterial activity against Gram-positive and Gram-negative bacteria, are stable against β-lactamase produced by bacteria, have low toxicity, are well absorbed at oral or parenteral administration and have an excellent therapeutic effect on human and animal diseases.

The invention further provides a process for the preparation of the new cephalosporin derivatives and pharmaceutical preparations containing such a derivative or a salt thereof.

25 Further reference may be made to Chemistry and Biology or Beta-lactam Antibiotics, Part 1, Penicillins and Cephalosporins, published by Robert. B. Morin and Marvin Gorman, Academy Press, 1982, pp. 387-391 and pp. 420-425, which describes a number of cephalosporin derivatives, including commercially available ones. In the compounds described in this literature, the substituent on the 3-exomethylene group of the cephalic ring is quite different from that of the compounds of the invention. In addition, Journal of Medicinal Chemistry, Vol. 22, pp. 1416-1418 (1979), describes cephalosporin derivatives with 2- and 4-pyridone groups on the 3-methylene group of the cephem ring and German Offenlegungsschrift 2,714,880 describes cephalosporin derivatives with and (substituted tetrazolyl ) thiomethyl group at the 3-position of the cephem ring.

Finally, Chemical Abstracts 90 (1979) 16828t and Chemical Abstracts 93 (1988) 26447w, which refer to JP-A-78/119885 and JP-A-79/92986 3- (succinimidomethyl) and analogous cephalosporins, respectively.

The invention will be further illustrated in detail below.

Unless otherwise specified, the term "alkyl" means a straight or branched chain C 1 alkyl group including, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, secondary butyl, tertiary butyl and 40 pentyl.

The symbol R., in the formulas in this description, represents a hydrogen atom or a carboxil protecting group, including those commonly used in the field of the penicillins and cephalosporins, for example an ester-forming group, which can be removed by a catalytic hydrogenation, a chemical reduction, or a treatment under 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: 50 (a) alkyl groups, for example, C 1-6 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, hydroxil, cycloalkyl, aryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, 5-alkyl-2-oxo-1,3-dioxol-4-yl, 1-indanyl, 2-indanyl, furyl, pyridyl, 4-imidazolyl, phthalimido, succinimido, azetidino, aziridino, pyrrolidino, piperidino, morpholine, thiomorpholino, N-lower-55 alkylpiperazino, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, oxadiazolyl, oxadiazolyl , benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, cumarinyl, 2,5-dimethylpyrrolidino, 1,4,5,6-tetrahydropyrimidinyl, 4-methylpiperidino, 192792 2 2,6-dimethylpiperidino, 4- (5-methyl-2-pyrrolinyl) 4- (2-pyrrinyl), N-methylpiperidinyl, 1,3-benzodioxolanyl, alk ylamino, dialkylamino, acyloxy, acylthio, acylamino, dialkylaminocarbonyl, alkoxycarbonylamino, aikenyloxi, aryloxy, aralkyloxy, cycloalkyloxi, cycloalkenyloxi, heterocyclic oxy, alkoxicarbonyloxi, alkenyloxicarbony-Loxi, aryloxicarbonyloxi, aralkyloxicarbonyl, heterocyclic oxicarbonyloxi, alkenyloxycarbonyl, aryloxicarbo-5-phenyl, aralkyloxicarbonyl, cycloalkyloxicarbonyl cycloalkenyloxicarbonyl, heterocyclic oxicarbonyl or alkyl anilino group or an alkyl anilio 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, 10 (d) alkenyl groups; (e) alkynyl groups; (f) phenyl group; 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 -Yr is -CH = CH-O-, -CH = CH-S-, -CH 2 CH 2 S-. -CH = N-CH = N-, -CH = CH-CH = CH-, -CO-CH = CH-CO- or -CO-CO-CH = CH-, or a substituted derivative thereof, wherein the substituents are selected from those specifically mentioned under (b) or groups represented by the formula 29 wherein -Y2- is a lower alkylene group such as - (CH2) 3- or - (CH2) 4- or a substituted derivative thereof, wherein the substituents selected from those specifically mentioned under (b), (g) aralkyl groups such as benzyl or substituted benzyl groups in which at least one of the substituents are selected from those specifically mentioned 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] decyl and the like, (j) phthalidylidene-lower alkyl groups or substituted derivatives thereof, wherein the substituents are halogens or lower alkyl groups.

The above carboxil protecting groups are typical examples, and the carboxil protecting group may also be selected from the other protecting groups described in the following literature: US Patents 3,499,909, 3,573,296 and 3,641,018; German Patents 2,301,014, 2,253,287 and 2,337,105.

Among these carboxil protecting groups / all preferably diphenylmethyl, 5-lower alkyl 2-oxo 1,3-dioxol-4-yl lower alkyl groups, acyloxialkyl groups, acylthioalkyl groups, phthalidyl group, the indanyl group, phenyl 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 R21 represents a known unsubstituted or substituted alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group; R22 is a hydrogen atom or a known unsubstituted or substituted alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group; R23 is a hydrogen atom, a halogen atom or a known unsubstituted or substituted alkyl, cycloalkyl, aryl or heterocyclic group, or - (CH2) nCOOR21 (wherein R21 has the same meaning as previously given, and n represents 0, 1 or 2) and m 0,1 or 2.

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-dioxo-4-yl-methyl, 5-ethyl 2-oxo 1 , 3-dioxol-4-yl-methyl, 5-propyl 2-oxo 1,3-dioxol-4-yl-methyl and the like; acyloxialkyl groups such as acetoximethyl, pivaloyl oximethyl, propionyloximethyl, butyryoximethyl, isobutyryl oximethyl, valeryoximethyl, 1-acetoxiethyl, 1-acetoxy n-propyl, 1-pivaloyloxiethyl, 1-pivaloyloxy 45 n-propyl and the like; acylthioalkyl groups such as acetylthiomethyl, pivaloylthiomethyl, benzoylthiomethyl, p-chlorobenzoylthioethyl, 1-acetylthioethyl, 1-pivaloylthioethyl, 1-benzoylthioethyl, 1- (p-chlorobenzoylthio) -ethyl and the like; alkoximethyl groups such as methoximethyl, ethoximethyl, propoximethyl, isopropoximethyl, n-butyloximethyl and the like; alkoxicarbonyloxialkylgroepen such as methoxicarbonyloximethyl, ethoxicarbonyloximethyl, propoxicarbonyloximethyl, isopropoxicarbonyloximethyl, n-butoxicarbonyloximethyl, 50 tert.-butoxicarbonyloximethyl, 1-methoxicarbonyloxiethyl, 1-ethoxicarbonyloxiethyl, 1-propoxicarbonyloxiethyl, 1-isopropoxicarbonyloxiethyl, 1-tert.-butoxicarbonyloxiethyl, 1-n-butoxicarbonyloxiethyl, and the like ; alkoxycarbonylmethyl groups such as methoxycarbonylmethyl, ethoxycarbonylmethyl and the like; phalidyl group; indanyl group; phenyl group; phthalidylidene alkyl groups such as 2- (phthalidylene) ethyl, 2- (5-fluorophthalidylidene) ethyl, 2- (6-chlorophthalidylidene) ethyl, 2- (6-methoxifalidylidene) ethyl and the like, etc.

When R5 is a protecting amino group, the protecting group is selected from groups commonly used in the field of the penicillins and cephalosporins, such as readily removable acyl groups, for example 2,2,2-trichloroethoxicarbonyl, 2,2,2-tribromoethoxycarbonyl, benzyloxicarbo-3 192792 nyl, p-toluenesulfonyl, 4-nitrobenzyloxicarbonyl, 2-bromobenzzyloxicarbonyl, acetyl, (mono-, di-, tri-) chloroacetyl, trifluoroacetyl, formyl, tert.-amyloxicarbonyl, tert-butoxymethyl, tert-butoxymethyl 3,4-dimethoxibenzyloxicarbonyl, 4- (phenylazo) -benzyloxicarbonyl, 4- (4-methoxiphenylazo) benzyloxicarbonyl, pyridine-1-oxide-2-yl-methoxicarbonyl, 2-furyloxicarbonyl, diphenylmethoxicarbonyl, 1,1-5 dimethylpropoxicarbonyl 1-cyclopropylethoxicarbonyl, phthaloyl, succinyl, 1-adamantyl-oxicarbonyl, 8-quinolyloxicarbonyl and the like; further readily removable groups, for example trityl, o-nitrophenylsulfonyl, 2,4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy 1-naphthylmethylene, 3-hydroxy 4-pyridylmethylene, 1-methoxicarbonyl 2-propylidene, 1-ethoxicarbonyl 2-propylidene, 3-ethoxicarbonyl-2-butylidene, 1-acetyl 2-propylidene, 1-benzoyl 2-propylidene, 1- [N-2-10 methoxiphenyl) carbamyl] -2-propylidene, 1-IN- (4-methoxiphenyl) carbamyl] -2-propylidene, 2-ethoxicarbonylcyclohexylidene, 2-ethoxicarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl 5-oxocyclohexylidene, 4-nitrofurfurylidene and the like; di- or tri-alkylsilyl group; and such.

Formula 68 includes tautomers, as shown in Scheme A, wherein R5 is an unprotected or unprotected amino group, and such tautomers are also included in this invention, Rs 15 having the same meaning as defined above and R5a an unprotected or imino group proposes. In these formulas, the R 5a imino protecting group includes those groups used in the peniciliins and cephalosporins field, and specifically the same groups as the monovalent groups among the amino protecting groups mentioned above for R 2.

When the -CH2R2 group in formula 1 is a group of formula 69, wherein R6 has the meaning given previously, there are tautomers as indicated in scheme B, wherein R6 is a hydrogen atom, and these tautomers are also included in the invention .

The compounds of the salts of formula 1 include salts to the basic group and the acid group, which are well known in the art of the peniciliins 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, succinic, formic, trichloroacetic, trifluoroacetic, 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-trimethylbenzenesulfonic acid), naphthalene 1-sulfonic acid, naphthalene 2-sulfonic acid, phenylmethanesulfonic acid, benzene 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-trisulfonic acid and the like. The salts on the acid group include salts with alkali metals such as sodium, potassium and the like, salts with alkaline earth metals such as calcium, magnesium and the like; ammonium salts; and salts with nitrogen-containing organic bases, such as procaine, dibenzylamine, N-benzyl β-phenetylamine, 1-ephenamine, Ν, Ν-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, Ν, Ν-dimethylaniline, 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. Next, pharmacological effects of some typical compounds 40 represented by the formula 1 will be shown.

1) Antibacterial activity (Table A)

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 45 Oak Kagaky) is known at 37 ° C for 20 hours 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 O ^ g / ml ). The amount of the inoculated bacteria is 104 cells per plate (106 cells per ml). The MIC values of the following test compounds are as shown in Table A: 50 (A) trifluoroacetic acid salt of 7- [2- (2-aminothiazol-4-yl) 2- (syn) -methoxy-iminoacetamido] 3 - {[1- (2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)] methyl} A3-cephem-4-carboxylic acid, (B) trifluoroacetic acid salt of 7- [2- (2-aminothiazol-4-yl) 2- (syn ) -methoxy-iminoacetamido] 3 - {[1- (4-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} A3-cephem-4-carboxylic acid (C) trifluoroacetic acid salt of 7- [2 - (2-aminothiazol-4-yl) 2- (syn) -methoxy-iminoacetamido] 3 - {[1- (4-ethyl 55 2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl} A3-cephem-4-carboxylic acid, D) trifluoroacetic acid salt of 7- [2- (2-aminothiazol-4-yl) 2- (syn) -methoxy-iminoacetamido] 3 - {[1- (4-isopropyl-2,3-dioxo- 1,2,3,4-tetrahydropyrazinyl)] methyl} A3-cephem-4-carboxylic acid 192 792 4

TABLE A

Antibacterial activity

Organism Compound A B C D

5 - E. coli NIHJ s0.1 s0.1 s0.1 s0.1 E. coli TK-3 * s0.1 s0.1 s0.1 s0.1 KI. pneumoniae Y-50 s 0.1 s 0.1 <0.1 s 0.1 KI. pneumoniae Y-41 s0.1 s0.1 s0.1 s0.1 10 KI. pneumoniae Y-4 * s 0.1 0.2 s 0.1 0.39

Ser. marcescens W-134 s0.1 s0.1 sO, 1 sO, 1

Ser. marcescens I ID620 s0.1 s0.1 s0.1 s0.1

Pro. morganii T-216 s0.1 s0.1 s0.1 £ 0.1

Pro. mirabilis T-111 s0.1 s0.1 s0.1 0.2 15 Pro vulgaris GN76 ** s0.1 0.2 1.56 0.39

Cit. freundii N-7 0.39 1.56 0.78 1.56

Ps. aeruginosa GN 918 ** 12.5 25 6.25 - * Penicillinase producing strain.

** Cephalosporinase producing strain.

2) Acute toxicity

The LDS0 values of the following test compounds were 3 g per kg or more when the compounds were administered intravenously to mice (ICR, male, body weight 20-24 g). Test compounds: Sodium 7- [2- (2-aminothiazol-4-yl) 2- (syn) -methoximino-acetamido] 3 - {[1- (2,3-dioxo 1,2,3,4-25 tetrahydropyrazinyl) ] -methyl} A3-cephem 4-carboxilate, Sodium 7- [2- (2-aminothiazol-4-yl) 2- (syn) -methoxiimino-acetamido] 3 - {[1- (4-methyl 2,3- dioxo 1,2,3,4-tetrahydropyrazinyl)] - methyl} A3-cephem 4-carboxilate.

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

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

In the above formulas, R 1, R 2, R 5, R 6, R 7, and Ria have the same meaning as defined above; R1Sa represents the group R1B except a hydrogen atom; R28 represents an amino group, or a group of formula 72, wherein each R31_33, which may be the same or different, represents a hydrogen atom or an organic moiety not participating in the reaction, or a group of formula 73, 35 wherein each of the R34 and R35, which may be the same or different, represent a hydrogen atom or an organic residue that does not participate in the reaction; R29 represents an unsubstituted or substituted acyloxy or carbamyl oxio group; Rg benzyl, phenoximethyl or a group of the formula 100, wherein R5 and A have the meanings given previously, 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.

40 A further detailed explanation will be given below. R28 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 R31-35 include those well known in the art, especially substituted or unsubstituted aliphatic radicals, alicyclic radicals, aromatic radicals, aromatic-aliphatic radicals, heterocyclic radicals, acyl groups and the like. More specifically, the following 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: heterocyclic 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 and include aromatic aliphatic carboxylic acids, aromatic oxialiphatic carboxylic acids, aromatic thioaliphatic carboxylic acids, heterocyclic aliphatic carboxylic acids, heterocyclic and heterocyclic 55 thioaliphatic carboxylic acids, wherein an aromatic moiety or a heterocyclic group is attached directly or through 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 attached to the carbonyl group via an oxygen, nitrogen or sulfur atom; aromatic carboxylic acids; heterocyclic carboxylic acids and the like.

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

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

Each of the groups forming these organic carboxylic acids may be further substituted by a substituent such as a halogen atom, a hydroxil group, a protected hydroxil group, an alkyl group, an alkoxy group, acyl group, nitro group, amino group, a protected amino group, a carboxil group or a protected carboxil group .

The substituted or unsubstituted acyloxy and carbamyloxy groups for R29 also include alkanoyloxy groups such as acetoxy, propionyloxy, butyryloxy and the like; alkenoyloxy groups such as acryloyloxi and the like; Aryloxy groups such as benzoyloxi, naphthoyloxi 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, hydroxil, carboxil, sulfamyl, carbamyl, alkoxicarbonylcarbamyl groups, arylcarbamyigrows, alkoxicarbonylsulfamyl groups, aryl groups, carbyl groups.

In the above substituents for R29, the hydroxil group, amino group, carboxil group and the like can be protected with protecting groups commonly used, and specifically include the hydroxil protecting, amino protecting and carboxil protecting groups mentioned above for R2.

a) Conversion reaction to the 3-position 7-substituted or unsubstituted amino 3-substituted methyl cephemcarboxylic acid of formula 4 or a salt thereof can be obtained in high yield with high purity by an industrially easy procedure by a 2 , React 3-dioxo 1,2,3,4-tetrahydropyrazine of the formula 3a or a salt thereof with a cephalosporanic 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 is removed, the carboxil group is protected or the resulting compound is converted 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, pp. 1888-1890 (1975).

Further, if necessary, the substituent of the amino group at the 7 position can be removed in a conventional manner to obtain a 7-unsubstituted amino compound. According to this procedure, not only A3 cephem compounds can be used but also A2 cephem compounds as starting compounds, and when the A2 cephem compounds are used as the starting compounds, the reaction product can further convert the A2 cephem compounds to A3 cephem compounds .

Also, not only compounds in which> Z is> S but also compounds in which> Z is> S- »0 can be used as starting materials, and in the latter case> S-» 0 can be converted to> S during the reaction or in the post-treatment stage.

When the 2,3-dioxo 1,2,3,4-tetrahydropyrazine of the formula 3a, which is used as a reagent, has a basic or acidic group as a substituent, these compounds can, if necessary, be used in the form of the corresponding salt at The reaction. In this case, among the salts on the basic groups and the salts on the acid groups, those referred to as the salts of the compounds of formula 1 are included.

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 formula 2 can be isolated beforehand and then used, or can be prepared in situ.

As the acids or the complex compounds of acids used in the reaction, there may be mentioned, for example, protonic acids, Lewis acids or complex compounds of Lewis acids. The protonic acids include sulfuric acids, sulfonic acids and superacids (superacids means 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, fluoro sulfuric acid, and the like, sulfonic acids, for example, alkyl (mono- or di) sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and the like, aryl (mono-, di- or tri) sulfonic acids such as p-toluene sulfonic acid and the like, superacids such as perchloric acid, magic acid (FS03H-SbF5), FS03H-AsF5, CF3S03H-SbF5, HF-BF3, 192792 H2SO4-SO3 and the like.

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

The reaction is preferably carried out in the presence of an organic solvent. 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 acetonitrile, butyronitrile and the like; and sulfolanes such as sulfolan and the like. These solvents can be used mixed with two or more. In addition, complex compounds formed from these organic solvents and Lewis acids can be used as the solvent. It is sufficient that the amount of the acid or the complex compound of the acid is at least equimolar to the amount of the compound represented by the formula 2 or 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 using the complex compound 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 or a salt thereof is at least equimolar to the amount of the compound represented by the formula 2 2 or a salt thereof , and in particular the use in an amount of about 1.0-5.0 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 penoxide, polyphosphoric acid, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride and the like; an organic silylating agent such as N, O-bis (trimethylsilyl) acetamide, trimethylsilylacetamide, trimethylchlorosilan, dimethyldichlorosilan 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 using a compound represented by the formula 2, wherein R, represents a carboxil protecting group, as a starting material, one can directly obtain a compound represented by the formula 4, wherein R, is a hydrogen atom, in some cases 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.

45 3915-3918 (1981).

A mixture of the isomer represented by the formula 17 or a salt thereof and the isomer represented by the formula 18 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-tetrahydropyrazine of the formula 3a or a salt thereof in the presence of a base. The base includes alkali carbonates 50 (e.g. sodium carbonate, potassium carbonate and the like), alkali hydrogen carbonates (e.g. sodium hydrogen carbonate, potassium hydrogen carbonate and the like), alkali hydroxides (e.g. sodium hydroxide, potassium hydroxide and the like), nitrogen-containing organic bases, e.g. triethylamine, pyridine dimethylaniline and the like.

The 3-position reaction is generally carried out in a suitable solvent. The solvent includes halogenated hydrocarbons such as chloroform, methylene chloride and the like; ethers such as tetrahydrofuran, dioxane and the like; N, N-dimethylformamide; Ν, Ν-dimethylacetamide; acetone; water and mixtures thereof.

7 192792

In this case, the compound 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 A3 cephem compound thus obtained, ie a mixture of the isomer represented by formula 17 or a salt thereof, and the isomer represented by formula 18 or a salt thereof, can be easily converted to the A3 cephem compound to obtain the compound of formula 18 or a salt thereof, which is then converted into the compound of formula 19 or a salt thereof by the deacylation. Such conversion reaction and deacylation are known in the art of penicillins and cephalosporins and are specifically described in Journal of Organic Chemistry, Vol. 35, no. 7, pp. 2430-2433 (1970) and "Cephalosporins and Penicillins” Flynn, Academy Press), pp. 56-64.

When the substituents of the 2,3-dioxo 1,2,3,4-tetrahydropyrazine of the formula 3a or its salt, which are used as the reagents in the reaction, are substituted by a hydroxil group, an amino group, a carboxil group and such, 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, on the carboxil group or converted to the salt by a conventional method to obtain the intended compound. Also, the compound of formula 4, wherein R28 represents an amino group, can be converted into a reactive derivative on the amino group or the compound represented by the formula 19, as mentioned below, by a conventional method.

b) Acylation

When the compound represented by the formula 5, 6, 7, 8 or 13, 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 formula 1,9,10,11 resp. 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 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 preceded by the formula 4 or a salt thereof with a silyl compound, such as bis (trimethylsilyl) acetamine, trimethylsilyacetamine, 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) 2PCI, (CH 3 CH 2) 2PCI and the like, or a tin compound such as (C4H9) 3 SnCI 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 N, N-dimethylformamide, Ν, Ν-dimethyl-acetamide and the like with a halogenating agent such as phosgene, thionyl chloride, phosphorus pentachloride, phosphorus tribromide, phosphorus oxychloride, phosphorus pentachloride, trichloromethyl chloroformate, oxalyl chloride and the like.

If each of the compounds represented by formulas 5, 6, 7, 8 and 13 is used in the form of a free acid or a salt, a suitable condensing agent is used. The condensing agent includes Ν, Ν'-disubstituted carbodiimides, such as Ν, Ν'-dicyclohexylcarbodiimide; azolide compounds, 192792 8 such as Ν, Ν'-thionyl-dimidazole; dehydrating agents such as N-ethoxoxycarbonyl 2-ethoxy 1,2-dihydroquinoline, phosphorus oxychloride, alkoxiacethylenes and the like; 2-halo pyridinium salts, such as 2-chloropyridinium 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 or a salt thereof, which can be converted to the compound or salt represented by the formula 1b or its salts, can be produced by the following procedure: 15 To the compound represented by the formula 9 or a salt obtaining it using the compound represented by the formula 4 or a salt thereof, one can obtain a 4-halogen-3-oxo-butyryl halide obtained by the reaction of diketene with a halogen, such as chlorine or bromine [Journal of the Chemical 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 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 of 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, wherein R, is a carboxil protecting group, to the compounds represented by formulas 1, 9, 10, 11 and 14, wherein R., 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. a carboxilbe 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 1, R 2, and R 5 contain groups active for the reaction, these groups can also be suitably protected with conventional protecting groups before reacting in this acylation reaction, and the protecting groups can also be removed by a conventional method after the reaction.

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

c) Nitrosation 45 To obtain the compound represented by the formula 10 or a salt thereof from the compound predominated by the formula 9 or a salt thereof, a nitrosating agent can then be reacted with the compound represented by the formula 9 or a salt thereof. The reaction is usually carried out in a solvent, and as the 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 acoxide and the like. The reaction is usually carried out at a temperature of -15 ° C to 30 ° C and the reaction time is usually 10 minutes from 192792 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 by the formula 10 or a salt thereof thus obtained can be isolated and purified by a well-known method, it can be used for the subsequent reaction without isolation.

d) etherification and phosphorylation

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 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 a 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, Ν, dim-dimethyl acetamide, water or a mixture thereof.

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 conducted 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 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 1a or 1b or a salt thereof of 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-40 dimethylacetamide, N-methylpyridone, alone 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. Furthermore, in the compound represented by the formula 1a or 1b, the protection of the carboxil group and removal of the protective carboxil group or the conversion of a product 50 into a salt thereof can be carried out in a conventional manner to convert the compound into the corresponding intended link. If Rv R 2 and R 5 in formula 1a or 1b contain groups 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 1a or 1b or the salt thereof, thus obtained 55, can be isolated or in a conventional manner.

192792 10 f) Oximation

The compound represented by the formula 1b 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 15 includes hydrochlorides, hydrobromides, sulfates and the like. This reaction is usually carried out not only in a solvent such as water, an alcohol, Ν, Ν-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 of 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 alone for the reaction, it can also be reacted in the presence of a base, for example an inorganic base such as an alkali hydroxide (e.g. sodium hydroxide, potassium hydroxide and the like), an alkaline earth hydroxide (for example, magnesium hydroxide, calcium hydroxide and the like), an alkali carbonate (for example, sodium carbonate, potassium carbonate and the like), an alkaline earth carbonate (for example, magnesium carbonate, calcium carbonate and the like), an alkali hydrogen carbonate (for example, sodium hydrogen carbonate, potassium hydrogen carbonate and for example), an alkaline earth phosphate calcium 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 trialkylamine (e.g. trimethylamine, triethylamine and the like), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4,3,0] 5-nonene, 1,4-diazabicyclo [2,2,2] octane, 1,5-diazabicyclo [5,4,0] 7-undecene and the like. The compound represented by the formula 1b or a salt thereof of this invention, thus obtained, can undergo conversion of R in a conventional manner, and can also be isolated by a conventional method. 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 for the purpose of treating or protecting against baceterial infections. It is preferred to administer the compound 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 for the compound to be formed into a dosage form commonly used with cephalosporin medicaments, eg tablets, capsules, powders, fine grains, granules, syrups, injections (including drops), suppositories and the like. When the above drug is formed into a dosage form, diluents and / or additives can 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, 40 and in general it is sufficient to administer orally or parentally to a adult at a dose of approximately 50-5000 mg in 1-4 servings per day.

The invention will now be explained below with reference to the reference examples and examples, which are purely illustrative and in no way limit.

45 Reference Reference 1 (1) To a solution of 20.0 g of ethyl N- (2,2-diethoxiethyl) oxamate in 60 ml of ethanol, 6.1 ml of a 70 wt.% Ethyl amine 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 obtain 17.0 g (yield 85.1%) of N-ethyl N '- (2,2-diethoxiethyl) oxamide, m.p. 131-132 ° C. IR (KBr) cm -1: uc = 0 1650.

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

11 192792

TABLE B

(CH3CH20) 2CHCH 2NHCOCONHR6 R6 Solvent for Smpt. (° C) IR (KBr) cm -1 uc = 0 5 recrystallization -H Ethyl acetate 141-142 1650, 1635 -CH3 Ethanol 135-136 1645 10 - - (CH2) 2CH3 Acetone 84-85 1645 / CH3 Acetone n-Hexane 145-146 1650, 1635 -CH \ CH3 15 - - (CH2) 3CH3 n-Hexane 111—12 1645 - (CH2) 4CH3 n-Hexane 92-93 1650 20 (2) To a solution of 17.0 g N- ethyl N '- (2,2-diethoxiethyl) 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 and 6.8 g (yield 61.8%) of 4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazine, mp 173-174 ° C, are obtained.

IR (KBr) cm -1: uc = 0 1680-1620

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

30 TABLE C

R6 Solvent for Smpt. (° C) IR (KBr) cm'1: υ0 = 0 recrystallization 35 -H -> 280 1680-1640 -CH3 Ethanol 220-231 1690-1635 - {CH2) 2CH3 Acetone 182-183 1680-1640 40 - / CHo Acetone 215-219 1680, 1625 - ° H \ CH3 - (CH2) 3CH3 Acetone 149-150 1680, 1640 45 - - {CH2) 4CH3 Acetone 171-172 1685, 1660, 1620 (3) To a suspension of 5.2 g 4- (2,4-dimethoxibenzyl) 2,3-dioxo 1,2,3,4-tetrahydropyrazine obtained as 50 under (2) in 26 ml Ν, Ν-dimethylformamide, 4.1 g potassium carbonate is added and stirred the mixture 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 ethyl acetate and 200 ml water, the organic layer is separated, washed with 100 ml water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the residue was purified by column chromatography (Wako silica gel C-200, eluent chloroform) to obtain 4.9 g (66.0%) 1- (2,4-dimethoxy). benzyl) 4- (5-methyl 2-oxo 1,3-dioxol-4-yl) methyl 2,3-dioxo 1,2,3,4-tetrahydropyrazine with a 192792 12 melting point of 154-156 ° C.

IR (KBr) cm -1: uc = 0 1820, 1675, 1630 (4) 3.7 g of 1- (2,4-dimethoxybenzyl) 4- are dissolved in a mixed solvent of 37 ml of trifluoroacetic acid and 10.8 g of anisole. (5-methyl 2-oxo 1,3-dioxoi-4-yl) -methyl 2,3-dioxo 1,2,3,4-tetrahydropyrazine obtained under (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) -methyl 2, 3-dioxo 1,2,3,4-tetrahydropyrazine, mp 225-226 ° C.

IR (KBr) cm -1: uc = 0 1825, 1805, 1725, 1690, 1670.

(5) To a solution of 2.6 g of 1-carboximethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazine in 13 ml of N, N-dimethylacetamide, 3.9 g of diphenyldiazomethane is added at room temperature and left mixture 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 of 15 (80.4%) 1-diphenylmethyloxicarbonylmethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazine with a melting point of 97-98 ° C.

IR (KBr) cm -1: uc = 0 1750, 1675, 1645.

Example I

(1) To a solution of 10 ml of ethyl acetate containing 2.71 g of boron trifluoride, 2.72 g of 7-aminocephalosporanoic acid (herein referred to as 7-ACA) and 1.54 g of 4-ethyl 2,3-dioxo are added 1,2,3,4-tetrahydropyrazine and allow the mixture to react 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, then dried to give 3.10 g (88.1%) of 7-amino 3 - {[1 - (4-ethyl-2,3-dioxo) 1,2,3,4-tetrahydropyrazinyl)] methyl} A1 2 3-cephem 4-carboxylic acid, mp 191-195 ° C (decomposition).

IR (KBr) cm'1: uc = D 1795, 1670, 1620 NMR (CF3COOD) δ values: 30 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, SN), 35> CH - 5.48 (2H, s, Ce-) H, C7-H), Z2 6.74, 7.00 (2H, ABq, J-6Hz, formula 78.

(2) The reaction reaction at the 3-position mentioned under (1) above is carried out under the reaction conditions shown in Table G to obtain 7-amino 3 - {[1- (4-ethyl 2,3-dioxo 1, 2,3,4-40 tetrahydropyrazinyl)] methyl} A2-cephem 4-carboxylic acid in the yields shown in Table D.

TABLE D

No. Starting material Solvent Acid or complex Reaction conditions Quantity 45 compound of (yield)

7-ACA

HNv = / N "CH2CH3 50 1 2.72 g 1.54 g SulfolanlOml Boron trifluoride Room temperature 2.6 g (73.9%) 2.71 g ture 2 hours 2.72 g 1.54 g Nitromethane 14 Boron trifluoride Room temperatures - 2.85 g (81.0%) 2 ml diethyl ether 16 hours 3 55 complex 5.7 g 13 192792 (3) In a manner as under (1) above, the compounds shown in Table E are obtained. In this case, the intended compounds are obtained by pouring the reaction mixture at the 3-position in ice water after the completion of the reaction and adjusting the pH to 3.5 with 28% ammonia under ice-cooling.

5

TABLE E

"2NT <S1 2 N Y ^" CH2-ir 10 _COOH_

No. R2 Mp. (° C) IR (KBr) cm * 1: NMR (d6-DMS0) δ values uc = o ï 196-199 1800, 1678, 0.91 (38.t, 0-71 *.> N (CH2I, 08 , 1.

15 -N n (CH_) .CH_ (decomposition) 1630 1.10-1.95 (6h, m,> nch2 (ch2) ch), - - 3.63 {2H, bs, C2-H), 3 .77 (2H, t, J = 7Hz,)> NCII2 (CH2) 3CH3), 4.34, - 4.82 (211, ABq, J = 15HZ,}>, 20 Ά CH2 - (4) On such manner as under (1) above, the crude crystals shown in Table F are obtained.

25 TABLE F

o / -nY5J "CH2R

30 COOH

No, R2

-N N-H

Q-: / - - - y—? 40 -N N-CH3 - - - y-k -N N-CH-CH-.CH-, 45 W 2 2 3_ 4 ° H ° ^ ch3

-N N-CH

N = / ^ CH_ 50__ 9 O ^ p -N N (CH ^) -jCH-, -f 23 3 55.

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

192792 14

Example II

To a suspension of 3.0 g of 7-amino 3 - {[1 - (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)] methyl} A3-cephem 4-carboxylic acid obtained according to example 1- 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 diphenyldiazo-5-methane are slowly added to the solution and the resulting mixture is reacted 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%) of 7-amino 3 - {[1- (4- ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl] methyl} A3-cephem 4-carboxilate, mp 183-186 ° C (decomposition).

IR (KBr) cm1: uc = 0 1765, 1730, 1680, 1630.

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

TABLE G H2N1 — i ^ S '"l

20 I

ΓνΆ 2

O CH2R

COOCH (/ (5)) 2 N - R 2 Mp. (° C) IR (KBr) cm1: t> c = 0 ^ _P 129-130 (decomposition) 1765, 1725, 1690, 1630 30 ^ “

-N NH

_ ^ _ ¢, ° 127-128 (decomposition) 1770, 1725, 1690, 1640 -N N-CH, 35 W 3_ 169-171 (decomposition) 1765, 1730, 1685, 1635 -NN (CEL ·) 0CH_ \ - / 4 2 3 40 - = 1 ° sv_P 179-180.5 (decomposition) 1760, 1720, 1685, 1630 7 λ / CH3 -N NCHC ° ch3 45 - ^ 180-189 (decomposition) 1760, 1725, 1680, 1630 - NN (CEL) -, CH_ \ -✓ 2 3 3_ 50 185-194 (decomposition) 1765, 1730, 1685, 1630 -NN (CH_) „CH- S- / 2 4 3__

55 example III

4.9 g of diphenylmethyl 7-amino 3- [1-C2,3-dioxo 1- (2,3,4-tetrahydropyrazinyl] A3-cephem 4-carboxilate and dissolved in a mixed solvent of 25 ml of trifluoroacetic acid and 10 ml of anisole. let the solution react at room temperature for 2 hours 192792. 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. with 40 ml diethyl ether and then dried to obtain 4.25 g (97.0%) of trifluoroacetic acid salt of 7-amino 3 - {[1- (2,3-dioxo-1,2,3,4-tetrahydropyrazinylmethyl} A3-) cefem 4-carboxylic acid, mp 105-106 ° C (with decomposition).

IR (KBr) cm-1: vc = 0 1780, 1700-1630 NMR (CF3COOD) δ values: 3.72 (2H, bs, C2-H), 5.14, 5.52 (2H, ABq, H = 15Hz, formula 79), 5.44 (2H, s, C6-H, C7-H), 6.78, 6.98 (2H, ABq, H = 6Hz, formula 78).

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

TABLE H

15 S

CF 3COOH 1 H 2NT-f ^ ^ H2-R2

O COOH

20 --—— - p2 Omnt IR fKRrt / (dg-DMSO + CF COOD) 11 \ R Mp. (C) IR (KBr) NMR ((CF3COOD 3) 12) δ values

Cm: υ0 = 0 \ (dg-DMSO + D20) 13/25 ° ^ ° 109-110 1795,1680, 3'36 <3H '^^ 31, 3'5 ° <2H' bS '° 2 ~ Η> -N N-CH .. (decomposition) 1635 4.53, 5.11 (2H, ABq, J = 15HZ,}, w oh -2-5.06 (1H, d, J = 5Hz, Cg-H), 5.17 (lil, d, 30 J = 5Hz, C -, - Η), 6.73 (2H, bs,) = {

Η H

* 3 152—155 1780,1675, ° 91 13 «. '> «' CH2> 2¾1 · 35 -N Mic» 2> AjCH3 (decomposition) 1635 1.35-2.08 <2H, m, ^ NCH2CH2CH3), 3.52 (2H, bs, C2-H), 3 .77 (2H, t, J = 7Hz, ^ NCH0CH0CH,), ^ _2 2 3 s 40 4.31, 4.86 (2H, ABq, J = 15Hz,), hu i / ^ CH2-5.35 (2H, bs, Cg-H, C? -H), 6.73 (2H, bs, 45} = K>

Η H

192792 16 TABLE H (continued) d2 Cmnt, .n IR fK-Rrt / (dg-DMSO + CF COOD) * 1 \ R Srnpt. (C) IR (KBr) NMR ((CF3COOD 3) * 2) fi values cm: vc = 0 V (dg-DMSO + D o) * 3/5 2 ^ - (° .CH0 159.5-161.5 1780, 1.46 (6H> d / y = 7hz,> NCH ^ C ^ 3), -M N-CHv 3 (decomposition) 1680-1620 xciu, Λ J 3.70 (211, bs, C -H) .70 i CH S>, 4.77-5.60 (3H, m,> NCH <^ 3,}), nch3 ^ ch2-5.46 (211, bs, Cg-H, C? -H), 15 6.82, 7.04 (2H, ABq, J = 6Hz,)

Η H

* 2 20 ----- 158-162 1780, 0.92 (3H, t, J = 7Hz,> N (CH2) 3CH3), -Nv n- (ch2) 3ch3 (decomposition) 1675-1635 1.10 -1.90 (4H, m,> nch2 (ch ^) 2ch3), 3.62 (2H, bs, C2-H), 3.75 (2H, t, J = 7Hz,> NCH2 (CH2) 2CH3 ), 4.56, 5.18 (2H, ABq, J = 15Hz, ^), <^ ch2-3Q 5.29 (2H, s, C6-H, C? -H), 6.70 (2H, bs, y = ^)

Η H

* 1 35 ----------- --—-—---— 0 0 ** 139-140 1780.1710, 3.46 * 2H 'bs' C2-H *' 4'47 '5'07 (2H' ABq ') - ((decomposition) 1690-1620 j = ishz,), 5.04 <1H, d, j = 5Hz, -n NU 1 „„ S- / i ^ CH2- 40 Cg-H), 5.20 (1H, d, J = 5Hz, C? -H), 6.34, 6.59 (2H, ABq, J = 6Hz, UK)

Η H

* 3 45 __ — ____ OO „152_155 1780 1 690i 3.35 (3H, a,> NCH3), 3.48 I2H, bs, C.-Il, / - \ (decomposition) 1660.1620 4.50, 5 , 12 (2H, ABq, J = 15Hz,),

-N N-CH, J

W 3 ^ CH2- 50 4.87 (1H, d, J = 5Hz, Cg-H), 5.03 (1H, d, J = 5Hz, C7-II), 6.70 (2H, bs,> = <) Η H * 3 * = Free connection; the intended compounds were obtained by reaction in a mixed solvent of trifluoroacetic acid and anisole, then removal of the solvent, dissolving the residue in water and adjusting the pH to 3.5 with 28% aqueous ammonia.

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

17 192792

Example Ν (1) To a solution of 2.69 g of 1- (5-methyl 2-oxo 1,3-dioxol-4-yl) methyl 2,3-dioxo 1,2,3,4-tetrahydropyrazine in 27 ml 2, ium-dimethylformamide, 1.52 g of potassium carbonate are added and the resulting mixture is stirred at room temperature for 20 minutes. Then 4.67 g of tert-butyl 5 7-phenylacetamido 3-bromomethyl A2-cephem 4-carboxilate are added thereto under ice-cooling, and the mixture is allowed to react at room temperature for 2 hours. The reaction mixture is placed in a mixed solvent of 200 ml of ethyl acetate and 150 ml of water, and the organic layer is separated, washed with 150 ml of water and then dried 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) of 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 C-200, eluent chloroform) to obtain 2.70 g (43.2%) 7-phenylacetamido 3 - {[1- [ 4- (5-methyl 2-oxo-1,3-dioxol-4-yl) methyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl]] methyl} A3-cephem 4-carboxilate 1-oxide with melting point 135-136 ° C (under decomposition).

IR (KBr) cm -1 uc = 0 1820, 1790, 1720, 1685, 1650.

(2) 3.0 g of 20 tert.-butyl 7-phenylacetamido-3 - {[1- [4- (5-methyl-2-) are dissolved in a mixed solvent of 12 ml of Ν, Ν-dimethylformamide and 6 ml of acetonitrile. oxo 1,3-dioxol-4-yl) methyl 2,3-dioxo 1,2,3,4-tetrahydropyraziny]] - methyl} A3-cephem 4-carboxilate-1-oxide. 1.0 g of standard chloride and 1.58 g of acetyl chloride are added to the solution in this order under ice-cooling, and the mixture is allowed to react at room temperature for 30 minutes. The solvent is removed by distillation under reduced pressure and 50 ml of ethyl acetate and 50 ml of water are added to the residue, and the resulting mixture is adjusted to pH 6.0 with sodium 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 acetate = 3: 2 by volume) to give 2.12 g (72.4%) of t. butyl 7-phenylacetamido 3 - {[1- [4- (5-methyl 2-oxo 1,3-dioxol-4-yl) methyl 2,3-dioxo 1,2,3,4-30 tetrahydropyrazinyl]] methyl} A3-cephem 4-carboxilate with melting point 120-122 ° C with decomposition.

IR (KBr) cm'1: uc = 0 1820, 1775, 1715, 1685, 1645 NMR (CDCI3) δ values: 1.58 (9H, s, -C (CH3) 3, 2.28 (3H, s, -CH3) 3.17, 3.61 (2H, ABq, J = 18Hz, C2-H).

35 3.77 (2H, s, formula 80), 4.53, 5.13 (2H, ABq, J = 15Hz, formula 79), 4.71 (2H, s,> NCH2 -), 5.03 ( 1H, d, J = 5Hz, C6-H), 5.93 (1H, dd, J = 5Hz, J = 8Hz, C7-H), 40 6.53, 6.89 (2H, ABq, J = 6Hz , formula 78), 7.32-7.51 (5H, m, formula 81), 7.57 (1H, d, J = 8Hz, -CONH-) (3) 2.0 are dissolved in 30 ml of anhydrous methylene chloride g tert.-butyl 7-phenylacetamido 3 - {[1- [4- (5-methyl 2-oxo-1,3-dioxol-4-yl) methyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl]] methyl } A3-cephem 4-carboxilate obtained at (2) 45 above. 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 allowed to react at -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 a further 30 minutes. The reaction mixture is then adjusted to pH 0.5 with 6 N hydrochloric acid, and the aqueous layer is 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-tetrahydropyrazinylmethyl} A3-cephem 4-carboxilate, mp 185-188 ° C with decomposition.

192792 18 IR (KBr) cm'1: uc = 0 1820, 1786, 1705, 1690, 1635 NMR (CDCI3-d6-DMSO) δ values: 1.52 (9H, s, -C (CH3) 3), 2 .24 (3H, s, -CH3), 3.46 (2H, bs, Cz-H), 4.35, 5.08 (2H, ABq, J = 15Hz, formula 79), 4.76-5 .09 (4H, m,> NCH2-, C6-H, C7-H), 6.74 (2H, s, formula 78).

Example V

(1) 2.29 ml of Ν, Ν-dimethylacetamide and 4.58 ml of acetonitrile are dissolved in 2.29 g of 2- (2-formamidothiazol-4-yl) 2- (syn) -methoxy-iminoacetic acid and added the resulting solution is added dropwise 1.62 g of phosphorus oxichloride and the mixture is allowed to react 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)] methyl} A3-cephem 4-carboxilate is added to the reaction mixture and allowed to 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- (2-20 formamidothiazol-4-yl) 2- (syn) -methoxy-iminoacetamido] 3 - {[ 1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)] methyl} A3-cephem 4-carboxilate mp 165-168 ° C.

IR (KBr) cm'1: uc = 0 1780, 1720, 1680, 1640 NMR (d6-DMSO) δ values: 1.18 (3H, t, J = 7Hz,> N-CH2CH3), 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, C6-H), 6.02 (1H, dd, J = 5Hz, J = 8Hz, C7-H), 30 6.50, 6 .62 (2H, ABq, J = 6Hz, formula 78) 7.04 (1H, S, -CH <), 7.17-7.82 (11H, m, formula 81, x2, 8.63 (1H, S, HCO-), 9.89 (1H, d, J = 8Hz, -CON-), S-12.68 (1H, bs, HCONH-).

In such a manner, the compounds shown in Tables I and J are obtained.

TABLE I

40 HCONH- J — f - ^ - jPQ.CBjR2 N T rr \ \ 0CH3 C00CH <\ 0>) 2 45 (syn-isom ^ r)

R2 Mp. (° C) IR (KBr) cm -1: vc = D

50 ° P 120-125 (decomposition) 1780, 1720, 1680-1640 -N N-CH, ° /? 154-156 (decomposition) 1785, 1720, 1685, 1645 55 -N N- (CH-) 4CH.,

«^ 4 J

19 192792

TABLE J

fH3 N — τι — C-CONH —- r ^ S ^ | CH3CH2-q-OCONH-f J i | ^ _i ^ kCH7R2 ch3 \ 0 I / v bR18 COOCH (^ O)) 2 (syn isomer) 10 - R2 R18 Mp. (° C) IR (KBr) cm1: υ0 = ο \ P -CH3 176-179 (decomposition) 1780, 1720, 1680, '1640

-N NH

15 \ y ° λ? -CH3 152-155 (decomposition) 1780,1720,1680, -N_N- (CH?) 2CH3 1640 20 —---- // -CH3 158-160 (decomposition) 1780,1720,1680, / (XCH3 1640 - N NCHCb XCH3 25 ----—- _9 -CH3 166-167 (decomposition) 1780,1720,1685, / \ 1645 -N N- (CH _) - CH, V = / 2 3 3 30 ^ / 9 -CH2CH3131 (decomposition) 1786,1723,1684, / \ 1645 -N N- (CH_), CH, V = / 23 3 35 (2) To a solution of 6.05 g of diphenylmethyl 7- [2- (2-formamodithiazole) 4-yl) 2- (syn) -

methoxyiminoacetamido] 3 - {[1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)] methyl} A3-cephem 4-carboxilate in 31 ml methanol 0.5 ml concentrated hydrochloric acid is added, and let the mixture react at 35 ° C for 2 hours. After the completion of the reaction, the solvent is removed by distillation under reduced pressure. 100 ml of ethyl acetate and 100 ml of water are added to the residue and the pH of the resulting solution is adjusted to 6.0 with sodium hydrogen carbonate. The organic layer was 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%) of diphenylmethyl 7- [2- (2-aminothiazol-4-yl) 2- (syn) -methoxy-iminoacetamido].

3 - {[1 - (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)] methyl] A3-cephem 4-carboxilate, mp 45 165-167 ° C.

IR (KBr) cm'1: uc = 0 1780, 1720, 1680, 1640 NMR (d6-DMS0) δ values: 1.18 (3H, t, J = 7Hz,> N-CH2CH3), 3.55 (2H , bs, C2-H), 3.75 (2H, q, J = 7Hz, ^ -CHgCHg), 50 3.90 (3H, s, -OCH3), 4.41 5.02 (2H, ABq, J = 15Hz, formula 79), 5.26 (1H, d, J = 5Hz, C6-H), 6.01 (1H, dd, J = 5Hz, J = 8Hz, C7-H), 6.52, 6 .65 (2H, ABq, J = 6Hz, formula 78) 55 6.68 (1H, s, formula 82), 7.07 (1H, s, -CH (), 7.15-7.84 (10H, m, formula 81, x2,), 192792 20 9.81 (1H, d, J = 8Hz, -CONH-),

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

TABLE K

5

N-i-C-CONH-f S

H2N-vCi 10 OCH3 C00CH <<Ö>) 2 (syn isomer R2 Mp. (°) IR (KBr cm'1: υ0 = 0 15 -% P 158-166 (decomposition) 1780, 1720, 1680, 1640

-N N-CH0 \ = / J

20 ^^ 151-156 (decomposition) 1780, 1720, 1680, 1640

-N N- (CH 3), CH., - / 2 4 J

(3) 5.1 g of diphenylmethyl 7- [2- (2-formamodithiazol-4-yl) 2- (syn) -methoxyiminoacetamido] 3 are dissolved in a mixed solvent of 20.5 ml of trifluoroacetic acid and 7.86 g of anisole. - {[1 - (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)] methyl} A3-cephem 4-carboxilate and let the solution react at room temperature for 2 hours. 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) -methoxy] iminoacetamido] 3 - [1 - (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)] methyl] A3-cephem 4-carboxylic acid, mp 15. -157 ° C under decomposition.

IR (KBr) cm'1: υ0 = ο 1775, 1710-1630 NMR (d6-DMS0) δ values: 1.21 (3H, t, J = 7Hz,> N-CH2CH3), 35 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, C6-H), 40 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-), 45 In such a manner the compounds shown in Tables L and M are obtained.

21 192792

TABLE L

N-n-C-CONH -, -

cf3cooh.h2n- (sA4 II

^ ΟΟΗ3 COOH (syn-isomee) R2 Mp. O IR (KBr cm'1: NMR (s6-DMSO) δ values υο = ο 10 .- ° M ° 95-102 1773.1670, 3.34 <3H's,> N-CH3), 3.51 ( 2H, bs, C2-H), “nwn_CH3 (decomposition) 1660.1640 4 ^ 00 (3Hi Sf_OCh3) f 4.52, 4.90 (2H, ABq, J = 15Hz, S" |), 5.25 <1H, d, 15 Clh ~ J = 5Hz, Cg-H), 5.90 (1H, dd, J = 5Hz, J = 8Hz, C? -H), 20 6.68 (2H, bs,> = <), 6.99 (1H, s, N1T}, »» S J1 9.85 (1H, d, J = 8Hz, -CONH-) 25 --- M ° 115-125 1770,1670, °: 86 <3H 't * J = 7Hz,> N- <CH2), 1.05 -nwn' (cii2.4CH3 (decomposition) 1660.1635 ^ 85 <6H, m,> n-ch2 <ch2) 3ch3), 3.53 <2H, bs, C2-H), 3.73 (2H, t, J = 7Hz, 30> N-CH2 (CH2) 3CH3), 3.93 (3H, s, -OCH3), 4, 40, 5.05 (2H, ABq, J = 15Hz, S), J-ch2- 5.20 (1H, d, J = 5Hz, Cg-H), 5.86 (1H, dd, J = 5Hz, J = 8Hz, C ^ -H), 6.6B (2H, bs,> = <), 6.95 (1H, s, NTT), ü * sm 40 9.85 (1H, d, J = 8Hz, - CONH-) 192792 22 TABLE Μ

ΛΝ-η-C - C ° NH -T — r'S

s cf3cooimi2n- (sJ # U Lch2-b2 \ 1 ol OR COOH (syri-isom ^ x) R2 R18 Mp. (°) IR (KBr NMR (s6-DMSO) δ values 10 cm'1: υο = ο ° M ° -CH3 165-167 1770, ° '90 (3H 't' J = 7Hz ·> N-CH ^^ CH ^), 1.32- -N N- (CIV2CH3 (dec-1710- 2.01 (2li, m CH 2 CH 2 CH 3.53 (2H, bs, 15th) 1630 - C2 H), 3.73 (2H, t, J = 7Hz,> N-CH 2 CH 2 CH 3), 3.96 (3H, s, -OCH3), 4.48, 5.14 (2H, ABq, J = 15Hz, S "|), 5.14 (1H, d, J = 5Hz, 20 J-CII2-C6-H ), 5.91 (1H, dd, J = 5Hz, J = 8Hz, C? -H), 6.24 (3H, bs, -NH®), 6.69 (2H, bs, X => (),

BRA

25 6.92 (1H, s,), 9.82 (1H, d, J = 8Hz,

S H

-CON1I-) 30 "7; -ή-cn3 -OHg 160-162 1770, 1) 25 <6H« d- J = 7Hz,> N-CH (C »3) 2), 3.48 (2H, - N N-CH (decomposition 1710- "w" CH3 thing) 1630 bs' C2 “H), 3.93 (3H, s, -OCH3), 4.44, 5.08 (211, ABq, J = 15Hz ,), 4.64-5.12 {lil, 35 1 Λοη, - m,> N-CH (CU3) 2), 5.21 (1H, d, J = 5Hz, Cg-H), 5.86 (111, dd, J = 5Hz, J = 8Hz, C? -H), 6.36 40 (3! 1, bs, -NH®), 6.72 (2H, bs,), ^ H 2i 6, 91 (1H, s,), 9.79 (1H, d, J = 8Hz,

45 S H

-CONH-) 23 192792 TABLE M (continued) R2 R18 Mp. (°) IR (KBr NMR (s6-DMSO) δ values cm'1: 5 υα = σ ~ o Ö - <\ j -CH3 155-157 1775, 0.89 (3H, t, J = 7Hz,> N (CH2) 3CH3), 1.03 -WICH2'3CH3.1 (411,> N-CH2 (C12) 2CH3), 3.43 <2H.

10 1630 bs, C2-H), 3.74 (2h, t, J = 7Hz,> NCH2 (CH2) 2CH3), 3.92 (3H, S, -OCH3), 4.41, 5.11 (2H , ABq, J = 15Hz, 1 2 "|)» 15 5.21 {III, d, J = 5Hz, C6-II), 5.81 (1H, dd, J = 5Hz, J = 8Hz, C -H ), 6.65 (2H, bs,

* Η H

20 μ {Ώ 6.87 (1H, s, 1 ^), 7.26 (3H, bs, -NH3 ^),

S H

9.81 (1H, d, J = 8Hz, -CONH-) 25.

-CH2CH3 169-174 1775, ^ 20 (3li 'tf J = 7Hz »> NCH2C ^ 3)' 1.29 (3H, t '-NwN-CH2Cn3 (dec-1645 j = 7Hz, -OCH-CH), 3.52 (2H, bs, C2 ~ H), thing) 2 - 3.47 {2II, q, J = 7Ilz,> N-CH2CH3), 4.26 (211, qn q, J = 7Hz, -OCH2CH3), 4 .45, 5.13 (2H, ABq, J = 1511z, 2Ί), 5.26 (1H, d, J = 5Hz, J-ch2- 35 c6-H), 5.90 (1H, dd, J = 5Hz, J = 8Hz, C? -H), 6.70 (2H, bs,) C ::: ^), 6.95 (1H, s, NT ~),

Η Η ’/ V

- - S H

40 9.86 {1H, d, J = 8Hz, -C0NH-) ° M ° -CH3 168-170 1770, 3> 50 <2H 'bs' C2_H)' 3'95 (3H's' ~ 0CH3) ' -N NH (ontie- 1710-4.47, 5.15 (2H, ABq, J = 15IIz, Sv |),

thing) 1630 'CH

45 -2 5.24 (1H, d, J = 5Hz, Cg-H), 5.85 (1H, dd, J = 5Hz, J = 8Hz, C? -H), 6.46, 6.62, (211 , ABq, J = 6Hz,> = <), 6.94 (1H, s, NT ~), 7.03 50 Η H x'V.

- - S II

(3H, bs, -NH®), 9.85 (1H, d, J = 8Hz, -CONH-) 55

6.35 g of trifluoroacetic acid salt of 7- [2- (2-aminothiazol-4-yl) 2- (syn) -methoxy-2-iminoacetamido] are dissolved in 30 ml of water. 3 - {[1- (2,3-dioxo 1, 2,3,4-tetrahydropyrazinyl)] methyl] A3-cephem 4-carboxylic acid and adjusts the 192792 24 solution obtained 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%) of sodium 7- [2- (2-aminothiazol-4-yl) 2- (syn) -methoxminoacetamido ] 3 - {[1 - (2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] methyl] A3-cephem 4-carboxilate having a melting point of 200 ° C or more.

IR (KBr) cm -1: i> c = 0 1763, 1670, 1650-1620.

In such a manner, the following compounds are obtained:

Sodium 7- [2- (2-aminothiazol-4-yl) 2- (syn) methoxyiminoacetamido] 3 - {[1- (4-methyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)] methyl} A3-cefem 4-carboxilate.

Mp. 190-195 ° C (dec.) 10 IR (KBr) cm -1: 0 = 0 1760, 1670, 1650, 1630.

Example VI

(1) To a solution of 3 g of 2 (- (2-tritylaminothiazol-4-yl) 2- (syn) -tert.-butoxicarbonylmethoxyiminoacetic acid in 15 ml of Ν, Ν-dimethylacetamide is added dropwise 0.93 g of phosphorus oxichloride at -10 ° C and the mixture is reacted 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)] - methyl} A3-cephem 4-carboxylic acid and contains 2.25g bis (trimethylsilyl) acetamide at -5 ° to 0 ° C. After everything has been added dropwise, the mixture is reacted at the same temperature for 30 minutes and then at 0-10 ° C for 30 minutes. After completion of the reaction, the methylene chloride is removed by distillation under reduced pressure and added a mixed solvent of 100 ml of saturated aqueous sodium chloride solution and 100 ml of acetonitrile is added to the residue, then the organic layer is separated and n twice with 50 ml portions of saturated aqueous sodium chloride solution and then remove the solvent by distillation under reduced pressure. The resulting residue is dissolved in 50 ml of methanol, then 1 g of diphenyldiazomethane is added to the solution at 5-10 ° C and the mixture is allowed to react 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, benzene / ethyl acetate eluent = 3: 1) to obtain 1.6 g (27.8% Sidwnylmethyl) 7- [2- (2-tritylaminothiazol-4-yl) 2 - (syn) -tert.butoxicarbonylmethoxiiminoacetamido] 3 - {[1 - (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)] methyl} A3-cephem 4-carboxilate, m.p. 98- 100 ° C under decomposition.

IR (KBr) cm1: vc = Q 1780, 1720, 1680, 1630.

NMR (d6-DMSO) δ values: 1.17 (3H, t, J = 7Hz,> NHCH2CH3), 1.44 (9H, s, -C (CH3) 3), 35 3.62 (2H, bs, C2-H), 3.74 (2H, q, J = 7Hz, ^ -CHgCH ,,), 4.55 (2H, s, formula 86), 4.51 5.16 (2H, ABq, J = 15Hz, formula 79), 5.27 (1H, d, J = 5Hz, C6-H), 40 5.87 (1H, dd, J = 5Hz, J = 8Hz, C7-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), 45 8.86 (1H, bs, formula 83), 9.54 (1H, d, J = 8Hz, -CONH-), (2) 1.6 g of diphenylmethyl 7- are dissolved in a mixed solvent of 8 ml of trifluoroacetic acid and 3 ml of anisole. [2- (2-tritylaminothiazol-4-yl) 2- (syn) -tert.-butoxicarbonylmethoxyiminoacetamido] 3 - {[1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)]} A3-cefem 4-carboxilate 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 55 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% 7- [2- (2-aminothiazol-4-yl) 2- (syn) -carboxi-methoxy-iminoacetamido] 3 - {[1 - (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)] methyl] A3-cephem 4-carboxylic acid, m.p. 192792 139-140 ° C under decomposition.

IR (KBr) cm1: uc = 0 1775, 1695, 1680, 1635 NMR (d6-DMSO) δ values: 1.22 (3H, t, J = 7Hz,> NCH2CH3), 3.53 (2H, bs, C2 -H), 5.74 (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, C6-H), 5.90 (3H, dd, J = 5Hz, J = 8Hz, C7-H), 10 6.69 (2H, s, formula 78), 6 94 (1H, s, formula 82), 9.70 (1H, d, J = 8Hz, -CONH-),

Example VII

(1) To a solution of 1.68 g of diketene in 8.40 ml of anhydrous methylene chloride, a solution of 2.08 g of bromine and 6.25 ml of anhydrous methylene chloride is added dropwise with stirring at -30 ° C to -20 ° C 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 containing 5.20 g of diphenylmethyl 7-amino 3 - {[1 - (4-ethyl-2,3-dioxo 1, 2,3,4-tetrahydropyrazinyl)] - methyl} A3-cephem 4-carboxilate and contains 4.08 g of 20 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. 50 ml of diisopropyl ether are added to the residue and the crystals thus obtained are collected by filtration to obtain 5.85 g (85.6%) of diphenylmethyl 7 - (- 4-bromo-3-oxobutyramido 3 - {[1- (4 ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)] - methyl} A3-cephem 4-carboxilate mp 138-142 ° C (decompn.).

30 IR (KBr) cm'1: uc = 0 1778, 1720, 1680, 1640 NMR (d6-DMSO) δ values: 1.22 (3H, t, J = 7Hz,> NCH2CH3), 3.40 (2H, bs, C2-H), 3.85 (2H, q, J = 7Hz,> NCH2CH3), 3.87 (2H, bs, BrCH2COCH2-), 4.18 (2H, bs, BrCH2CO-), 4.47, 4.96 (2H, ABq, J = 15Hz, formula 79), 5.04 (1H, d, J = 5Hz, C6-H), 5.90 (1H, dd, J = 5Hz, J = 8Hz, C7-H ), 6.15, 6.50 (2H, ABp, J = 6Hz, formula 78), 40 6.98 (1H, s, -CH (q), 7.40 (10H, bs, formula 81 x 2), 8, 55 (1H, d, J = 8Hz, -CONH-), (2) To a solution of 5.50 g of diphenylmethyl 7 - (- 4-bromo 3-oxobutyramido 3 - {[1- (4-ethyl 2,3) -dioxo 1,2,3,4-tetrahydropyrazinyl)] - methyl} A3-cephem 4-carboxilate in 30 ml of acetic acid, a solution of 5 ml of water, containing 0.74 g of sodium nitrite, is added dropwise with ice cooling in the course of 45 drops. of 1 hour, and the resulting mixture is reacted at room temperature for 2 hours. After 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 dries. The crystals are then dissolved in 10 ml of chloroform and then purified by column chromatography (Wako silica gel C-200, eluent benzene / ethyl acetate = 2: 1 to 50 by volume) to obtain 3.15 g (54.9%) diphenylmethyl 7- (-4-bromo-2-hydroxyimino 3-oxobutyramido 3 - {[1 - (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)] - methyl} A3-cephem 4-carboxilate with melting point 127- 132 ° C (decomposition) IR (KBr) cm1: vc = Q 1778, 1720, 1680, 1635 NMR (CDCI3) δ values: 1.26 (3H, t, J = 7Hz,> NCH2CH3), 55 3, 47 (2H, bs, C2-H), 3.81 (2H, q, J = 7Hz,> NCH2CH3), 4.52 (2H, S, BrCH2CO-), 192 792 26 4.53, 4.78 (2H , ABq, J = 15Hz, formula 79), 5.11 (1H, d, J = 5Hz, C6-H), 5.80-6.15 (1H, m, C7-H), 6.13 6, 52 (2H, ABq, J = 6Hz, formula 78), 5 7.02 (1H, s, -CH <), 7.41 (10H, bs, formula 81 x 2), 9.20 (1H, d, J = 8Hz, -CONH-), (3) 3.00 g of the diphenyl 7 - (- 4-bromo-2-hydroxyimino 3-oxobutyramido 3 - {[1- (4-ethyl-2,3-dioxo-1) are dissolved , 2,3,4-tetrahydropyrazinyl)] - methyl} A3-cephem 4-carboxilate obtained under (2) above and 0.42 g of 10 thiou rheumatism in 12 ml of Ν, Ν-dimethylacetamide 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-aminothiazol-4-yl) 2- (syn) -hydroxiiminoacetamido 3 - {[1- (4- ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)] - methyl} A3-cephem 4-carboxilate mp 137-140 ° C (decompn.). IR (KBr) cm'1: uc = 0 1778, 1720, 1680, 1640 NMR (d6-DMS0) δ values: 20 1.19 (3H, t, J = 7Hz,> N-CH2CH3), 3.48 ( 2H, bs, C2-H), 3.68 (2H, q, J = 7Hz,> N-CH2CH3), 4.46, 5.04 (2H, ABq, J = 15Hz, formula 79), 5.28 (1H, d, J = 5Hz, Ce-H), 5.97 (1H, dd, J = 5Hz, J = 8Hz, C7-H), 6.57 6.75 (2H, ABq, J = 6Hz , formula 78), 6.79 (1H, S, formula 82), 7.07 (1H, s, -CH <), 7.53 (1 OH, bs, formula 81 x 2), 9.70 ( 1H, d, J = 8Hz, -CONH-), (4) 2.00 g of the diphenylmethyl 7 - (- 2-aminothiazol-) are dissolved in a mixed solvent of 10.0 ml of trifluoroacetic acid and 2.0 ml of anisole. 4-yl) 2- (syn) -hydroxiiminoacetamido 3 - {[1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)] - methyl} A3-cephem 4-carboxilate, obtained under ( 3) above and let the resulting solution react at room temperature for 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 are 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-aminothiazol-4-yl) 2- (syn) -hydroxiiminoacetamido 3 - {[1 - (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)] - methyl} A3-cephem 4-carboxylic acid, mp 112-118 ° C (decomposition). IR (KBr) cm'1: vc = 0 1780, 1680, 1620, NMR (d6-DMSO) 40 b values: 1.19 (3H, t, J = 7Hz,> NCH2CH3), 3.47 (2H, bs , C2-H), 3.72 (2H, q, J = 7Hz,> N-CH2CH3), 4.45, 6.70 (4H, m, formula 79, C6-H, C7-H), 45 6 59 6.83 (3H, m, formula 78, 82),

Example VIII

(1) To a solution of 7.1 g of diphenylmethyl 7- (4-bromo 2-hydroxyimino 3-oxobutyramido 3 - {[1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)] - methyl } A3-cephem 4-carboxilate in 70 ml of anhydrous methylene chloride 50, a solution of diazomethane in diethyl ether is slowly added at -5 ° C to 0 ° C and the resulting solution is reacted at the same temperature for 30 minutes. disappearing of the diazomethane, the solvent is removed by distillation under reduced pressure, then the residue obtained is purified by column chromatography (Wako silica gel C-200, eluent, benzene: ethyl acetate = 3: 1 by volume) to give 2.32 g ( 32.0%) diphenylmethyl 7- (4-bromo 55 2- (syn) -methoxyimino 3-oxobutyramido 3 - {[1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)] - methyl} A3-cephem 4-carboxilate, m.p. 135-140 ° C (decomposition).

IR (KBr) cnr1: uc = 0 1778, 1720, 1682, 1638 NMR (CDCI3) δ values: 27 192792 1.25 (3H, t, J = 7Hz,> NCH2CH3), 3.48 (2H, bs, C2 -H), 3.84 (2H, q, J = 7Hz,> NCH2CH3), 4.00 (3H, S, -OCH3), 5 4.10 (2H, s, BrCH2CO-), 4.48, 4 .67 (2H, ABq, J = 15Hz, formula 79), 5.10 (1H, d, J = 5Hz, C6-H), 6.05 (1H, dd, J = 5Hz, J = 8Hz, C7- H), 6.38, 6.73 (2H, ABq, J = 6Hz, formula 78), 6.98 (1H, s, -CH <), 7.32 (10H, bs, formula 81 x 2), 9.18 (1H, d, J = 8Hz, -CONH-) (2) 2.3 g of diphenylmethyl 7- (4-bromo-2- (syn) -methoxiimino-3-oxobutyramido 3 - {[1- (4) are dissolved ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)] - methyl} A3-cephem 4-carboxilate and 0.32 g thiourea in 14 ml N, N-15 dimethyl acetamide and react the resulting solution at room temperature for 3 hours After the reaction, the reaction mixture is poured into a mixed solvent of 50 ml of water and 150 ml of ethyl acetate, then sodium hydrogen carbonate is added to adjust the pH of the mixture to 6.7 and the organic then low off aqueous layer further 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 7- [2- (2-aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamido 3 - {[1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)] - methyl} A3-cephem 4-carboxilate mp 165-167 ° C.

IR (KBr) cm -1: µc = 0 1780, 1720, 1680, 1640.

The same cyclization reaction as above and then the reaction mentioned in Example V- (3) or Example VI- (2) are performed to obtain the compounds shown in Tables N and P.

TABLE N

00 / N-tt-C— CONH-Ί- CF COOH.H „N- ^ I JZ \ NS-Y N f" CH2R2

OCH COOH

___ (syn-sum) 35 R2 R2 Q ~ ~--N N-CH-.

40 W 3___ 00 0 0 v_y '^ _ & -NWN- <C »2) 4CH3 -Ν ^ Λ (ΟΗ2) 2θΗ3 45" - ~ f \ / oh _ -N N-CH 3 _nch OO - 50) - <- NwN (CH2) 3ch3 __ _ _> - <} ~ i

55 -N NCIUCII- -N NH

W 2 3_w___ 192792 28

TABLE P

, N - C - CONH - \ H0N - f | Ü I 2

2 µ N Y-N ^ CH R

5 '' OCH, cY | .

J COOR1 (syn isomer) 10 R1 R2 -CH0C0C (CH3) 3 cA, -Nwnch2ch3 -CHOCOC (CH3) 3 cA, -NwNCH3

20 -CHOCOC (CH3) 3 9 ^ _✓P

cA, -NWN-"CH2> 4CH3

-CH2OCOC (CH3) 3 9n / P

25 - N NCH2CH3 -CHOCOOC (CH,) ~ Ö TÖ I 3 M: 30 CH3 N NCH2CH3 .o / P o .o

- (Y

) - (- N NCH, CH,

35 _ © _W

(ch2), ch3 U5 - N NCH-CH-, \ - / 2 3 40 ------ -CH_C = C-CH- O .0 2 / \ 3

Ov / O —N NCH.CH- Y ^ 2 3 45 _2 * Hydrochloride

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

50 Example IX

(1) To a suspension of 2.2 g of 2- (2-formamidothiazol-4-yl) glyoxilic acid in 11 ml of N, N-dimethyl acetamide, 1.8 g of phosphorus oxychloride are added dropwise at -20 ° C and left resulting mixture react at the same temperature for 2 hours. To this reaction mixture is then added 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]] - 55 methyl} A3-cephem 4-carboxilate, 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 192792 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 obtain 1.4 g (20.0%) diphenylmethyl 7- [2- (2-formamidothiazole) -4-yl) glyoxilamido] 3 - {[1 - (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)] - methyl} A3-cephem 4-carboxilate mp 140-145 ° C (decomposition) . IR (BKr) cm'1: t> c = 0 1780, 1720, 1680, 1670, 1640. NMR (d6-DMSO) δ values: 1.20 (3H, t, J = 7Hz,> NCH2CH3), 10 3 .50 (2H, 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, C6-H), 6.00 (1H, dd, J = 5Hz, J = 9Hz, C7-H), 15 6.50 6.62 (2H, ABq, J = 5Hz, formula 78), 7.04 (1H, s, -CH <), 7.30 (10H, bs, formula 81 x 2), 8.64 (1H, s, formula 82), 8.81 (1H, s, HCONH -), 20 10.20 (1H, d, J = 9Hz, -CONH-) 12.90 (1H, bs, HCONjH-) (2) To a solution of 7.0 g of diphenylmethyl 7- [2- (2 -formamidothiazol-4-yl) glyoxilamido] -3 - {[1- (4-ethyl) 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)] - methyl} A3-cephem 4-carboxilate in 35 ml Ν, Ν- dimethylacetamide, 1.7 g of methoxiamine 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 mixed solvent of 250 ml of water and 250 ml of ethyl acetate and the organic layer is separated, washed with 250 ml of water and 250 ml of a saturated aqueous sodium chloride solution in this order, and dried 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-formamidothiazol-4-yl) 2- (syn ) -methoximinoacetamido] -3 - {[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] - methyl} Δ3-cephem 4-carboxilate, mp 165-168 ° C.

IR (KBr) cm -1: tjc = 0 1780, 1720, 1680, 1640.

The same oximation reaction as above and then the reaction mentioned in Example V- (2), (3) and / or Example VI (2) are carried out to obtain the following compound and the compounds shown in Tables Q 35 and R:

Trifluoroacetic acid salt of 7- [2- (2-amino-5-bromothiazol-4-yl) 2- (syn) -methoxiiminoacetamido] 3 - {[1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl) )] methyl} A3-cephem 4-carboxylic acid, m.p. 147 ° C (decompn.).

IR (KBr) cm -1: uc = 0 1775, 1680, 1640.

40 TABLE Q

/ N —n— C— CONH -> - f

CF COOH-H N- (|| L_N

J z \ S-Jl N \ ^^ CH „R2 45 \ I Δ OCH3 cooh (syn isomer) R2 R2 50 --- -N N-CH, w 3 55 - 192792 30 TABLE Q (continued) R2 R2 - - - 5 5 5 _f y- ^ -N N- {CH „), CH _ -NN (CH0) 0CH, W 2 4 3 \ = / 2 2 3 70 ° H ° / CH3 -N N-CH W ^ ch3 - - '5 -NWN <CH2 »3CH3 - _ Q £ yA y ~ i

-N NCH2CH3 -N NH

25 * Hydrochloride

TABLE R

-Ί-C— CONH x 30 H? N ~ \ i! i / Lch r2

2 sJ N / 7— ^ ^^ ~ Cd2R

^ OCH O |

J COOR

(syn-ismser) 35 R1 R2

-CHOCOC (CH3) 3 \ _P

40 I '' '-N NCH-CH- CH3 \ 2 3 -CH0C0C (CH3) 3' J, -N NCH, 45 Cn3 \ / j

-CHOCOC (CH3) 3 / jP

CH, -NWN- (CH2) 4CH3 50 ----- -CH, OCOCCH ,,, Μ! - N NCH-CH-, v- / 2 o 31 192792 TABLE R (cont.) R2 R2 5 -CH0C00C (CH3) 3 Q_ ^ pu —N NCH-CH, v- / 2 = 5 ^ V? ) - (- N NCH-CH., (C) W 2 3 - (CH 2) 3 CH 3 15 - N NCH-CH-.

\ == / 2 3

-CHnC = C-CH ~ Q O

, 0 2 / \ 3 Q? 0/0 —N NCH-CH-y Y 2 3 _O________ * Hydrochloride 25

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

Example X.

(1) 7.29 g of diphenylmethyl 7- [2- (2-formamidothiazol-4-yl) 2- (syn) -methoxyiminoacetamido] -3- are dissolved in a mixed solvent of 37 ml of trifluoroacetic acid and 10.8 g of anisole. {[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] -methyl} A3-cephem 4-carboxilate and react the dissolved 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-formamidothiazol-4) -yl) 2- (syn) -methoximinoacetamido] -3 - {[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] - methyl} A3-cephem 4-carboxylic acid with melting point 155-158 ° C (decompn.).

IR (KBr) cm1: uc = 0 1775, 1710, 1675, 1640. NMR (d6-DMSO) δ values: 1.20 (3H, t, J = 7Hz,> NCH2CH3), 40 3.49 (2H, bs , C2-H), 3.73 (2H, q, J = / Hz,> NCH2CH3), 3.91 (3H, s, -OCH3), 4.42, 4.95 (2H, ABq, J = 15Hz , formula 79), 5.21 (1H, d, J = 5Hz, C6-H), 45 5.89 (1H, dd, J = 5Hz, J = 8Hz, C7-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-), 50 12.58 ( 1H, bs, HCONH-)

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

192792 32

TABLE S

N — π— C-CONH--, HCONH ^ J || o ^ U ^ LCH2R2

Xoch3 ° C00K

(syn isomer) 10 R2 Mp. (° C) IR (KBr) cm * 1: dc = 0 ° \\ / ° 195-198 (dec.) 1775, 1720, 1680-1640 -N N-CH0CH0 \ = / 2 3 15 ---—- 122-125 (dec.) 1775, 1680, 1640 -N_ ^ N- (CH2) 4CH3 20 (2) To a solution of 5.63 g of 7- [2- (2-formamidothiazol-4-yl) 2- ( syn) -methoxiiminoacetamido] -3 - {[1- (4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)] - methyl} A3-cephem 4-carboxylic acid in 25 ml N, N-dimethylacetamide 1.52 g of 1,8-diazabicyclo [5,4,0] -7-undecene and 3.84 g of 1-pivaloyloxiethyl iodide are added under ice cooling and the resulting mixture is reacted 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 (79.6%) of 1-pivaloyloxiethyl 7- [2- (2-formamidothiazol-4-yl) 2- (syn) -methoximinoacetamidol-3 - {[1- (4-ethyl 2,3-dioxo 1,2,3,4-30 tetrahydropyrazinyl)] - methyl} A3-cephem 4-carboxilate mp 140-142 ° C.

IR (KBr) cm * 1: uc = Q 1780, 1740, 1680, 1640.

In such a manner, the compounds shown in Table T are obtained. In this case, the compounds shown in Table T can also be obtained in the same manner as in Example V- (1), provided that the corresponding esters are substituted for the diphenylmethyl esters.

35

TABLE T

N -ip C-CONH

40 HCON „- / sJ | II j-sJ-CH2 O 2 OCHO COORx (syn isomer) R1 R2 Mp. (° C) IR (KBr) cm * 1: Dc = 0 45 .................

-CHOCOC (CH3) 3 0 \\ / β 182-188 (dec.) 1780, 1740, 1680-1640 U_-NwN'CH3_ 50 -CH0C0C (CH3) 3 ° y ^ 120-122 (dec.) 1783, 1740 , 1680, 1640 U -NwN <C ,, 2> 4CH3 -CH2OCOC (CH3) 3 ip 158-160 1780, 1742, 1680, 1640 55 / λ -N N-CH0CH ^ V — v 2 3 33 192792 TABLE T ( continued) R1 R2 Mp. (° C) IR (KBr) cm'1: uc = 0 5 -CHOCOOCH2CH3 ° P 150-152 1780, 1760, 1680, 1640 L -N N-CH „CH_ Οπ3 \ - / 2 3 _A ^ ° 9 \ P 160-162 1780,1680-1630 10 <p) -N N-CH_CH_ λ— '\ -f 2 3 —f-CH2) 3CH3 9 ° 136-141 (dec.) 1780, 1720, 1680, 1640 -N N-CH 2 -CH 1 -CH 2 Cl = Cch 3 O 165-168 (dec.) 1810.1775.1720.1670 / N 1640 -N N-CH-CH-.

\ X 2 3 20 xcr

II

o 25 (3) To a solution of 5.5 g of 1-pivaloyloxiethyl 7- [2- (2-formamidothiazol-4-yl) 2- (syn) -methoxyiminoacetamido] -3 - {[1- (4-ethyl 2 1,3-dioxo 1,2,3,4-tetrahydropyrazinyl)] - methyl} A3-cephem 4-carboxilate obtained according to (2) above in 27.5 ml of methanol, 1.13 ml of concentrated hydrochloric acid are added and the resulting mixture react at 35 ° C for 2 hours. After the reaction, the solvent is removed by distillation under reduced pressure. 50 ml of ethyl acetate and 50 ml of water are added to the residue and the 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, and the solvent is removed by distillation under reduced pressure. 45 ml of diethyl ether are added to the residue and sat. melt the crystals by filtration to obtain 4.65 g (88.1%) of 1-pivaloyloxiethyl 7- [2- (2-aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamido] -3 - {[1- ( 4-ethyl 2,3-dioxo 1,2,3,4-tetrahydropyrazinyl)] - methyl} A3-cephem 4-carboxilate 35 mp 148-150 ° C.

IR (KBr) cm -1: uc = D 1780, 1740, 1680, 1640. NMR (d6-DMS0) δ values: 0.90-1.39 (12H, m, -C (CH3) 3,> NCH2CH3) , 1.52 (3H, d, J = 5Hz, formula 87b), 3.52 (2H, bs, C2-H), 40 3.76 (2H, q, J = 7Hz,> N-CH2CH3), 3.88 (3H , s, -0CH3), 4.38, 5.04 (2H, ABq, J = 15Hz, formula 79), 5.21 (1H, d, J = 5Hz, C6-H), 5.87 (1H, dd, J = 5Hz, J = 8Hz, C7-H), 45 6.61 (2H, bs, formula 78), 6.78 (1H, s, formula 82), 7.04 (1H, q, J = 5Hz, formula 87a), 7.22 (2H, bs, -NH2), 9.67 (1H, d, J = 8Hz, -CONH-), 50 In such a manner, the compounds shown in Table U are obtained.

192 792 34

TABLE U

N-3-C-CONH-3/3 OCH 3 coorl (syn isomer) R 1 R 2 Mp. IR NMR (d6-DMS0) δ values (° C) (KBR) 10 cm'1: vc = 0 -CH0C0C (CH3) 3 198-201 1780, M9 i9H's' "C (CH3) 3), I" N_N-CH3 (dec.) 1740]. 54 (3H, d, J = 5Hz, -OCHO-),

CH3 1680-1

15 1640 ch3 3.30 (3H, s,> N-CH3), 3.54 (2H, bs, C2-H), 3.88 (3H, s, -OCH3), 4.40, 5.06 (2H, ABq, J = 15Hz,), 5.24 (1H, d, J = 5Hz, J-cn2-

Cfi-H), 5.91 (1H, dd, J = 5Hz, 25 J = 8Hz, C? -H), 6.46, 6.60 (2H, ABq, J = 6Hz,> = <), 6 , 80 (1H, s, 11 11 30 -

NT *), 7.07 (1H, q, J = 5Hz, -CH-), S ^ H1

ch3 35 7.26 (2H, bs, -NH2), 9.74 (1H, d, J = 8Hz, -CONH-) -CH0C0C (CH3) 3 139-141 1783, ° '87 (3H 't' J = 7Hz '> N <CH2l 4C ^ V' I -N ^ N- (CH2) 4CH3 (dec.) 1740, 1.18 (9H, S, -C (CH3) 3), 1.53 40 CH3 1680, 1640 (3H, d, J = 5Hz, —CHO—), ch3 1.04-1.85 (6H, m,> NCH2 (CH2) 3CH3), 45-3.59 (2H, bs, C2-H) , 3.72 (2H, t, J = 7Hz,> NCH2 (CH2) 3CH3), 3.91 (3H, s, -OCH3), 4.45, 5.08 50 (2H, ABq, J = 15Hz, S.),

Ah2- 35 192792 TABLE U (continued) R1 R2 Mp. IR NMR (d6-DMS0) δ values (° C) (KBR) 5 cm'1: vc = 0 5.28 (1H, d, J = 5Hz, Cg-H), 5.92 (1H, dd, J = 5Hz, J = 8HZ, C - H), 10 '6.65 (2H, bs,> = 0.685 (1H,

Η H

s, J7> »7? 00 <1H 'S' J = 5Hz,

S H

15 -OCHO-), 9.82 (1H, d, J = 8Hz, Γ CH3 -CONH-) 20 - -CH2OCOC (CH3) 3 145-147 1780, 1.01-1.35 (12H, m, - C (CH3> 3, -KJ M-CH CH 1740 W i 'iX> NCH2CH_), 3.47 (2H, bs, C.-H), 1675, i 1 1640 3.70 (2H, q, J = 7Hz,> NCH2CH), 25 - 3.78 (3H, s, -OCH3), 4.30, 5.01 (2H, ABq, J = 15Hz, S), 30 5.14 (1H, d, J = 5Hz, Cg-H), 5.67-6.06 (3H, m, -0CH20-, C7 ~ II), 6.55 (2H, bs, X), 6.70 (1H,

Η H

N-n-s, A), 7.12 (2H, bs, -NH-),

S H

9.52 (1H, d, J = BHz, -CONH-) 40 - 192792 36 TABLE U (continued) R1 R2 Mp. IR NMR (d6-DMSO) δ values (° C) (KBR) cm'1: vc = 0 -CHOCOOCH2CH3 155-157 1780, ^ 23 <6H 'J = 7Hz, NCI ^ CHj, | -Ö “CH2CH3 1760 '-OCH, CU,), 1.55 (3H, d, J = 5Hz, CH3 W 1680, 2 _U 1640 -OCHO-), 3.53 (2H, bs, C, -H ), ch3 3.76 (2H, q, J = 7Hz,> NCH2CH3), 15 3.86 (3H, s, -OCH3), 4.19 (2H, q, J = 7Hz, -OCH2CH3), 4, 40, 5.05 (2H, ABq, J = 15Hz, S), 20 Vch, - 5.21 (1H, d, J = 5Hz, C6-H), 5.86 (lil, dd, J = 5Hz, J = 8Hz, C? -H), 6.52, 6.65 (2H, ABq, J = 6Hz, 25 Nn-X), 6.74 (1H, s, X),

Η H S H

6.87 (1H, q, J = 5Hz, -OCHO-), Γ 30 CI13 7.02 (2H, bs, -NH2), 9.65 (1H, d, J = Hz, -CONH-) * 1 * 2> 200 1780, 1.21 <3H, t, J = 7Hz,> NCH CH),

35 O O 0 0 2 -A

XV M 3 ^ 67 <2H 'bs' C2 ~ H) '3'81 (2H' \ —ί -N NCH2C »3 1640 2 (OJ W t, J = 7Hz,> NCH2CH3), 3.99 (3H, s, -OCH3), 4.17-5.13 (5H, m, _40 ff) -2 -NHy), 5.22 (1H, d, J = 5Hz, Cg-H), 5, 83 (1H, dd, J = 5Hz, J = BHz, C7-H), 6.95, 6.77 (2H, ABq, 45 J = 7Hz,> = <), 6.95 (0.5H, s,

Η H

T), 7.00 (0.5H, s, Tl.

S H S H

50 HO 7.58-8.15 (511, m, -VV'0),

II— <0> —H H> —2 — H

9.87 (1H, d, J = 8Hz, -CONH-) 55 37 192792 TABLE U (continued) ri r2 Mp. IR NMR (d6-DMS0) δ values (° C) (KBR) 5 cm'1: vc = 0 OO .... H_0_ 0.63-1.85 (10H, m, - (CH2) 3CH3 yf 139- 144 1780, -NNCII-CH, (dec.) 1720, -C00CH_CHoCH ~ CH ..,> NCH-CH,), ^ 2 3 1680, 2-2-2 3 2 - 10 1640 3.55 (2H, bs, C2-H), 3.76 (2H, q, J = 7Hz,> NCH2CH3), 3.89 (3H, s, -OCH3), 4.30 (2H, t, J = 7Hz, 15 -COOCH2CH2CH2CH3), 4.39, 5.12 (2H, ABq, J = 15Hz, S.), 2o 5.25 (1H, d, J = 5Hz, Cg-H), 5.92 (1H, dd, J = 5Hz, J = 8Hz, C7 ~ H), 6.68 (2H, bs,> = <), 6.82 (1H,

Η H

25 .. X), 7.28 (2H, bs, -NH,), SH * 9.79 (1H, d, J = 8Hz, -CONH-) 30 -CII2C = CCH3 173-Ί75 1820 1.19 ( 3H, t, J = 7Hz ^ NCH ^), -O-N N-CH2CH3 (dec.) 1780, 2.20 (3H, s, -C = C-CH-), 3.53 / 1730, 1 / -1 || 1680, O 1640 <2H 'bs' C2-H)' 3'73 <2H 'q' 35 J = 7Hz,> NCH2CH3), 3.84 (3H, s, -OCH3), 4.34, 5.06 (2H, ABq, J = 15Hz,), 5.09-5.30 40 J-ch2- (3H, m, C6-H, -OCH2C =), 5.87 (1H, dd, J = 5Hz, J = 8Hz, C? -H), 45 6.59 (2H, bs,> = <), 6.74 (1H, 11 11 s, X), 7.17 (2H, bs, -NH,), SH z 50 9.62 <1H, d, J = 8Hz, -CONH-) * 1 Diastereomer * 2 Hydrochloride (the salt is prepared in a conventional manner)

Preparation Example 1 55 An aqueous sodium salt solution of 7- [2- {2-aminothiazol-4-yl) 2- (syn) -methoxyiminoacetamido] -3 - {[1-2,3-dioxo 1,2, is treated. 3,4-tetrahydropyrazinyl)] - methyl} A3-cephem 4-carboxylic acid in a conventional manner to obtain a freeze-dried and sterilized sodium salt, 1 g is dissolved

Claims (6)

192792 38 (potency) of the sodium salt in 20 ml of physiological saline to give 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. 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 injection liquid. In addition, the other compounds of the formula 1 can also be formed into the corresponding freeze-dried products (sodium salts) or injection liquids by proceeding in the same manner as in the preparation examples 1-3. 15 1. A cephalosporin derivative of the formula 1 in the formula sheet wherein R1 represents a hydrogen atom or a carboxil protecting group, R2 represents a heterocyclic group, R5 represents a protected or unprotected amino group, and A represents a group of formula 21 wherein R18 represents a methyl or ethyl group, and salts thereof, characterized in that R 2 represents a group of formula 23 wherein R 6 represents a hydrogen atom or a C 1 -C 5 alkyl group. 2. 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3 - {[1- (2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)] -25 methyl} A3-cephem 4-carboxylic acid, an ester or a salt thereof, 3. 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3 - {[1 - (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) J-methyl} -A3-cephem 4-carboxylic acid, an ester or a salt thereof, 4. Process for the preparation of a compound according to any one of claims 1-3, characterized in that a compound of the formula 92, wherein R28 is an amino group, a group of the formula wherein R31, R32 and R33 is used. , which may be the same or different, represent a hydrogen atom or a non-reacting moiety, or a group of formula 73 wherein R34 and R35, which may be the same or different, are a hydrogen atom or an organic moiety not participating in the reaction and R1 and R2 have the meaning given in claim 1, react with a compound of formula 93, wherein R5 and A have the meaning given in claim 1, or with a reactive derivative thereof in the carboxil group, or b . a compound of the formula 94, wherein X represents a halogen atom and R 1, R 2 and A have the meaning given in claim 1, or react a salt thereof with a compound of the formula 95, wherein R 5 has the meaning given in claim 1, or 40 c. a compound of the formula 96, wherein R 1, R 2 and R 5 have the meaning as defined in claim 1, or react a salt thereof with a compound of the formula 97, wherein R18 has the meaning as defined in claim 1, or a salt thereof and optionally removing the protecting group after step a, b or c, protecting the carboxil group or converting the product into a salt thereof. Pharmaceutical composition for treating bacterial infections in humans and animals containing an antibacterially effective amount of a cephalosporin derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or pharmaceutically acceptable diluent, characterized in that the cephalosporin derivative comprises a compound according to any one of claims 1-3. Hereby 5 sheets drawing