FI75827B - FOERFARANDE FOER FRAMSTAELLNING AV ETT NYTT TERAPEUTISKT ANVAENDBART 7-THIAZOLYL-3-PYRAZINYLMETHYLPHALOSPORIN SAMT EN I FOERFARANDET ANVAENDBAR MELLANPRODUKT. - Google Patents

Description

1 75827

The invention relates to a process for the preparation of a therapeutically useful 7-thiazolyl-3-pyrazinylmethyl-cephalosprorin of formula I, to pharmaceutically acceptable salts thereof and to a pharmaceutically acceptable salt thereof, and to a process for the preparation of a therapeutically useful 7-thiazolyl-3-pyrazinylmethyl-cephalosporin, and to an intermediate useful in the process. - A - CONH - f

II I '2 1 r5A.s- ^ o / - 15 COOR1 in which R1 is a hydrogen atom or an ester group selected from the group consisting of C1-5 acyloxy-C1-8 alkyl, phthalidyl and 5-C1-10 alkyl-2-oxo-1 , 3-dioxol-4-yl-methyl and a group of the formula -CH-OCOOR, wherein R 22 21 22 R and R may be the same or different and are 2 C 1-6 alkyl groups; R is a group of the formula V 0 - N N - R 4, wherein R 0 is a hydrogen atom or a C 1-6 alkyl group; R 1 is an amino group which may optionally be protected by an amino group protecting group; and A is a group of the formula wherein C is a C 1-4 alkyl-N OR 10 (syn) 1b group.

The invention further relates to intermediates for the preparation of these cephalosporins.

---- - τ 2 75827

The object of the invention has been to find compounds with a broad antibacterial spectrum which have excellent antibacterial activity against gram-positive and gram-negative bacteria which are resistant to bacterial β-lactamase, which have low toxicity and which are at the same time highly absorbed orally or parenterally, and have an excellent therapeutic effect on bacterial diseases in humans and animals. As a result, it has been found that these excellent properties are achieved with novel cephalosporins characterized by a substituted or unsubstituted 2,3-dioxo-1,2,3,4-tetrahydropyrazinyl group attached to the exomethylene group at the 3-position of the cephem ring by a carbon-15 nitrogen bond and the following group is attached to the amino group at the 7-position: c / N-nA-CO-i S-20 wherein A and R 1 have the meanings defined above.

The invention also relates to a 7-amino-pyrazinylmethyl-cephalosporin of formula I which is useful as a starting material in the preparation of compounds of formula I.

NB2tO

/ - N'Y ^ J_ CH2r2

30 I

COOR1 wherein R is a hydrogen atom or a carboxyl group protecting group;

O O

2-6 and R is a group of the formula wherein R6 is a hydrogen atom or a C1-5 alkyl group.

3 75827

Carboxyl protecting groups include those conventionally used in the regions of penicillins and cephalosporins, e.g., an ester-forming group that can be removed by catalytic hydrogenation, chemical reduction, or treatment under other mild conditions; an ester-forming group that is readily eliminated in the body; or an organic silyl group; an organic phosphorus-containing group, * or an organic tin-containing group, etc., which can be easily removed by treatment with water or alcohol; as well as various other well-known ester-forming groups.

Among these protecting groups, the following are preferred groups: a) alkyl groups, e.g. C 1-6 alkyl; b) substituted lower alkyl groups in which at least one of the substituents is selected from a halogen atom or groups nitro, acyl, alkoxy, oxo, cyano, hydroxyl, cycloalkyl, aryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, 5-alkyl-2-oxo-1,3 -dioxol-4-yl, 1-indanyl, 2-indanyl, furyl, pyridyl, 4-imidazolyl, phthalimido, succinimido, azetidine, aziridine, pyrrolidine, piperidine, morpholine, thiomorpholine, N-lower alkylpiperazine, Pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, tritiazolyl, oxatriazolyl, tetrazolyl, quinolyl, phenazinyl, benzofuryl, benzothienyl, benzothienyl, benzo-benzoyl, benzo-benzyl dimethylpyrrolidine, 1,4,5,6-tetrahydropyrimidinyl, 4-methylpiperidine, 2,6-dimethylpiperidine, 4- (5-methyl-2-pyrrolinyl), 4- (2-pyrrolinyl), N-methylpiperidinyl, 1,3-benzodioxolanyl, a alkylamino, dialkylamino, acyloxy, acylthio, acylamino, di-35-alkylaminocarbonyl, alkoxycarbonylamino, alkenyloxy, aryloxy, aralkyloxy, cycloalkyloxy-7-aryloxy, aryloxyloxy, arylcarbonyloxy, heterocyclic oxy, alkoxycarbonyloxy, alkoxycarbonyloxy carbonyloxy, alkenyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, heterocyclic ox-5-carbonyl or an alkylaniline group or an alkylaniline group substituted with an alkyl atom or a halogen atom, an allyl atom, c) cycloalkyl; lower alkyl-substituted cycloalkyl; or (2,2-di-lower alkyl-1,3-dioxol-4-yl) methyl; d) alkenyl groups; e) alkynyl groups; f) a phenyl group; substituted phenyl groups when at least one of the substituents is selected from the substituents specifically mentioned in b) above or aryl groups, such as groups represented by the formula -CO * 20 wherein -Y1- is -CH = CH-O-, - CH = CH-S-, -CH2CH2S-, -CH = N-CH = N-, -CH = CH-CH = CH-, -CO-CH = CH-CO- or -CO-CO-CH = CH- , or a substituted derivative thereof, wherein the substituents are selected from those substituents specifically mentioned in b) above or from the groups represented by formula 1

II

wherein -Y- is a lower alkylene group such as or - (C 1-4) -, or a substituted derivative thereof, wherein the substituents are selected from those substituents specifically mentioned in b) above; g) aralkyl groups, such as benzyl or substituted benzyl groups, in which at least one of the substituents 35 is selected from those substituents specifically mentioned in b) above; 5 75827 h) a heterocyclic group or substituted heterocyclic groups in which at least one of the substituents is selected from those substituents specifically mentioned in b) above; 5 i) indalyl or phthalidyl groups or substituted derivatives thereof, wherein the substituents are methyl or halogen; tetrahydronaphthyl groups or their substituted derivatives in which the substituents are methyl or halogen; trityl, cholesteryl, bi-10 cyclo [4.4.4.0% decyl; and so on.; j) phthalidylidene-lower alkyl groups or substituted derivatives thereof, wherein the substituents are halogens or lower alkyl groups.

The above carboxyl protecting groups are typical examples, and the carboxyl protecting group may also be selected from other protecting groups described in the following references: U.S. Patent Nos. 3,499,909, 3,573,296 and 3,641,018; DE-A-2 301 014, 2 253 287 and 2 337 105.

Among these carboxyl protecting groups, diphenylmethyl, 5-lower alkyl-2-oxo-1,3-dioxo-4-yl-lower alkyl groups, acyloxyalkyl groups, alkylthioalkyl groups, phthalidyl group, indanyl group, substituted alkyl group or phenyl group are preferred. matte phthalidylidene lower alkyl groups or those groups which are readily eliminated in the body, such as groups represented by the following formulas: -CH (CH-) OR21 -CH0C00R21 -CH (CHO) COOR21. 2 m 1 .1 2 m 30 ^ 22 '' r22 and r23 21 wherein R represents a known substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group; R is a hydrogen atom or a known substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group; R is a hydrogen atom, a halogen atom or a known substituted or unsubstituted alkyl, cyclo. _____ 6 75827 alkyl, aryl or heterocyclic group or - (CH 2) (R 2 is as defined above and n is 0, 1 or 2); and m is 0, 1 or 2.

In particular, 5-lower alkyl-2-5 oxo-1,3-dioxol-4-ylmethyl groups such as 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl, 5-ethyl- 2-oxo-1,3-dioxol-4-ylmethyl, 5-propyl-2-oxo-1,3-dioxol-4-ylmethyl, etc .; acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 1-acetoxy-n-propyl, etc.-pivaloyloxyethyl, 1-pivaloyloxyethyl, 1-pivaloyloxymethyl acylthioalkyl groups such as acetylthiomethyl, pivaloylthiomethyl, benzoylthiomethyl, p-chlorobenzoylthiomethyl, 1-acetylthioethyl, 1-pivaloylthioethyl, 1-benzoylthioethyl, 1- (p-chlorobenzoyl) etc .; alkoxymethyl groups such as methoxymethyl, ethoxymethyl, propoxymethyl, iso-propoxymethyl, n-butyloxymethyl, etc .; alkoxycarbo-20-oxyloxyalkyl groups such as methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, n-butoxycarbonyloxymethyl, tert-butoxycarbonyloxymethyl, 1-butyl; oxycarbonylethyl, 1-tert-butoxycarbonyloxyethyl, 1-n-butoxycarbonyloxyethyl, etc .; alkoxycarbonylmethyl groups such as methoxycarbonylmethyl, ethoxycarbonylmethyl, etc .; a phthalidyl group; indanyl-30; a phenyl group, phthalidylidene alkyl groups such as 2- (phthalidylidene) ethyl, 2- (5-fluorophthalidylidene) ethyl, 2- (6-fluorophthalidylidene) ethyl, 2- (5-methoxyphthalidylidene) ethyl and the like; and so on.

7 75827

Amino protecting groups include all commonly used amino protecting groups such as easily removable acyl groups, e.g., 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, benzyloxycarbon-5-yl, p-toluenesulfonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl , acetyl (mono-, di-tri-) chloroacetyl, trifluoroacetyl, formyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl-10-oxycarbonyl, 4- (phenylazo) carboxy (4-methoxyphenylazo) -benzyloxycarbonyl, pyridine-1-oxide-2-ylmethoxycarbonyl, 2-furyloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropynylcarbonyl, isopropoxycarbonyl, 1-sycloxy , 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, etc .; further readily removable groups, e.g. trityl, o-nitrophenylsulfonyl, 2,4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-20 hydroxy-1-naphthylmethylene, 3-hydroxy-4-pyridylmethyl lene, 1-methoxycarbonyl-2-propylidene, 1-ethoxycarbonyl-2-propylidene, 3-ethoxycarbonyl-2-butylidene, 1-acetyl-2-propylidene, 1-benzoyl-2-propylidene, 1- / (N- (2-methoxyphenyl) carbamoyl] -2-propylidene-25, 1- {N- (4-methoxyphenyl) carbamoyl] -2-propylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylcyclo 3-dimethyl-5-oxocyclohexylidene, 4-nitrofurfurylidene, etc., di- or tri-alkylsilyl group, etc. Carboxyl-30 protecting groups include all commonly used carboxyl protecting groups and there are cases where the carboxyl group is protected with an ethyl group such as methyl. , n-propyl, isopropyl, tert-butyl, n-butyl, benzyl, Difen ylmethyl, trilyl, 4-nitrobenz-35-yl, 4-methoxybenzyl, benzoylmethyl, acetylmethyl, 4-nitrobenzoylmethyl, p-bromobenzoylmethyl, 4-methanesulfonylbenzoylmethyl, phthalimide methyl, 2,2,2-trichloroethyl, , 1-dimethyl-2-propenyl-β 75827, 1,1-dimethylpropyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, 3-methyl-3-butynyl, succinimidimethyl, 1-cyclopropylethyl, methylthiomethyl, phenylthiomethyl , dimethylaminomethyl, quinoline-1-oxide-2-ylmethyl, pyridine-1-oxide-2-ylmethyl, bis (p-methoxyphenyl) methyl, etc., when the carboxyl group is protected with a non-metal compound such as titanium tetrachloride, and when the carboxyl group is protected with a silyl compound such as dimethylchlorosilane, as described in JP Patent Application Kokai No. 7073/71 (made public) and NL Patent Application 7,105,259 (made public).

formula

. N-S

15 R1 — I

In the group of compounds of formula I, the compounds of formula I have tautomers as shown by the following equilibrium formulas with a protected or unprotected amino group, and such tautomers are within the scope of the invention:

B

/ n — p .n — r R1— ^ | R 5A | 25 S— S -

Il 5a

in which formulas R has the same meaning as above and R

represents a protected or unprotected imino group. In the above formulas, the imino protecting group for R3 comprises those groups used in the regions of penicillins and cephalosporins, and in particular the same groups as the monovalent groups among the aforementioned amino protecting groups.

2 9 75827

The symbol R may exist in the following tautomeric forms when the substituent is a hydrogen atom, and these tautomers are also within the scope of the invention:

0 v 0 0 OH

5 ^ -f - -ch ^ hh ^ -CH2-N n

Salts of the compounds of formula I comprise salts with a basic group and an acidic group which are well known in the regions of penicillins and cephalosporins. Salts in the basic group include salts with mineral acids such as hydrochloric acid, nitric acid, sulfuric acid, etc .; salts with organic carboxylic acids such as oxalic acid, succinic acid, other monetary acid, trichloroacetic acid, trifluoroacetic acid, etc .; as well as salts of sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluene-2-sulfonic acid, toluene-4-sulfonic acid, mesitylenesulfonic acid, (2,4,6-trimethylbenzenesulfonic acid, sulfonic acid), naphthalene 2-sulfonic acid, phenylmethanesulfonic acid, benzene-1,3-disulfonic acid, toluene-3,5-disulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid, naphthalene-2,7- With disulfonic acid, benzene-1,3,5-trisulfonic acid, benzene-1,2,4-trisulfonic acid, naphthalene-1,3,5-trisulfonic acid, and the like. Salts with an acidic group include salts with alkali metals such as sodium, potassium, etc .; salts with alkaline earth metals such as calcium, magnesium, etc.; ammonium salts; and salts with nitrogen-containing organic bases such as procaine, dibenzylamine, N-benzyl-N-phenethylamine, 1-efenamine, Ν, Ν-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, 35-, with dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, etc.

10 75827

The following are the pharmacological effects of some typical compounds of formula I.

1. Antibacterial activity (Table I) 5 According to the standard method of CHEMOTHERAPY of Japan Societe Chemotherapy, Vol. 23 (1975), pp. 1-2, a bacterial solution obtained by culturing a heart infusion broth (manufactured by Eiken Kagaku) was inoculated. ) At 37 ° C for 20 hours on cardiac infusion agar containing drug-10 and cultured at 37 ° C for 20 hours, after which bacterial growth was examined to determine the minimum concentration at which bacterial growth was inhibited (MIC; ug / ml). The number of inoculated bacteria was 10 cells / plate (10 cells / ml) The MIC values of the following test compounds are shown in Table I: A) 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyimino-acetamide-3-m- (2,3-dioxy-1,2,3,4-tetrahydropyrazinyl)} methyl-4H-cephem-4-carboxylic acid trifluoroacetic acid B) 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide] -3- [N- (4-methyl-2,3-dioxo- 1,2,3,4-Tetrahydro-pyrazinyl) -4-methyl-4- (3-cephem-3-carboxylic acid trifluoroacetic acid) ola; C) 1- {2- (2-Aminothiazol-4-yl) -2- (syn) -methoxyimino-acetamide) -3- (N- (4-ethyl-2,3-dioxo-1,2) (3,4-tetrahydro-pyrazinyl) -7-methyl-β-cephem-4-carboxylic acid trifluoroacetic acid salt; C) 7- [2- (2-Aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide] -3- [1- (4-isopropyl-2,3-dioxo-1,2) , 3,4-Tetra-30-hydropyrazinyl) -methyl} - (? 3-cephem-4-carboxylic acid trifluoroacetic acid salt).

Il 11 75827

Table I

Antibacterial activity ^^^ ~ "~ - ~ ^^ Compound MIC (} ig / ml)

Organisms A B C D

E. coli NIHJ # 0.1 £ 0.1 # 0.1 # 0.1 E. coli TK-3 ^ 1 2 60.1 # 0.1 ^ 0.1 # 0.1

Kl. pneumoniae Y-50 # 0.1 40.1 # 0.1 = 0.1

Kl. pneumoniae Υ-41 # 0.1 # 0.1 # 0.1 # 0.1

Kl. pneumoniae Y-4 ^ = 0.1 0.2 # 0.1 0.39

Ser. marcescens W-134 # 0.1 # 0.1 # 0.1 # 0.1

Ser. marcescens IID620 # 0.1 # 0.1 # 0.1 # 0.1

Pro. morganii T-216 # 0.1 # 0.1 # 0.1 # 0.1

Pro. mirabilis T-lll # 0.1 # 0.1 # 0.1 0.2

Pro. vulgaris GN76 ^ # 0.1 0.2 1.56 0.39

Cit. freundii N-7 0.39 1.56 0.78 1.56

Ps. Aeruginosa (ifie GN9181 12.5 25 6.25 penicillanase-producing strain 2 cephalosporinase-producing strain 12 75827 2 «Acute toxicity

The following test compounds had LD50 values of 3 g / kg or greater when administered intravenously to mice (ICR, male, body weight 5-20-24 g).

Test compounds: sodium 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide] -S- [1- (2,3-dioxo-1,2,3,4- tetrahydropyrazinyl) N-methyl-Z-r-cephem-4-carboxylate, and sodium 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide] -3-yl E 1- (4-methyl-2,3-dioxo-1,2,3,4-N 'S) 3 tetrahydropyrazinylmethyl-A-cephem-4-carboxylate.

FI patent application 812980 discloses cephalos-15 spore derivatives which differ in structure from the cephalosporin derivatives according to the present invention, in particular as regards the 3-position substituent. The following Table II shows the results of therapeutic comparative experiments comparing the antibacterial activity of two compounds according to the invention and a compound known from FI patent application 812980.

The reference compound known from FI patent application 812980 has the following structure: _ / S \ 25 N - I C-CONH - [„„ l | Γ II 1 / h9n b 0CH3 ° I 2.

COOH N

ch3 30

The antibacterial activity of the test compounds was determined according to the standard method (Japan Society of Chemotherapy) described in Chemotherapy, Vol. 23 (1975), ss. 1-2.

Il 13 75827

The bacterial solution obtained by culturing the bacterium in cardiac infusion broth (manufactured by Eiken Ka-gaku) at 37 ° C for 20 hours was incubated on cardiac infusion agar containing the test compound, and this was cultured at 37 ° C. for 20 hours. The bacterial growth was then examined and the minimum concentration of the test compound at which the bacterial growth was inhibited was determined as the MIC (μg / ml). The number of bacteria inoculated was 10 bacteria / plate (10 cells / ml).

From the results in Table 31, it is found that the MIC values of the compounds of the invention are substantially lower than those of the reference compound, indicating substantially better antibacterial activity of the compounds of the invention.

14 75827

Table H

Structure of the tested compounds:

Ny // I c — CONH —- ^ S \ h2n-V I II \

Nv A_ N \ -ch r \

och3 I

COOH

MIC (pg / ml)

Examined the invention „. .,,.

__compatible compound____ \ T r ~ ° y — f 'V-f0 / n-n

X \ - / NH -Nv I

Bacteria / N ^ P. mirabilis T-98 0.0125 0.0125 0.1 P. mirabilis T-99 0.025 0.0125 0.1 P. mirabilis T-119 0.025 0.025 0.05 P. rettgeri T-90 0 0.05 0.1 E. coli TK-32 0.025 0.025 0.1 E. coli TK-35 0.05 0.1 0.2 E. coli TK-60 0.025 0.05 0.2 E. coli TK-106 0.0125 0.05 0.1 P. aeruginosa IFO 3445 1.56 6.25 12.5

II

15 75827

The capped compounds of formula I are prepared according to the invention by a) obtaining a compound of the following formula or a salt thereof J-N 2 -CH 2 -R 2

o 'jP

COORla 10

Id wherein R is a hydrogen atom or a carboxyl protecting group; R is an amino group; and R is as defined above, to react with a compound of the following formula

! c, A-COOH

N-f H ^ / | S- 5 wherein R and A have the same meaning as above, or with a reactive derivative thereof having a carboxyl group, or b) a compound of the following formula or a salt thereof is obtained

25 S

xch2co-a-conh - {| -N -CH 2 R 2 COOR 30 where X is a halogen atom, and R * a, R 1 and A are as defined above, to react with a compound of formula H »NCR 5

2 II

S

5 wherein R 5 is as defined above, or c) a compound of the following formula or a salt thereof is obtained

S

10 N - COCONH —-S

wherein R * a, R2 and R5 are as defined above, to react with a compound of the following formula h2nor18 20 18 wherein R is as defined above, or a salt thereof, and, if desired, step a), b) or c) after deprotection or conversion of the product to a pharmaceutically acceptable salt.

25 The methods of preparation (including the preparation of starting materials) are shown schematically below:

II

17 75827 CM ^

Oi H

CM (O

K H

u o i '“L 3

Oi (O

^ § ö

CO ') - U (U

\ / CO

1— z 1 «—i ^ <0 MO, —lz ° o 0 0 U to \" Ä s) = λ aT * ~ CO (0 Ή NX / U rH m 'a MS-41' 'pS' ^ CO 7-8 H - Ä V- z £ 9 ~ IH £> G -AO $ ”.HS o S.«,

K tÖ * rM K u u O

O + j> 1 Z -P

0 a; -h o -h

U ro> 1 -P ~ U C

1 rM AJ β C H CM V

<V O O (V -H> -H c K -Λ *.

) -V 3 -H CO -— 'rö <U U -7 w

/ - \ CO + »-H H MJ β O

2L CO Ai t0> 1 -H U

X / β (O C 10 *> 1 CM ~

T 0) 0) C (0 W (0 Ai ffi-H

1 cot-iro— o Ή> 1 CJMJ

in Ό O o λ; x c

«-H OÄ U β O C -H

UHO cm i / i-H O O

P CO -n L K -P β -H

NX U RM-H ^> 1 W oa) «o ro kV m W u co o) ci \\ 10 XX CM MC \\ - XX ffi H Π3 \\ XX U <0 CO Yi / V \ X -P < U Λ \\ NX to O \\ VX "\ XX \ - 2" NX 5 MJ M XX ϋ

0 NX CM

P σ> XX OS

CO CM I ~ XX CM

• H O 'kD I <U X ^ ε CM 0 OS CT?, M J.!? cj ~ 4, —1 »r · (ΓΙ 0 I <3 0) CD CO CO Ή Id

(0 n ^ M Vzv I CO (0> to I OS «—I

> 0 os T n H -I c ο ε. — L 0 0 _I £ IJ H-HOO'HII) / λ O 0 / = ^ ri X to g ^ H (0 0 M CO CO CO \\ - U to «V8 0 0 *« y_ * Ö N — ® co · - '. ... 1 I ω

I c 7 “A

"AS 00 0 ^

00 O CM

CM-H OS

OS to

MJ

10 75827 18

<M

qj - »rO

CN H -H

S g «re§ s §

Va S »" T -¾ s ^ -Λ * § “" / 7 * ° «- s / C * Is. 5

§ «f S 1 8e * -g ft -S

5 05 C -H i — I \ O \\ 0 u = w (dea) \ _, V \ 5 c Z (0 <D -P Γ ^ Λ s <£, Vs' e 5 cn mma) / \ § ^ ss I Ύ * 'J «CN -S \ $' 05: o ™ ^ o cn cn M ffi Π3 H ^ 05

W Q) / u “JX JS

u ”S ri» c 5 ”o

_J OS 41 (n VS P Φ / £ S SJ

w X> - r> -Y “2 h M ') - O C

\ / I 2 Cl \ / Q) N-Z _k 3 «C N— Z 03

I V w * I

—I I ° _ -hS _i * * '' o rr ^ ov -p ^ z ° υ κ h ^ '1-1 o' oy = zo m .. e »u« R x «S zc u = zo u κ o £

° - J ^ wSo-h <-> G

UH * y \ O 2 i O c ™ - M g υ g £ u X £ ^ U fl Λ Ή XC - II \ ω o -p / \ rr "0 ** -H <0 \ 4J <D -H" ^ sx. z * IX * Iflal-PO -Η '' -HM β o

N \> 1 O 00 Η Λ! il 4-1 5¾. "? <e (d -H r-H I

X \ to ο ή o to oa -p ω <o> <m1 V \ <0 U 05 3 0) · η -HIMC to 05 NX - tJ «= Z — O to U 0, 'to - XX o CH' 'L - Z? XX UCC <U> 1 05 - // '_ NX fs a) a) cc to yy x \ ® to to -H a) (0 yx o Vv u> ic - yy 2 Vs. X · Η -rt Μ · Η / Υ Τ) - NX tO (0> 1 to yx to M 1 vs + »- p * a yy skin XX sy Λ

> --H NX / y, H Q

^ t0 -P I Νλ rs | / (0 · η H X A NX pj ►H 0 to 0 Xv <N c m 5 c a) η χ. K (0 ^ a) • H S to P c χ. U Ή (0 C C -Ό

rjo CD XX y 05 H -H tl) I-I

03 r “i - 5 C C Q) C y / O 0 to f — I

S y-SB-O <U <UC -P / s \ O 3 Λ5 »0 ij R to to -H (0 W \\ - U to> i C 6 W Rs,> i ζ. F - Λί V 5 -Η ^ λ 5 2> COC> i

e * (0 (0> i t0, HtU-H-HP

, 5 y + 4-ρλ; τ3 ^ to 4-1 ιο o

^ Λί C C

> X0 -H (0 β · Η (0 tsp) (0 g 00 -P M Ό (0 (N 05

II

19 75827

Preparation 2 (preparation of starting material for method a) r30_conh / S [XVI] / -N y ^ CH2X COOR1 or its salt VJ * (conversion at the HN NR6 [III-A] f3 position) or its salt 30 SO o R -CONH- p | ^ Ί | y p NR6 O T 1 '' f

COOR

+ U [XVII] R30-CONHp_ ^ S> | ° s \ /? N> ^ - CH.N NR6

T! 2 W

COOR

or a salt thereof (conversion to Δ3-cephem) R30-CONH-^ JN ^ -CH-N NR6 [XVIII] OJ 2 COOR1 or a salt thereof h2n tYSni Vf ° (deacylation) ^ jN Y ^ CH2N ^ NR6 [XIX] ^ COOR1 or a salt thereof 20 7 5 8 2 7

In the above formulas, R *, R * a, 2 5 6 18 29 R, R, R, R and A are as defined above; R is substituted or unsubstituted acyloxy or carbamoyloxy; R 2 is benzstyl, phenoxymethyl or a group of formula

S

5 wherein R and A are as defined above; X is a halogen atom; and> Z is> S or> S—> 0.

Substituted or unsubstituted acyloxy and carbamoyloxy groups for R include alkanoyloxy groups such as acetoxy, propionyloxy, butyryloxy, etc .; alkenoyloxy groups such as acryloxy, etc .; aroyloxy groups such as benzoyloxy, naphthoyl-15, etc .; and carbamoyloxy. These groups may be substituted by one or more substituents such as halogen atoms, nitro, amino, alkyl groups, alkoxy groups, alkylthio groups, acyloxy groups, acylamino groups, hydroxyl, carboxyalkyl, sulfamoyl, carbamoyl, carbamoyl, carbamoyl, alkoxy alkoxycarbonylsulfamoyl groups, aryl groups, carbamoyloxy, etc.

29

In the above-mentioned substituents for R, a hydroxyl group, an amino group, a carboxyl group, etc., may be protected with protecting groups commonly used, and these protecting groups include, in particular, conventional hydroxyl protecting groups, amino protecting groups and carboxyl protecting groups.

1) The conversion reaction at the 3-position of the 7-substituted or unsubstituted amino-3-substituted methylcephem carboxylic acid of formula IV or a salt thereof can be prepared in high yield in high purity using an industrially easy method by introducing 2,3-dioxo-1, 2,3,4-Tetrahydropyrazine of formula III-A, or a salt thereof, for reaction with a cephalosporanic acid represented by formula II, or a salt thereof, in the presence of an acid or an acid complex compound, and, if desired, deprotection, protection. -

II

21 75827 by leaving a carboxyl group or converting the obtained compound to a salt. Furthermore, the above-mentioned 2,3-dioxo-1,2,3,4-tetrahydropyrazine can be prepared by the method described in Journal of Chemical Society, Perkin I (1975), p. 1888 - 1890.

Furthermore, if necessary, the substituent on the amino group at the 7-position can be removed in the usual manner to form a 7-unsubstituted amino compound. According to this procedure, not only -A-cephem compounds but also A-cephem-2 compounds can be used as starting materials, and when A-cephem compounds are used as starting compounds, the reaction product, A-cephem compounds, is modified. further to A? -cephem compounds.

It is also possible to use not only compounds in which> Z is> S but also compounds in which> Z is> S -> O, as starting materials and in the latter case> S -> 0 can be converted to> S during the reaction or in the post-treatment step. .

If the 2,3-dioxo-1,2,3,4-20 tetrahydropyrazine of the formula III-A used as a reactant in the reaction has a basic or acidic group as a substituent, these compounds may, if necessary, be introduced into the reaction with the corresponding salt. in terms of. In this case, the salts in the basic groups and the salts in the acidic groups include those mentioned as salts of the compounds of formula I.

Salts of the compounds of formulas II and IV also include salts in basic groups and acidic groups, and these salts include those salts mentioned as salts of the compounds of formula I. The salts of the compounds of formula II may be isolated in advance and then used or may be prepared in situ.

As the acids or complexes of acids used in the reaction, for example, protic acids, Lewis acids or complexes of Lewis acids are mentioned. Protic acids include sulfuric acids, sulfonic acids, superacids (superacids refer to acids that are more potent than 100% sulfuric acid and include some of the 22 7 5 8 2 7 sulfuric acids and sulfonic acids mentioned above). In particular, protic acids include sulfuric acids such as sulfuric acid, chlorosulphuric acid, fluorosulphuric acid, etc., sulphonic acids, for example alkyl (mono- or di-) sulphonic acids such as methanesulphonic acid, trifluoromethanesulphonic acid, etc., aryl- (mono-, di- or di-). tri-) sulfonic acids such as p-toluenesulfonic acid, etc., superacids such as perchloric acid, "magic acid" (FSO3H-SbF5), FSO3H-AsF5, CF3SC> 4H-SbF5, HF-BF3, H2SO4-SC > 3 10 etc.

Lewis acids include, for example, boron trifluoride, and Lewis acid complexes include boron trifluoride complexes with dialkyl ethers such as diethyl ether, di-n-propyl ether, di-n-butyl ether, etc., amines such as ethylamine, n-propylamine, with butylamine, triethanolamine, etc., with esters such as ethyl formate, ethyl acetate, etc., with aliphatic acids such as acetic acid, propionic acid, etc., and with nitriles such as acetonitrile, propionitrile, etc.

The reaction is preferably carried out in the presence of an organic solvent. The organic solvents used which are inert to the reaction include, for example, nitroalkanes such as nitromethane, nitroethane, nitropro-head, etc., organic carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, dichloroacetic acid, propionic acid such as acetone, etc., ketones methyl ethyl ketone, methyl isobutyl ketone, etc., ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, anisole, dimethyl cellosolvate, etc., esters such as ethyl formate, ethyl formate, diethyl acetate, diethyl acetate , butyl acetate, etc., nitriles such as acetonitrile, butyronitrile, etc., and sulfolanes, etc. These solvents can be used as a mixture of two or more. In addition, complexes formed from these organic solvents and Lewis acids can be used as solvents. It is enough that the acid

II

23 75 82 7 or the amount of the acid complex compound used is at least equimolar with the amount of the compound of formula II or a salt thereof, and the amount may be varied depending on the corresponding cases. In particular, the use in a ratio of 2 to 10 moles per mole of the compound of the formula II or a salt thereof is preferred. When an acid complex compound is used, it can be used as a solvent per se, and two or more complex compounds can be used in the mixture.

It is sufficient that the amount of 2,3-dioxo-1,2,3,4-tetrahydropyrazine or a salt thereof is at least equimolar with the amount of the compound of formula II or a salt thereof, and in particular the amount of about 1.0 to 5.0 moles per mole is preferred.

This reaction is usually carried out at 0 to 80 ° C and is complete in 10 minutes to 30 hours. The presence of water in the reaction system may cause undesired side reactions such as lactonization of the starting material or products and cleavage of the γ-lactam ring, so it is desirable to keep the system under anhydrous conditions. To meet this requirement, it is sufficient to add a dehydrating agent suitable for the reaction system, e.g., a phosphorus compound such as phosphorus pentoxide, polyphosphoric acid, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, etc., an organic silylating agent such as Ν, trimethylsilylacetamide, trimethylchlorosilane, dimethyldichlorosilane and the like, an organic acid chloride such as acetyl chloride, p-toluenesulfonyl chloride and the like, anhydrous anhydride such as acetic anhydride; calcium carbide or the like.

If a compound of formula II wherein R is a carboxyl protecting group is used as a starting material, in some cases a compound of formula IV having a hydrogen atom may be obtained directly in the reaction, or this compound may be obtained by deprotection in a conventional manner.

24 75827

The following describes the conversion reaction at the 3-position, which is described in Preparation 2.

The halogenated compound of formula XVI can be prepared according to the method described in Tetrahedron Letters no. 46 (1974), ss.

3991-3994; and Tetrahedron Letters No. 40 (1981), p. 3915 - 3918.

A compound of formula XVII or a salt thereof can be prepared by reacting a halogenated compound of formula XVI 10 or a salt thereof with 2,3-dioxo-1,2,3,4-tetrahydropyrazine of formula III-A or a salt thereof in the presence of a base. The base comprises alkali metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonates (e.g. sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxides (e.g. containing sodium hydroxide, potassium hydroxide, etc.), nitrogen. triethylamine, pyridine, Ν, Ν-dimethylaniline, etc.

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

In this case, the compound of the formula III-A or a salt thereof is preferably used in an amount of about 1.0 to 2.0 moles per mole of the compound of the formula XVI or a salt thereof. The reaction is generally carried out at a temperature of 0 to 50 ° C for a period of 30 minutes to 10 hours.

The mixture of A-3a A cephem compound thus obtained, i.e. a compound of formula XVII or a salt thereof, can be readily converted to a Δ-cephem compound to give a compound of formula XVIII or a salt thereof, which is then converted to a compound of formula XIX or 35 to its salt by deacylation. This conversion reaction and de-acylation are known in the regions of penicillins and cephalosporins and have been specifically described in the publication.

II

25 7 5 8 2 7 in the Journal of Organic Chemistry, Vol. 35, No. 7 (1970), p. 2430-2433; and "Cephalosporins and Penicillins" (Flynn, Academic Press), p. 56 - 64.

The compound of formula IV or XIX may also, if necessary, be protected at the carboxyl group or converted into a salt in a conventional manner to give the desired compound.

2) Acylation

When a compound of formula V, VI, VII, VIII 10 or XIII, or a salt thereof or a reactive derivative thereof, is reacted with a compound of formula IV or a salt thereof or a derivative thereof in an amino group, a compound of formula I, IX, X, XI or XIV, or a salt thereof.

Salts of a compound of formula V, VI, VII, VIII or XIII comprise salts in a basic group or an acidic group, in particular those salts mentioned as salts of the compound of formula I.

Reactive derivatives with an amino group of a compound of formula IV include all derivatives often used in acylation, e.g. isocyanate; A Schiff base prepared by reacting a compound of the formula IV or a salt thereof with a carbonyl group such as an aldehyde, a ketone or the like (with a ketime type or an isomer thereof, namely an enamine type); silyylijoh-derivative thereof; a phosphorus derivative or a tin derivative prepared by reacting a compound of the formula IV or a salt thereof with a silyl compound such as bis (trimethylsilyl) acetamide, trimethylsilylacetamide, trimethylsilyl chloride and the like; a phosphorus compound such as phosphorus trichloride,

Γ ° \ / ~ 0V

PCI, PCI, (PCI, (CHtCH 2 O) -PCI

Lo 2 ChJ-O 2 V (/ 3 2 2 35 * or (CH 2 Cl 2 / PCl or the like; or with a tin compound such as (CH 2 Cl 2 / SnCl or the like).

26 75827

Reactive derivatives of the compounds of formulas V, VI, VII, VIII and XIII include in particular acid halides, acid anhydrides, mixed acid anhydrides, active acid amides, active esters, reactive derivatives obtained from the compounds of formulas V, VI, VII, VIII and XIII. by reaction of the compounds with Vilsmeier's reagent. The mixed acid anhydride comprises a mixed acid anhydride with a monoalkyl carbonate such as monoethyl carbonate, monoisobutyl carbonate, etc., a mixed acid anhydride with a lower alkanoic acid which may be substituted with a halogen such as pivalic acid, trichloroacetic acid, etc. The active acid amide comprises N-acylsaccharin, N-acylimidazole, N-acylbenzoylamide, N, N1-dicyclohex-15-yl-N-acylurea, N-acylsulfonamide, etc. The active ester comprises cyanomethyl ester, substituted phenyl esters, substituted phenyl esters, substituted titrated thienyl esters, etc.

Reactive derivatives obtained by reaction with a Vilsmeier reagent obtained by reacting an acid amide such as kuten, Ν-dimethylformamide, N, N-dimethylacetamide, etc. with a phosphorus tribromide such as phosgene, thionyl chloride, phosphorus trichloride , phosphorus oxychloride, phosphorus pentachloride, trichloromethyl chloroformate, oxalyl chloride, etc.

with.

If a compound of formulas V, VI, VII, VIII and XIII is used in the form of a free acid or salt, a suitable condensing agent is used. Condensing agent 30 comprises N, N'-disubstituted carbodiimides such as N, N'-dicyclohexylcarbodiimide, azolidine compounds such as N, N'-thionyldiimidazole, dehydrating agents such as N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline, phosphorus oxychloride, alkoxyacetylenes, etc., 2-35 halopyridinium salts such as 2-chloropyridinium methyl iodide and 2-fluoropyridinium methyl iodide, etc.

Il 2? 75827 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, e.g., a halogenated hydrocarbon such as chloroform, methylene chloride, etc., an ether such as tetrahydrofuran, dioxane, etc., N, N-dimethylformamide, Ν, Ν-dimethylacetamide, acetone, water , or a mixture thereof. As the base, an inorganic base such as alkali metal hydroxide, alkali metal hydrogencarbonate, alkali metal carbonate, alkali metal acetate, etc., a tertiary amine such as triethylamine, tributylamine, secondary amine, N-methylpiperidine, N-methylimide, N-methylimide, N-methylimide can be used. such as dicyclohexylamine, diethyl-lamine, etc.

A compound of formula IX or a salt thereof which can be converted into a compound of formula I and its salts can be prepared by the following method:

To obtain a compound of formula IX or a salt thereof using a compound of formula IV or a salt thereof, a 4-halo-3-oxo-butyryl halide obtained by the reaction of diethylene with a halogen such as chlorine or bromine is obtained (Journal of the Chemical Society 97 ( 1910, 1987), to react with a compound of formula IV or a salt thereof according to a conventional method.

Reaction conditions and methods known in the art can be used for this reaction. A salt of a compound of formula IX may be readily prepared in a conventional manner and the salt comprises the same salts as those set forth above as salts of a compound of formula I. Although formula IX

The compound or a salt thereof can be isolated and purified, it can be used for the subsequent reaction without isolation.

In addition, the compound of the formulas V, VI, VII, VIII and XIII or a salt thereof or a reactive derivative thereof is preferably used in an amount of about 1 mole to several moles per mole of the compound of the formula IV or a salt thereof. The reaction is usually carried out at a temperature of -75 to 40 ° C. The reaction time is usually 10 minutes to 48 hours.

Furthermore, the compounds of the formulas I, IX, X, XI and XIV in which R * is a carboxyl-protecting group can be converted into the compounds of the formulas I, IX, X, XI and XIV in which R * is a hydrogen atom or their salts in the customary manner, and similarly, compounds of formulas I, IX, X, XI and XIV in which R * is a hydrogen atom may be converted into compounds of formulas I, IX, X, XI and XIV in which R * is a carboxyl-protecting group or salts thereof, and salts of the compounds of formulas I, IX, X, XI and XIV may be converted to the corresponding free acid forms respectively.

12 5

Also in this acylation reaction, if R, R and R 15 contain reaction-active groups, these groups can be protected with conventional protecting groups before the reaction, and the protecting groups can also be removed by a conventional method after the reaction.

The compound of the formula I of the present invention or a salt thereof obtained by the above-mentioned method can be isolated in a conventional manner.

3) Nitrosation

Next, to obtain a compound of the formula X or a salt thereof from the compound of the formula IX or a salt thereof, a nitrosating agent is reacted with a compound of the formula IX or a salt thereof. The reaction is usually carried out in a solvent inert to the reaction, such as water, acetic acid, benzene, methanol, ethanol, tetrahydrofuran, etc. Preferred examples of nitrosating agents include nitric acid and its derivatives, e.g., nitrosyl halides such as nitrosyl chloride, etc. nitrosyl chloride, nitrosyl chloride, nitrosyl chloride. , al-potassium nitrites such as sodium nitrite, potassium nitrite, etc., alkyl nitrites such as butyl nitrite, pentyl nitrite, etc. If a nitric acid salt is used as the nitrosating agent, it is preferable to carry out the reaction with an inorganic or organic acid such as hydrochloric acid .

Il 75827 29 in the west. If an alkyl nitrite is used as the nitrosating agent, it is preferable to carry out the reaction in the presence of a strong base such as an alkali metal alkoxide or the like. The reaction is usually carried out at a temperature of -15 to 30 ° C, and the reaction time is usually 10 minutes to 10 hours. A salt of a compound of formula X can be easily prepared in a conventional manner and this salt comprises the same salts mentioned above as salts of a compound of formula I. Although the compound of formula X10 thus obtained or a salt thereof can be isolated and purified by a well-known method, it can be used for the subsequent reaction without isolation.

4) Etherification

To obtain a compound of the formula XI or a salt thereof from the compound of the formula X or a salt thereof, a compound of the formula X or a salt thereof is subjected to an etherification reaction.

The etherification reaction can be carried out by a conventional method as described in JP Patent Application Nos. 137 988/78, 105 689/80, 149 295/80, etc. (Kokai).

For example, alkylation can be carried out in the usual way. The reaction is generally carried out at a temperature of -20 to 60 ° C and is complete in 5 minutes to 10 hours.

As the solvent, a reaction-inert solvent such as tetrahydrofuran, dioxane, methanol, ethanol, chloroform, methylene chloride, ethyl acetate, butyl acetate, Ν, Ν-dimethylformamide, N, N-dimethylacetamide, water or a mixture thereof is used.

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

The salt of the compound of formula VI can also be easily obtained according to a conventional method, and the salt comprises the same salts mentioned above as the salts of the compound of formula I.

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

Although the compound of formula XI or a salt thereof thus obtained can be isolated and purified by a conventional method, they can be used for the subsequent reaction without isolation.

15 5) Ring closure reaction

A compound of formula I or a salt thereof is obtained by reacting a compound of formula XI or a salt thereof with a thioformamide or thiourea of formula XII.

This reaction is usually carried out in a solvent.

As the solvent, a reaction-inert solvent such as water, methanol, ethanol, acetone, tetrahydrofuran, dioxane, di, Ν-dimethylformamide, N, N-dimethylacetamide or N-methylpyridone is used alone or as a mixture of two or more. Although it is not essential to add an acid scavenger, the reaction sometimes proceeds steadily by adding an acid scavenger in such an amount that the cephalosporin backbone is not affected. The acid scavenger used for the reaction comprises inorganic and organic bases such as alkali metal hydroxide and alkali metal bicarbonates, triethylamine, pyridine, Ν, Ν-dimethylaniline, etc. The reaction is usually carried out at a temperature of 0 to 100 ° C. Thioformamide or thiourea is usually used in an amount of about 1 mole to several moles per mole of the compound of formula XI 35 or a salt thereof. The reaction time is 1 to 48 hours, preferably 1 to 10 hours. Furthermore, in a compound of formula I, the carboxyl group may be protected and deprotected or the product modified

II

3i 75827 to a salt is carried out in the usual manner to convert the compound to the corresponding target compound. If R, R and R in the formula I contain reaction-active groups, these groups can be suitably protected with a conventional protecting group before the reaction, and the protecting groups can be removed by a conventional method after the reaction. The target compound of formula I thus obtained or a salt thereof can be isolated in a tunnel manner.

6) Oximation A compound of the formula I or a salt thereof is obtained by reacting a compound of the formula XIV or a salt thereof with a compound of the formula XV or a salt thereof. The salt of the compound of formula XV comprises hydrochlorides, hydrobromides, sulfates, etc. This reaction is usually carried out not only in a solvent such as water, alcohol, N, N-dimethylacetamide, etc., but also in other reaction-inert solvents. or their mixed solvents. The reaction is carried out at a temperature between 0 and 100 ° C, preferably between 10 and 50 ° C. The reaction time is usually 10 minutes to 48 hours. The compound of the formula XV or a salt thereof is used from about 1 mole to several moles per mole of the compound of the formula XIV or a salt thereof. Although a salt of a compound of formula XV may be used as such for the reaction, it may also be reacted with a base, e.g., an inorganic base such as an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g., magnesium hydroxide). , calcium hydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g., magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonate (e.g., sodium bicarbonate, alkali metal carbonate, potassium bicarbonate). 35 (e.g. magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphate e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate) or alkali metal acetate (e.g.

32 75827 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 [1-, 3.07-5-noneene, In the presence of 1,4-diazabicyclo [2.2.2] octane, 1,5-diazabicyclo [delta], 4,07-7-undecene and the like. In the compound (Ib) of the present invention thus obtained or a salt thereof the conversion of R 1 can take place in a conventional manner and can also be isolated by a conventional method.

The compound of formula I thus obtained, or a salt thereof, may 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 treatment and protection against bacterial infection. It is preferred to administer the compound parenterally in the form of a free acid or a pharmaceutically acceptable salt, or to administer the compound in the form of a pharmaceutically acceptable ester. In this case, it is sufficient to formulate the compound into a dosage form commonly used in cefa-20 losporin drugs, e.g., tablets, capsules, powders, fine granules, granules, syrups, injections (including instillation), suppositories, and the like.

When the above-mentioned drug is formulated into a dosage form, diluents and / or additives may be used, e.g., intermediates such as starch, milk sugar, sugar, calcium phosphate, calcium carbonate, etc .; binders such as acacia, starch, fine crystalline cellulose, carboxymethylcellulose, hydroxypropylcellulose and the like; lubricants such as talc, magnesium stearate and the like; disintegrants such as carboxime-style calcium, talc and the like.

When administering a compound of formula I or a salt thereof, the dose, time of administration and method of administration may be varied depending on the symptoms of the patient, and it is generally sufficient to administer orally or parenterally to an adult a dose of about 50-5000 mg. 1 "5 in 4 divided doses per day.

The present invention will be explained below with reference to Comparative Examples and Examples, which are given by way of illustration only and not by way of limitation.

Comparative Example 1 10 (1) To a solution of 20.0 g of ethyl N- (2,2-diethoxyethyl) oxamate in 60 ml of ethanol was added 6.1 ml of a 70% by weight aqueous ethylamine solution, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, the precipitated crystals were collected by filtration and recrystallized from ethanol to give 17.0 g (yield: 85.1%) of N-ethyl-N '- (2,2-diethoxyethyl) oxamide, m.p. 131-132. ° C.

IR (KBr) cm-1: 1650 In a similar manner, the compounds shown in Table III were obtained.

34 75827

Table III

(ch3ch2o) 2chch2nhcoconhr6 5 ____

Solvent re- IR (KBr)

Compound crystallization Sp. (° C), -, 1 - for 1 c R 6 = O 10 -H ethyl acetate 141 - 142 1650, 1635 -CH 2 ethanol 135 - 136 1645 - (CH 2) 2 CH 3 acetone 84 - 85 1645 15 / CH 3 -CH . acetone CH3 n-hexane 145-146 1650, 1635 20 "^ CH2 ^ 3CH3 n-hexane 111 - 112 1645 - (CH2) 4CH3 n-hexane 92-93 1650 25 (2) To a solution of 17.0 g of N- ethyl N '- (2,2-diethoxyethyl) oxamide obtained in (1) above in 85 ml of acetic acid was added 0.05 ml of concentrated hydrochloric acid. The mixture was heated to reflux for 30 minutes. When the reaction was complete, the solvent was removed by distillation under reduced pressure, and 70 ml of acetone was added to the residue, and the crystals were collected by filtration. The crystals were recrystallized from methanol to give 6.8 g (yield: 61.8%) of 4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine, m.p. 173-174 ° C.

35 IR (KBr) cm -1: 1 = C = 01680-1620

In a similar manner, the compounds shown in Table IV were obtained.

Il 35 7 5 8 2 7

Table IV

° w ° s HN N-R6

W

SP. IR (KBr, «1 = r 6 for which ^ C = O -H -> 280 1680-1640 -CH 3 Ethanol 220-231 1690-1635 - (CH2) 2CH3 Acetone 182-183 1680-1640 -CH <“ 3 Acetone 215-219 1680, 1625 CH 2 - (CH 2) 3 CH 3 Acetone 149-150 1680, 1640 - (CH ~) CH-, Acetone 171-172 1685, 1660, 4 J 1620 36 7 5 8 2 7

Example 1 (starting material) (1) To a solution of 10 ml of ethyl acetate containing 2.71 g of boron trifluoride were added 2.72 g of 7-aminocephalosporanic acid (hereinafter referred to as 7-ACA) and 1.54 g of g of 4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine, and the mixture was reacted at room temperature for 16 hours. When the reaction was complete, the reaction mixture was taken up in 50 ml of methanol under cooling, and then 3.16 g of pyridine-10 was added dropwise thereto. The precipitated crystals were collected by filtration, washed with sufficient 30 ml of methanol and then dried to give 3.10 g (yield 88.1%) of 7-amino-3-O-4'-ethyl-2,3-dioxo- 1,2,3,4-Tetrahydro-pyrazinyl-N-methyl-Δι} -Δ3-cephem-4-carboxylic acid with a melting point of 191-195 ° C (decomposed).

IR (KBr) cm-1: ν Q 1795, 1670, 1620 NMR (CF 3 C 10 D) δ values: 1.44 (3H, t, J = 7Hz,> NCH 2 CH 3), 3.69 (2H, bs, C 2 -H ), 4.08 (2H, q, J = 7Hz,> NCH 2 CH 3>, 5.14, 5.51 (2H, ABq, J = 15Hz, S), JC * 2 "5.48 (2H, s, C6-H, C2-H), 6.74, 7.00 (2H, ABq, J-6Hz, = = /)

20 / N

H H

(2) The conversion reaction at the 3-position mentioned in (1) above was carried out under the reaction conditions shown in Table V to give 7-amino-3H- (4-ethyl-2,3-dioxo-1,2,3, 4-Tetrahydropyrazinyl) -7-methyl} -N-cephem-4-carboxylic acid in the yields shown in Table V.

Il 37 75827 .—. e # P <#> 0 tn 4-) tn is o: rö C - in - M id vo ro oo i — i: n3 cd - r ~ - oo: (d 10 (Ν'- cn —- S ~ 4 - · 0) Cd IÖ (0 10) r4 td (-4 * r4 O 4-) C -H -HC -r4 4-)

• H Ä 0) 4-) 4-) 0) 4-) C

4-1 3 0) MD C 0): 03 4 * to C Oh 3 C Oh 4->

Cd O O g 4J O g

0) «H p: cd p: cd VD

Oh O ί rl N X3 Ή r-l

I I

• H Ή I

T3 Ό -H

• H · Η M

P MO)

0) O O -P

> 14-13 3 4- »

Oh 10 rH HO) O -H g -H 44 44 0) Ή

X Cd O Ό -H -H -H CO

X -P X Λ P M H, ¾ 3> i 4-) Ö) 4-)> i 0)

rH O C -H -H * 4 H

3 ftorn pr4 p4Ja cd a a. X o i "o a> g E4 cdnJO) o * o -h o

KX! R4 4304 Ä fl AI

C -H

• H I 1C

4.) O -H f-4 o <Ö 0 44 egp cd 3 -4 Cd 4J 4-> • H 3 <Ö o -HO) t-3 to r4 r4 Cg ro aa u Γ4 U tn tn V% - s 1 J3 »o” __________— £ "tn tn .λ <

U CN (N

<r- r- ~ r- cn cn 0 i — i cm ·· e 38 7 5 8 2 7 (3) In the same manner as in (1) above, the compounds shown in Table VI were obtained.

(In this case, the target compounds were obtained by pouring the reaction mixture into ice water at the 3-position of the conversion to completion and adjusting the pH to 3.5 with 28% by weight aqueous ammonia solution under ice-cooling.)

II

39 7582 7

V

OF

K

in

rH

4J II * 0 l-J 03> XI ^ 3-1 · »*.

(0 - * - - O1 * N- / K | 1 n g k n m k j fO SC I E <ni

IV Γ "» - m r- - X

ha vo n ^ nffiCN O '- "K * K n n c / a - .—. u oi ^ u - - * g 4J nln n | J3 -P n in -» ω Q K | (J \ · - ^ cn K X)

I »ylv N» * (NOO * I

VO ffi rH K K! K K - - Γ- -

Ό n - »cj n n u ^ UK

- - (NJ | ^ ^ - | (N

(vj κ m mi - m ·. -

a: K rHUOKnr'Kl'a · KK

l g ov ^ r-nutor ^ u n U l vo sT Z O / \ rH / \ n n J \ ^ en U j / -jv O Ä ° μ · '\\ O V. Il * ·.

k en \ - U m o oo o ^ ./ K U or-n n \ '^ rH <\ oo vo vo

u j Z | i — I rH i — I

X I K E

3 HU

rH -J-- (0 "HO _ σν .— Z σν (0 m _ rH (Ö

K U O

0 I n • - <0

vo jC

. ov -

Dl h en n

K

u

TT

m

K

O) u + * oK ~ ® z \

Ό <n I

Λ K I

* z 'O l _____ 40 7 5 8 2 7 (4) In the same way as in (1) above, the crude crystals shown in Table VII were obtained.

Table VII

h2nt <s1 2

o S ^ NY-CII2R

COOH

Compound n: ° R2

x U

· 1 -N N-H

\ __ /

O. O

2 -N N-CHo 3

O O

3 ^ J -N N-CH0CH0CHq \ - / 2 2 3

Q -O

4 M / CH

q -N N-CHC

This compound was obtained by introducing into methanol, filtering insolubles and adding pyridine to the filtrate.

75827 41

Example 2 (starting material)

To a suspension of 3.0 g of 7-amino-3- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl) -Δ 3 -cephem-4-carboxylic acid obtained in 5 g. in Example 1- (1), in 30 ml of methanol, 1.62 g of p-toluenesulfonic acid monohydrate was added to form a solution, and then 5.0 g of diphenyldiazomethane was slowly added to the solution, after which the resulting mixture was reacted at room temperature for 15 minutes. When the reaction was complete, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was dissolved in a mixed solvent of 20 ml of ethyl acetate and 20 ml of water. The solution was adjusted to pH 7.0 with sodium bicarbonate. The organic layer was then separated and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by flash chromatography (Wako Silica Gel C-200, eluent; benzene / ethyl acetate = 1: 4, by volume) to give 3.1 g (yield 70.3%) of diphenylmethyl-7-amino-3- (4- ethyl 2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) n-ethyl} -Δ3-cephem-4-carboxylate, m.p. 183-186 ° C (decomposed).

IR (KBr) cm-1: Vc = q 1765, 1730, 1680, 1630

In a similar manner, the compounds shown in Table VIII were obtained.

42 7 5 8 2 7

Table VIII

"τα,

0 / CH2R

COOCH (^)) 2 _Compound_ M.p. (° C) IR (KBr) cm-1:

r2 vC = O

0 P

-NNH 129-130 1765, 1725, W (decomposes) 1690 '1630 O O' ύ - <(NN γη 127-128 1770, 1725, \ = J 3 (decomposes) 1690 '1640

O O

K 169-171 176-5, 1730, -N N (CH 2) 2 CH 3 (decomposes) 1685, 1635

0 P

γ-Λ CH., 179-180.5 1760, 1720, -N NCH 2 J (decomposes) 1685, 1635 ch 3

O O

t 180-189 1760, 1725, -N N (CH 2), CH 2. , 1680, 1630

O O

185-194 1765, 1730, -N N (CH 2) .CH. ; 1685, 1630 s_✓ 2 4 3 (decomposes) 1

II

* I "- 43 75827

Example 3 (starting material)

In a mixed solvent of 25 ml of trifluoroacetic acid and 10 ml of anisole was dissolved 4.9 g of diphenylmethyl-7-amino-3- [1- (2,3-dioxo-1,2,3,4-tetrahydropyrazine-5]. methyl) methyl <7-β-cephem-4-carboxylate and the solution was reacted at room temperature for two hours. When the reaction was complete, the solvent was removed by distillation under reduced pressure, and 50 ml of diethyl ether was added to the residue, followed by collecting the crystals by filtration. The crystals were washed with sufficient 40 ml of diethyl ether and then dried to give 4.25 g (yield 97.0%) of 7-amino-3- [1- (2,3-dioxo-1,2,3,4-tetrahydropyrazinyl). ) 7-Methyl-β-cephem-4-carboxylic acid trifluoroacetic acid salt, m.p. 105-106 ° C (decomposed).

IR (KBr) cm -1: 1) c = 0 170, 1700-1630 NMR (CF 3 C 10 D) δ values: 3.72 (2H, bs, C 2 -H), 5.14, 5.52 (2H, ABq, J = 15Hz, CH 2 Cl 2 4.44 (2H, s, C 6 H 6, C 2 -H), W>

6.78, 6.98 (2H, ABq, J = 6Hz, H'H

25

In a similar manner, the compounds shown in Table IX were obtained.

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ä <N

f U I

cn | K ^ cO> s I h mu'- '.κι: - ° r-X r- Y i

.: = ^ -ί Help I

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o m —'Λ Q m rH s

O · »II I

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U O <N

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K vo vo tn Ό K

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Explanations of the notes to Table IX: *) = this compound was obtained by the method of methanol, filtration of insolubles and addition of pyridine to the filtrate 5 **) = comment was made because it was not established whether the chlorine atom was in the 4- or 5-position and whether the product consisted of one for a single compound or mixture ***) = note means that the product was a mixture of a 4-substituted compound and a 5-substituted compound 10 a) = free compound; obtained by treating the trifluoroacetic acid salt with pyridine in methanol.

Example 4 (final product) (1) 2.29 g of 2- (2-formidithiazol-4-yl) -2- (syn) were dissolved in 2.29 ml of Ν, Ν-dimethylacetamide and 4.58 ml of acetonitrile. -methoxyiminoacetic acid and 1.62 g of phosphorus oxychloride were added dropwise to the resulting solution, after which the mixture was reacted at -5 ° -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) -N-methyl} -Δ cephem-4-carboxylate and the mixture was reacted at -5 ° to 0 ° C for 1 hour. When the reaction was complete, the reaction mixture was poured into a mixed solvent of 80 ml of water and 80 ml of ethyl acetate, and the resulting solution was adjusted to pH 6.5 with sodium hydrogen carbonate.

The organic layer was then separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and 60 ml of diethyl ether was added to the residue. The crystals were then collected by filtration to give 6.05 g (yield 83.0%) of diphenylmethyl-7- [2- (2-formamidothiazol-4-yl) -2- (syn) -methoxyiminoacetamide] -3- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl) -4-cephem-4-carboxylate, m.p. 165-168 ° C.

Il 49 75827 IR (KBr) cm-1: λ max = 1780, 1720, 1680, 1640 NMR (d 6 -DMSO) δ values: 1.18 (3H, t, J = 7Hz,> N-CH 2 CH 3), 3.59 (2H, bs, C 2 -H), δ 3.72 (2H, q, J = 7Hz,> N-CH 2 CH 3), 3.97 (3H, s, -OCH 3), 4.42, 5.04 ( 2H, ABq, J = 15Hz,),> CH2- 5.30 (1H, d, J = 5Hz, C8-H), 6.02 (1H, dd, J = 5Hz, J = 8Hz, C? - H), 6.50, 6.62 (2H, ABq, J = 6Hz, v,), 7.04 (1H, S, -CH <), 7.17-7.82 (11H, m, - (d) x2 , NX).

T 1. . s H

8.63 (1H, s, HCO-), 9.89 (1H, d, J = 8 Hz, -CONH-), 12.68 (1H, bs, HCONH-)

In a similar manner, the compounds shown in Tables X and XI were obtained.

50 75827

Table X

N - C - CONH --S 'S ^ HCONH —0 I II' 2

N Λ- —CH ~ R

\ Y

OCH-, / - \ COOCH (<ΤΛ> 2 (syn isomer)

The compound Sp. (° C) IR (KBr) cm-1 2 N?

R C = O

Y 1 120-125 1780, 1720, Y 2 N-CH 3 (decomposes) 1680-1640

oN_ O

7 \ 154 - 156 1785, 1720, -N N- (CH-), CH0 ,,. . n, oc ^ j 24 3 (decomposes) 1685, 1645 51 75827

Table XI

CH, / Sv.

I 3 N - C— CONH —-— <N

CH, CH., - C-OCONH— (f II! ^ J

i «3 N 0 ^ Nv ^ -CH2 * or18 * fRs COOCH (\\ Jf> 2 (syn isomer)

Compound _ IR (KBr) cm -1.

R2 r18 Sp »'C) vc_0% P r' 176-179 1780, 1720, -NNH3 #h. , 1680.1640 \ / / (decomposes) OO -CH, 152-155 \ 12 * 'jMf 3 (decomposes) 1680, 1640 -N N- (CH0) -vCH-'223 0 n rH 158-160 1780, 1720 , M / CH, 3 (decomposes) 1680 '18 * ° -N NCHCl 2 / ch 3 O o rH 166-167 1780, 1720, M 3 (decomposes) 1685, 1645 -NwN- (CH 2) 3 CH 3 O 0 -CH 2 CH, 131 HS? ' H? R '^ 23 (decomposes) 1684, 1645 -N N-CH 2 CH 3 52 7 5 8 2 7 (2) To a solution of 6.05 g of diphenylmethyl-7- [2- (2-formamidithiazole-4- yl) -2- (syn) -methoxyiminoacetamide] -3- [1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl] -Δ3 -cephem-4-carboxylate-5 in 31 ml of methanol, 0.5 ml of concentrated hydrochloric acid was added and the mixture was reacted at 35 ° C for 2 hours. When the reaction was complete, the solvent was removed by distillation under reduced pressure. To the residue were added 100 ml of ethyl acetate and 100 ml of water, and the resulting solution was adjusted to pH 6.0 with sodium hydrogencarbonate. The organic layer was then separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and 50 ml of diethyl ether was added to the residue. The crystals were collected by filtration to give 5.1 g (yield 87.7%) of diphenylmethyl-7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide] -3- [1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) / methyl) -Δ 3-cephem-4-carboxylate, m.p. 165-167 ° C.

IR (KBr) cm -1: vc = δ 1780, 1720, 1680, 1640 NMR (d 6 -DMSO) δ values: 1.18 (3H, t, J = 7H 2,> N-CH 2 CH 3), 3.55 (2H, bs, C 2 -H), δ 3.75 (2H, q, J = 7Hz,> N-CH 2 CH 3), 3.90 (3H, s, -OCH 3), 4.41, 5.02 (2H , ABq, J = 15Hz, S v.), 5.26 (1H, d, J = 5Hz, Cg-H), 6.01 (1H, dd, J-5Hz, J * 8Hz, C? -H ), 6. ^ .52, 6.65 (2H, ABq, J = 6Hz, v_ /), hMh

35 NT

6.88 (1 H, s);

S H

II

53 7582 δ 7.07 (1H, s, -CEZ 2), 7.15 - 7.84 (10H, m, x 2), 9.81 (1H, d, J = 8 Hz, -CONH-)

In a similar manner, the brochure compounds were obtained in Table XII.

Table XII

N -C — CONH -f N

H »N —0 I II I 2

2 N /? - —CH2R

0CH3 / F \ COOCH (\ iJ /) 2 (syn-isomer)

Compound IR (KBr) cm -1

~ 2- SP · <° C> "C = O

O O

/ \ 158 - 166 1780, 1720, _ ^ N ~ CH3 (decomposes) 1680, 1640

O O

^ ^ 151 - 156 1780, 1720, -N N- (CH2) 4CH3 (decomposes) 1680, 1640 54 75 82 7 (3) In a mixed solvent of 25.5 ml of trifluoroacetic acid and 7.86 g of anisole was dissolved 5 , 1 g of diphenylmethyl-7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide] -3- [1- (4-ethyl-2,3-dioxo-1 (2,3,4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl) cephem-4-carboxylate and the solution was reacted at room temperature for 2 hours. When the reaction was complete, the solvent was removed by distillation under reduced pressure. To the residue was added 40 ml of diethyl ether 10, and the crystals were collected by filtration to give 4.3 g (yield 91.1%) of 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide] -3 N-1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) / methyl} -N-cephem-4-carboxylic acid trifluoroacetic acid salt with a melting point of 155 -157 ° C (decomposed).

IR (KBr) cm-1s vc_0 1775, 1710-1630 NMR (d 6 -DMSO) δ values: 1.21 (3H, t, J = 7Hz,> N-CH 2 CH 3), δ 3.52 (2H, bs, C 2 - H), 3.73 (2H, q, J = 7Hz,> N-CH 2 CH 3), 3.96 (3H, s, -OCH 3), 4.44, 5.12 (2H, ABq, J = 15Hz, SN), 25 77 | 5.21 (1H, d, J-5Hz, C8-H), 5.83 (1H, dd, J = 5Hz, J = 8Hz, C7-H), 5.86 (3H, bs, -NH®), 6.71 (2H, bs);

H H

II

55 7 5 8 2 7 6.95 (1H, s,), s 9.90 (1H, d, J = 8Hz, -CONH-) 5 In a similar manner, the compounds shown in Tables XIII and XIV were obtained.

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1 S

^ oz 1) 0 ^ 2/62 75827 (4) In 30 ml of water was dissolved 6.35 g of 7- E 5- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide-7- Trifluoroacetic acid salt of η 2 -1- (2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) -N-methyl-β-β-cephem-4-carboxylic acid and the resulting solution were adjusted to pH 7.4 with sodium bicarbonate. This solution was then purified by passing through an Amberlite XAD-2 column to give 4.7 g (86.6% yield) of sodium 7 - [(2- (2-aminothiazol-4-yl) -2- (syn) -methoxy -iminoacetamide [-3- [1- [2,3-dioxo-1,2,3,4-tetrahydropyrazinyl] methyl} -Δ3-cephem-4-carboxylate having a melting point of 200 ° C or advanced.

IR (KBr) cm -1: 1 C = Q 1763, 1670, 1650-1620

In a similar manner the following compound was obtained Sodium 7- [2- (2-aminothiazol-4-yl) -2- (syn) -25-methoxyiminoacetamide] -3- [1- (4-methyl-2,3-dioxo - 1,2,3,4-tetrahydropyrazinyl N-methyl-cephem-4-carboxylate, mp 190-195 ° C (decomposed).

IR (KBr) cm-1: λ max 1760, 1670, 1650, 1630

Example 5 (starting material for Example 6) 20 d) To a solution of 1.68 g of diketene in 8.40 ml of anhydrous methylene chloride was added dropwise a solution of 2.08 g of bromine in 6.25 ml of anhydrous methylene chloride, stirring - At 30 ° C and the mixture was reacted at -30 ° to -20 ° C for 30 minutes. The reaction mixture thus obtained was added dropwise at -30 ° C or below to a solution of 50 ml of anhydrous methylene chloride containing 5.20 g of diphenylmethyl-7-amino-3- (n - (4-ethyl-2, 3-dioxo-1,2,3,4-tetrahydropyrazinyl) -β-methyl-α-cephem-4-carboxylate and 4.08 g of bis (trimethylsilyl) -30 acetamide.

After the dropwise addition was complete, the mixture was reacted at -30 ° to -20 ° C for 30 minutes and then at 0 ° to 10 ° C for 1 hour. When the reaction was complete, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was dissolved in 50 ml of ethyl acetate and 40 ml of water. The organic layer was then separated, washed with 40 ml of water and 40 ml of 63 75827 saturated aqueous sodium chloride solution in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. To the residue was added 50 ml of diisopropyl ether, and the crystals thus obtained were collected by filtration to give 5.85 g (yield 85.6%) of diphenylmethyl-7- (4-bromo-3-oxoethyramido) -3- [1- -ethyl 2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) -methyl-Δ 3 -cephem-4-carboxylate, m.p. 138-142 ° C (decomposed).

10 ir (KBr) cm -1: λ max Q 1778, 1720, 1680, 1640 NMR (dc-DMSO) δ values:

O

1.22 (3H, t, J = 7Hz, NCH2CH3), 3.40 (2H, bs, C2-H), 3.85 (2H, g, J = 7Hz,> NCH2CH3), 3.87 (2H, bs, BrCH 2 COCH 2 -), 4.18 (2H, bs, BrCH 2 CO-), 4.47, 4.96 (2H, ABq, J = 15Hz, S 1), 20 J-CH 2 - 5.04 (1H, d , J = 5Hz, Cg-H), 5.90 (1H, dd, J-5Hz, J = 8Hz, C2-H), 6.15, 6.50 (2H, ABq, J = 6Hz,> = > ();

25 'H H

6.98 (1H, s, -CH <?), 7.40 (10H, bs, - (δ) x 2), δ 8.55 (1H, d, J = 8Hz, -CONH-) 64 7 5 8 2 7 (2) To a solution of 5.50 g of diphenylmethyl-7- (4-bromo-3-oxobutyramido) -3H-d- (4-ethyl-2,3-dioxo-1,2,3,4 -tetrahydropyrazinyl) -methyl β-cephem-4-carboxylate in 30 ml of acetic acid, a solution of 5 ml of water containing 0.74 g of sodium nitrite was added dropwise under ice-cooling over 1 hour, and the resulting mixture was reacted at room temperature for 2 hours. When the reaction was complete, the reaction mixture was poured into 500 ml of water to precipitate crystals.

The crystals were collected by filtration, washed with sufficient water and dried. The resulting crystals were dissolved in 10 ml of chloroform and then purified by column chromatography (Wako Silika Gel C-200, eluent: benzene / ethyl acetate 2: 1, by volume) to give 3.15 g (54.9%) of diphenylmethyl-7. - (4-bromo-2-hydroxyimino-3-oxobutyramido) -3- (1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)) methyl) -4- cephem-4-carboxylate with a melting point of 127-132 ° C (decomposed).

IR (KBr) cm -1: ν 1778, 1720, 1680, 1635 NMR (CDCl 3) δ values: 1.26 (3H, t, J = 7Hz,> NCH 2 CH 1), 3.47 (2H, bs, C 2 -H), δ 3.81 (2H, q, J-7Hz,> NCH 2 CH 3), 4.52 (2H, s, BrCH 2 CO-), 4.53, 4.78 (2H, ABq, J = 15Hz, S · ·,), ^ Ch2- 5.11 (1H, d, J = 5Hz, C8-H), 5.80-6.15 (1H, m, C7-H),

6.13, 6.52 (2H, ABq, J = 6Hz, M>, f * H H

35/7; O 2 (1H, s, -CH <), 7.41 (10H, bs, - <p) x 2), 9.20 (1H, d, J = 8Hz, -CONH-) 65 75827

Example 6 (final product) (1) To a solution of 7.1 g of diphenylmethyl-7- (4-bromo-2-hydroxyimino) -3-oxobutyramido) -3- [4- (4-ethyl-2,3- dioxo-1,2,3,4-tetrahydropyrazinyl) -5-methyl-β-cephem-4-carboxylate in 70 ml of anhydrous methylene chloride, a solution of diazomethane in diethyl ether was slowly added at -5 to 0 ° C. and the resulting solution was reacted at the same temperature for 30 minutes. After confirming the disappearance of diazomethane, the solvent was removed by distillation under reduced pressure. The resulting residue was then purified by chromatography (Wako Silica Gel C-200, eluent: benzene / ethyl acetate 3: 1, v / v) to give 2.32 g (yield 32.0%) of diphenylmethyl-7- [4-bromo-2]. - (syn) -methoxyimino-3-oxobutyramido-3 - [(1- (4-ethyl-1,3-dioxo-1,2,3,4-tetrahydropyrazinyl)}} methyl } - cephem-4-carboxylate with a melting point of 135-140 ° C (decomposed).

IR (KBr) cm -1: vCs = δ 1778, 1720, 1682, 1638 δ NMR (CDCl 3) δ values: 1.25 (3H, t, J = 7Hz,> NCH 2 CH 3), 3.48 (2H, bs , C2-H), 3.84 (2H, q, J = 7Hz, nNCH2CH3), 4.00 (3H, S, -OCH3), 4.10 (2H, s, BrCH2CO-), 4.48, 4.67 (2H, ABq, J = 15Hz, 3-6), 30-2.10 (1H, d, J = 5Hz, C8-H), 6.05 (1H, dd, J = 5Hz, J = 8Hz, C., -H), 6.38, 6.7 δ (2H, ABq, J = 6Hz,),

35 H H

6.98 (1H, s, -CH <), 7.32 (10H, bs, ~ (θ) x 2), 9.18 (1H, d, J = 8Hz, -CONH-) 66 75827 (2) To 14 ml of Ν, Ν-dimethylacetamide was dissolved 2.3 g of diphenylmethyl-7- [4-bromo-2- (syn) -methoxyimino-3-oxobutyramido] -3- [1- (4-ethyl-2 (3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl 4-N-cephem-4-carboxylate and 0.32 g of thiourea and the resulting solution were reacted at room temperature for 3 hours. When the reaction was complete, the reaction mixture was poured into a mixed solvent of 50 ml of water and 250 ml of ethyl acetate. Sodium bicarbonate was then added to adjust the mixture to pH 6.7 and the organic layer was separated.

The aqueous layer was further extracted with 2 x 100 mL portions of ethyl acetate. The combined organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solution was removed by distillation under reduced pressure, 20 ml of diethyl ether was added to the residue, and the crystals were collected by filtration to give 1.92 g (yield 86.3%) of diphenylmethyl-7- -aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide] -3- [L] - (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl N-ke-20 pheme-4-carboxylate with a melting point of 165-167 ° C.

IR (KBr) cm-1: ν max = 1780, 1720, 1680, 1640.

The same ring closure reaction 25 above was carried out and then the reaction mentioned in Example 4 to (3) was carried out to obtain the compounds shown in Tables XV and XVI.

(I

67 7 5 8 2 7

Table XV

N - r — C- CONH __ ^ S \

CF-.COOH.H ~ N - (/ | H I

\ n ^> N 0J — n yii-CH2H2

0CH3 COOH

(syn isomer) r2 ^ 72? δ ö -N n_CH3 ° W ° -N_N- (CH2) 4CH3 ° x y.0 Ov 0 ^ —f ^ —f "

-N ^ _ ^ NCH2CH3 -N ^ _ ^ NH

Vf ° / C „3

-N N-CH

= y ch3 ° H ° -N N (CH -), CH., \ _ / 68 75827

Table XVI

M ..S

/ N— C CONH —- S \ H2N _ // I II Γ]

'S - N J N / J CH0R

\ 0 ^ 2

OCH3 I

COOR1 (syn-isomer) R1 R2

O O

-CHOCOC (CH3) 3 -N NCH2CH3 ch3O2 -CHOCO (CH-.) -N NCH- | 3 3 \ = / 3 ch3 O, -CHOCOC (CH.) 0 -N N- (CH0) .CH, | 3 3 \ / 243 CH3

P P

y ~ K

-CH2OCOC (CH3) 3 -N ^ JCH2CH3 (continued ...)

II

^ 75827

Table XVI (continued) ---- j ---— 0, 0 / Mi -CH0C00C (CH.,), —N NCH.CH, | 3j3 2 3 CH3

^ o O

-ν ^ νοη2οη3 -CH C = C-CH3 V ^ ° d o -n ^ nch2ch3

M

o i --—- *) hydrochlorides

The physical properties (m.p., IR and NMR spectra) of the above compounds were the same as those obtained in Examples 6, 11 and 12.

70 7 5 8 2 7

Example 7 (final product) (1) To a suspension of 2.2 g of 2- (2-formamidithiazol-4-yl) glyoxalic acid in 11 ml of N, N-dimethylacetamide was added dropwise 1.8 g of phosphorus oxychloro-5 dia. At -20 ° C and the resulting mixture was reacted at the same temperature for 2 hours. To this reaction mixture was then added a solution of 26 ml of methylene chloride containing 5.2 g of diphenylmethyl-4-amino-SC1- (4-ethyl-2,3-dioxo-1,2,3,4- tetrahydropyrazinyl) -10-methyl-β-cephem-4-carboxylate at -30 ° C to -20 ° C. After the dropwise addition was complete, the mixture was reacted at the same temperature for 1 hour.

When the reaction was complete, 70 ml of water and 50 ml of methylene chloride were added to the reaction mixture. Sodium hydrogen carbonate was then added to sii-15 to adjust the mixture to pH 6.5, and insolubles were removed by filtration. The organic layer was then separated, washed with 100 ml of water and 10 ml of saturated aqueous sodium chloride solution, respectively, and dried over anhydrous magnesium sulfate.

The solvent was then removed by distillation under reduced pressure. The residue was purified by column chromatography (Wako Silica Gel C-200, eluent: chloroform / methanol = 20: 1, by volume) to give 1.4 g (yield 20.0%) of diphenylmethyl-7- [2- (2-formamide). - thiazol-4-yl) glyoxylamide-3 - [(4-ethyl-2,3-

O

dioxo-1,2,3,4-tetrahydropyrazinyl) methyl) -4-cephem-4-carboxylate with a melting point of 140-145 ° (decomposed).

Δ 7582 δ IR (KBr) cm -1: ν> 0 1780, 1720, 1680, 1670, 1640 NMR (d 6 -DMSO) δ values: 1.20 (3H, t, J = 7Hz,> NCH 2 CH 3), δ 3.50 (2H, bs, C 2 -H), 3.69 (2H, q, J = 7Hz,> NCH 2 CH 3), 4.40, 5.00 (2H, ABq, J = 15Hz), 10 5, (1H, d, J = 5Hz, C 8 H), 6.00 (1H, dd, J = 5Hz, J = 9Hz, C 6 -H), 6.50, 6.62 (2H, ABq, J = 5Hz,),

H H

7.04 (1H, s, -CHCl 3), 7.30 (10H, bs, - (O) x 2), 8.64 (1H, s, Ν-, ρ),

S ^ H

Δ 8.81 (1H, s, HCONH-), 10.20 (1H, d, J = 9Hz, -CONH-), 12.90 (1H, bs, HCONH-) 25 72 7 5 8 2 7 (2) To the solution with 7.0 g of diphenylmethyl-7- (1- (2-formamidothiazol-4-yl) glyoxylamide] -3- [1- (4-ethyl-2,3-dioxo-1,2,3,4- tetrahydropyrazinyl) -N-methyl-A-cephem-4-carboxylate To 35 ml of N, N-di-5-methylacetamide, 1-7 g of methoxyamine hydrochloride was added under ice-cooling, and the resulting mixture was reacted at 15-20 ° C. When the reaction was complete, the reaction mixture was poured into a mixed solvent of 250 ml of water and 250 ml of ethyl acetate, and the organic layer was separated, washed with 250 ml of water and 250 ml of saturated aqueous sodium chloride solution, respectively, and The solvent was then removed by distillation under reduced pressure, 50 ml of diethyl ether was added to the residue, and the resulting crystals were collected by filtration to give 6.1 g (yield 83.7%) of diphenylmethyl-7- [2- (2-formamidithiazole). 4-yl) -2- (syn-methoxyiminoacetamide-3- [1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl] -N cephem-4-carboxylate, m.p. 165-168 ° C.

IR (KBr) cm-1: ν max 1780, 1680, 1640.

The same oximation reaction described above was carried out and then the reaction mentioned in Example 4 (2) and (3) was carried out to give the compounds shown in Tables XVII and XVIII.

Il 73 7 5 827

Table XVII

P —j C CONH -S 'S X.

The CF, COOH. H_N —0 I | l '2 \ S ^ N o ^ ~ -N ^ J-CH2r'

OCH. I

3 COOH

(Syn isomer)

R R

Vf ° i -N N-CH 3! 0 0 0 0 'y ~ ^ y f -N N- (CH2) 4CH3 -n N (CH2) 2ch3! ° v ^ 0 7 \ ch3

-N N-CH

\ ^ / CH3! -O 2 - (CH 2) 3 CH 3 V

-N NCH2CH3 -N NH

J____ 74 7582 7

Table XVIII

N —I-C-CONH-f X

H H - // I II '_ \ S ^ J ^ CH ^

° CH T

COOR1 (syn-isomer) R1 R2

O P

-CHOCOC (CH3) 3 N NCH2CH3 CH3 P / 0 -CHOCOC (CH ~) - -N NCH, | 3 3 \ - / 3 ch3 O, -CHOCOC (CH,) - -N N- (CH-) .CH, | o o \ / Z 4 j ch3

W

-CHOCOC (CH-), -N N- (CH-) - CH, | 3 3 N- / 2 5 3 CH3 (continued ...) 75 7582 7

Table XVIII (continued) ° v, 0 -CH 2 OCOC (CH 3) 3 -N 2 CH 2 CH 3 0 .0 -CHOCOOC (CH 3) -N NCH-CH. 3 3/2 3 CH3

(1 Q P

.o - \ Y -NwNCH2CH3 -CH C-C-CHj ° V-f ° o o nch2ch3 Ύ w

O

hydrochloride

The physical properties (m.p., IR and NMR spectra) of the above compounds were the same as those obtained in Examples 4 and 8.

76 75827

Example 8 (final product) (1) In a mixed solvent of 37 ml of trifluoroacetic acid and 10.8 g of anisole was dissolved 7.29 g of diphenylmethyl-7- [2- (2-formamidithiazol-4-yl) -2- (syn) -methoxy-5-iminoacetamide, 7-3- [1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl] -N- cephem-4-carboxylate and the resulting solution was reacted at room temperature for 2 hours, when the reaction was complete, the solvent was removed by distillation under reduced pressure, 50 ml of diethyl ether was added to the resulting residue, and the crystals were collected by filtration, washed sufficiently with 50 ml of diethyl ether. dried to give 5.2 g (yield 92.4%) of Ί-ζ2- (2-formamidothiazol-4-yl) -2- (syn) -methoxyiminoacetamide, 7-3- [1- (4-ethyl-2 , 3-dioxo-15 (1,2,3,4-tetrahydropyrazinyl-4-methyl) -Δ3- (6θθΐθθΐηΐ-4-carboxylic acid, m.p. 155-158 ° C (decomposed) · IR (KBr) cm-1: * Q = Q 1775, 1710, 1675, 1640 NMR (dc-DMSO) δ values:

O

1.20 (3H, t, J = 7Hz,> NCH 2 CH 3), 3.49 (2H, bs, C 2 -H), 3.73 (2H, q, J = 7Hz,), 3.91 (3H, s, -OCH 3), δ 4.42, 4.95 (2H, ABq, J = 15Hz, S.), 5.21 (1H, d, J = 5Hz, C 9 H), 5.89 (1H, dd, J = 5Hz, J = 8Hz, C - H), 30 '6.65 (2H, bs, V = K), 9 rl n

Nir 7.46 (1H, s, U),

S / XH

35.59 (1H, s, HCONH-), 9.77 (1H, d, J = 8Hz, -CONH-), 12.58 (1H, bs, HCONH-) 77 7 5 8 2 7

In a similar manner, the compounds shown in Table XIX were obtained.

Table XIX

S

N - C- CONH-1-f N

HCONH —0 | Il J_N CH "R2 \ s ^" Y 2

0CH3 COOH

(Syn isomer)

Compound IR (KBr) cm-1 --—— Sp. (<-)

R2 'C - O

0 oyf 195 - 198 1775, 1720, „^ ~ CH3 (decomposes) 1680 - 1640 ° w ° -N N- (CH2) 4CH3 122" 125 1775 '168 °' ^ / (decomposes) 1640 78 75827 (2) To the solution containing 5.63 g of N- [2- (2-formamide-thiazol-4-yl) -2- (syn) -methoxyiminoacetamide] -3- [1- (4-ethyl-2,3-dioxo- 1,2,3,4-tetrahydropyrazinyl), p-methyl-Δ3-cephem-4-carboxylic acid in 25 ml of Ν, Ν-dimethylacetamide, 1.52 g of 1,8-diazabicyclo [ 4.0-7-7-undecene and 3.84 g of 1-pivaloyloxyethyl iodide under ice-cooling, and the resulting mixture was reacted for 30 minutes, and when the reaction was complete, the reaction mixture was poured into a mixed solvent of 100 ml of water and 100 ml of ethyl acetate. the layer was separated, washed with water and dried over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, 50 ml of diethyl ether was added to the residue, and the crystals were collected by filtration to give 5.5 g (yield 79.6%) of 1-pivaloyloxyethyl 1-. 2-formamiditiatsol-4-yl) -2- (sy n) -Methoxyiminoacetamide-3- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) methyl] -3-cephem-4-carboxylate with a melting point of 140- 142 ° C.

20 IR (KBr) cm -1: J = Q 1780, 1740, 1680, 1640.

In a similar manner, the compounds shown in Table XX were obtained. In this case, the compounds shown in Table XX can be obtained by the same method as in Example 6- (1), except that the diphenylmethyl esters were replaced with the corresponding esters.

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z O m x · 5 m s is cm ^

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XX XX x

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so 75827 *

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r- vo vo

1-1 <H

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2 O

100 O CNJ

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r-H

i% * O o in vo oo ^ l i- vo n- - ~ «.

2 2 o o 00 00 rH rj.

p "* 00 VO

· “· Ή H 1-1 cn m ot» - «iH VO VO '^

• H —I i-l O

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C/O

ro ro B

S K o

u U <N

<N PM 33 1: Λ Λ: χί) i "1 1 1« Vi ----- 0) * +> X * «„ C / <0 O »τΓ1 · η S * _ po Ό S Ho ok 3 -Τ '\\ u .o, - | § ° ^ o) »o == o PO oT ^ O /

S K K

.0-0 ot "-" · 81 75827 (3) To a solution of 5.5 g of 1-pivaloyloxyethyl-7- [2- (2-formamidithiazol-4-yl) -2- (syn) methoxy -iminoacetamide β-3 - {"[1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl] methyl} -cephem-4-carboxyl-5-ylate obtained in ( 2), in 27.5 ml of methanol, 1.13 ml of concentrated hydrochloric acid was added, and the resulting mixture was reacted for 2 hours at 35 ° C. When the reaction was complete, the solvent was removed by distillation under reduced pressure. and 50 ml of water and the mixture was adjusted to pH 6.0 with sodium hydrogen carbonate, then the organic layer was separated and dried over anhydrous magnesium sulfate, then the solvent was removed by distillation under reduced pressure, 45 ml of diethyl ether was added to the residue, and the crystals were collected by filtration g (yield 88.1%) 1-pivaloyloxyethyl-7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide] -3- 1- (4-ethyl-2 , 3-dioxo-l , 2,3,4-tetrahydropyrazinyl (methyl) -Δ 3 -cephem-4-carboxylate-20 having a melting point of 148-150 ° C.

IR (KBr) cm -1: ν max δ 1780, 1740, 1680, 1640 NMR (d 6 -DMSO) δ values: 0.90-1.39 (12H, m, -C (CH 3> 3,> NCH (H 2), 25 - 1.52 (3H, d, J = 5Hz, -OCHO-), ch 3 3.52 (2H, bs, C 2 -H), 3.76 (2H, q, J = 7Hz,> NCH 2 CH 3) , 3.88 (3H, s, -OCH 3), 4.38, 5.04 (2H, ABq, J = 15Hz, S '), 82 7 5 8 2 7 5.21 (1H, d, J = 5Hz) , C6-H), 5.87 (1H, dd, J = 5Hz, J = 8Hz, C7-H), 6.61 (2H, bs,) c = s (),

5 H H

6.78 (1H, s, N-jj-), s ä 7.04 (1H, q, J = 5Hz, -OCHO-),

10 I

CH 3 7/22 (2H, bs, -NH 2), 9.67 (1H, d, J = 8Hz, -CONH-) In a similar manner, the compounds shown in Table XXI were obtained.

li 83 7 5 8 2 7 - - »X -« rt Λ (Nm v

- ^ X 'N X

- U N X - (N x.

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Preparation Example 1 1- (2- (2-Aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide-3- [1- (2,3-dioxo-1,2,3,4-tetrahydro-pyrazinyl) The aqueous sodium salt solution of 4-methyl} -N-cephem-4-carboxylic acid was treated in a conventional manner to obtain a lyophilized and sterilized sodium salt. One gram of (effective) sodium salt was dissolved in 20 ml of physiological saline to obtain a solution for injection.

10 Preparation Example 2

One gram (effective) of the lyophilized product obtained in Preparation Example 1 was dissolved in 4 ml of 0.5% (w / v) aqueous lidocaine hydrochloride solution to obtain a dilutable injection solution.

Preparation Example 3

One gram (effective) of the lyophilized product obtained in Preparation Example 1 was dissolved in 20 ml of a 5% glucose solution to obtain a solution for injection.

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

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Claims (7)

9i 75827 A process for the preparation of a therapeutically useful 7-thiazolyl-3-pyrazinylmethyl-5 cephalosporin of formula I and pharmaceutically acceptable salts thereof, g N - A - CONH - nR COOR1 wherein R 1 is a hydrogen atom or an ester group selected from C 1-6 acyloxy-C 1-5 alkyl, phthalidyl and 5-C. alkyl-2-oxo-1,3-dioxol-4-yl-1-methyl and a group of the formula -CH-OCOOR in which • 22 R 21 22 20. and R may be the same or different and are 2 C 1-5 alkyl groups; R is a group of the formula 6 - N N - R 6, wherein R is a hydrogen atom or a C 1-6 alkyl group; R 5 is an amino group which may optionally be protected by an amino group protecting group; and A is a group such that - C- I? ] Q 1a is of the formula “18, wherein R is a C 1-4 alkyl-? OR 6 (syn) group, characterized in that a) a compound of the following formula or a salt thereof 35 I 2 J- N o COORla 92 7 5 8 2 7 wherein R * a is a hydrogen atom or a carboxyl group protecting group; R is an amino group; and R is as defined above, to react with a compound of the following formula Process according to Claim 1, characterized in that 7 - [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- [2- 3-dioxo-1,2,3,4-tetrahydropyrazinyl] methyl-N, N-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof. 2 II s wherein R 5 is as defined above, or II 93 75827 c) giving a compound of the following formula or a salt thereof S Process according to Claim 1, characterized in that 7- (2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide) is prepared. -2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) -N-methyl-N-cephem-4-carboxylic acid or a pharmaceutically acceptable salt thereof. 4. 7-Amino-pyrazinylmethylcephalosporin, characterized in that it has the formula S X-N. - CH 2 R 2 and COOR 1 35 NH 2 - ^ ^ 94 7 5 8 2 7 wherein R 1 is a hydrogen atom or a carboxyl group protecting group; 20; and R is a group of formula '' c. , wherein N N * -R 0 R 2 is a hydrogen atom or a C 1-6 alkyl group. Compound according to Claim 4, characterized in that it is 7-amino-3- [1- (2,3-dioxo-1,2,3,4-tetrahydropyrazinyl) 7-methyl] -N3-cephem-4 -carboxylic acid or an ester or salt thereof. 5 N - COCONH —-S RMU1 oJ- “Y ^“ CHZR2 COORla 10 la 2 5 wherein R, R and R are as defined above, to react with a compound of the following formula 1 o h2nor 15 18 wherein R is as defined above above, or with a salt thereof, and, if desired, after step a), b) or c), the protecting group is removed or the product is converted into a pharmaceutically acceptable salt. 5 A-COOH N - \ R5 ^ S- 5 wherein R and A are as defined above, or with a reactive derivative thereof of a carboxyl group, or b) a compound of the following formula or a salt thereof is obtained 15 S xch2co-a-conh - ^ | Wherein X is a halogen atom, and R a, R 1 and A are as defined above, to react with a compound of formula H-NCR 5 Compound according to Claim 4, characterized in that it is 7-amino-3 - [(1- (4-ethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazinyl)). - N-Cephem-4-carboxylic acid or its ester or salt Li 95 7 5 8 2 7