JPS6019792A - Cephalosporin derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R1 is group of formula II or III(R<3> is H or lower alkyl); R2 is H or lower alkyl]. EXAMPLE:syn-Isomer of 7beta-[2-(2-aminothiazol-4-yl)-2-{(1,2,4-triazol-3-yl)methoxyimino}ace tamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate. USE:Antibacterial agent against Gram-positive and Gram-negative bacteria. PREPARATION:The objective compound of formula VIII is prepared by acylating the comound of formula VII with the compound of formula IV [R4 is H or amino-protecting group such as triphenyl-methyl, formyl, etc.; R5 is group of formula V or VI (R6 is H or amino-protecting group such as trityl)] preferably in the presence of a condensation agent such as Vilsmeier reagent. If necessary, the protecting group is removed from the product.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a cephalosporin derivative represented by the following general formula and a salt thereof.

Ra represents hydrogen or lower alkyl.

As a result of research on various cephalosporin derivatives, the present inventors discovered that the novel compound represented by the above formula (1) exhibits high antibacterial activity against a wide range of Gram-negative bacteria and Gram-positive bacteria, and 2 completed the present invention. did.

The deazole moiety, which is a part of the structure of the compound of the present invention and its synthetic intermediate, is thought to take a tautomer form of a 2-aminothiazole form and a 2-iminothiazoline form. Throughout this specification, structural and name references to 2-aminothiazole compounds are not meant to be limiting.

Similarly, 1, 7% 4-t'J azole and 1.2.8 which are part of the structure of the compound of the present invention and its intermediates
It is thought that several types of tautomers P1: structures with different substitution positions of -1-lyazole hydrogen may be taken. In this specification, these are representatively explained as one type of structure, but this is not meant to be limiting.

Furthermore, the compounds of the present invention having an oximino group and their synthetic intermediates (j, syn isomer (,T) and anti-isomer) exist, and one or a mixture thereof can be obtained. However, in general, the syn isomer is superior in antibacterial activity.

(J) (K) Next, the method for producing 9 Compound (1) of the present invention will be described in detail.

(R= represents hydrogen, triphenylmethyl (abbreviated as trityl), formyl, tertiary butoxycarbonyl, and other protecting groups for amino groups used in the synthesis of peptides and β-lactam compounds. The fingers are trityl, formyl, etc.) , which represents a protecting group for the amine 7 group used in the synthesis of peptides and β-lactam compounds, such as tertiary butoxycarbonyl, is acylated to obtain a compound represented by the formula 9. This acylation reaction can be carried out in the presence of a condensing agent. Examples of the condensing agent include the so-called Vilsmeier reagent produced from dicyclohexylcarbodiimide, dimethylformamide, and phosphorous chloride. Acylation can also be carried out after converting the compound (I) into a reactive derivative such as an active form such as an acid halide or an active ester. Suitable examples include acid chlorides, esters with N-hydroxy compounds such as N-hydroxysuccinimide and 1-hydroxybenztriazole, and the like. This reaction involves methylene chloride and tetrahydrofuran.

It is carried out in ethyl acetate, dimethylformamide or other solvents that do not adversely affect the reaction. Moreover, these reactions are appropriately selected depending on the type of compound (II) 5 − used.

From the compound (5) thus obtained, the compound represented by formula (I) can be obtained by removing the protecting group, if necessary. Removal reactions of protecting groups include hydrolysis,
This can be done by reduction etc.

Hydrolysis using acids is one of the most common methods,
It is a preferred method for removing protecting groups such as trityl, formyl, and tertiary butoxycarbonyl. The acids used include organic acids such as formic acid and trifluoroacetic acid, or inorganic acids such as hydrochloric acid. In this case, a solvent that does not adversely affect the reaction may be used, and the reaction may be carried out in the presence of a scavenger such as anisole or thioanisole.

Hydrolysis with a base is used to remove acyl groups, and an inorganic base such as sodium hydroxide or an organic base such as triethylamine is used. Further, in the case of a haloalkoxycarbonyl group such as trichloroethoxycarbonyl, the L-protecting group can be removed in the -0- reduction reaction.

In addition, using compound (n), formula 2 (R7 represents lower argyl, I (8 represents hydrogen or a protecting group for carboxylic acid used in the synthesis of β-lactam compounds such as tertiary butyl and benzhydryl) After the compound shown is acylated to obtain the compound shown by formula 9, if necessary, a protecting group can be added to obtain the compound shown by formula 9.The acylation reaction is performed by acylating compound (2) with compound rn). Similarly, the protecting group removal reaction is also performed on the compound (
It can be carried out under the same conditions as in the case of removing the protective group from 3). By reacting the compound (b) thus obtained with the compound represented by the formula (1),
) can be obtained.

The reaction between (5) and (4) may be carried out in the presence of sodium iodide, potassium iodide, sodium bromide, potassium thiocyanate, or the like.

The 9 reactions are also advantageously carried out in an aqueous solvent of p)I 5-8.

Furthermore, there is a method of acylating a compound represented by Formula 1 (X represents a halogen such as chlor or bromine) using the above-mentioned compound (n) to obtain an intermediate represented by Formula 9. The acylation reaction is
The reaction can be carried out in the same manner as in the case of acylating l] with a compound mill.

Then, the intermediate head is reacted with the above-mentioned compound (4) to obtain the compound shown. This reaction can be carried out in acetone, dichloromethane, acetonitrile, or any other solvent that does not adversely affect the reaction.

Next, compound (1) can be obtained by converting the sulfoxide of intermediate α0 into sulfide and then removing the protecting group. The reaction of deoxidizing the sulfoxide to form the sulfide can be carried out using reagents such as phosphorus trichloride, phosphorus king bromide, acetyl chloride and stannous chloride, and acetyl chloride and potassium iodide. Further, the reaction for removing the protecting group can be carried out in the same manner as in the case of removing the protecting group from compound (8).

Compounds of formula (I) are alkali metals, alkaline earth metals or derivatives thereof, such as hydroxides.

It is also possible to obtain a form in which the 4-position carboxylate becomes an alkali metal or alkaline earth metal salt by reacting it with a carbonate or the like by a conventional method.

The compound of formula (1) can be formed into a suitable acid addition salt, for example, as a -hydrochloric acid or dihydrochloride salt, or as a salt with an organic acid such as formic acid or maleic acid.

Compound (I[) used in the synthesis of compound (1) is 9 For example, a compound represented by the formula 9 and 9 IJH=QCH2-1? It can be obtained by reacting the compound represented by II[["110- with li. As the reaction solvent, use a solvent that does not have any adverse effect on the reaction, such as water, ethanol t, r, etc. I can do it.

The above compound (XI') can be prepared by reacting a compound represented by formula % [:) with N-hydroxy 7-talimide, or by reacting a compound represented by the formula with triphenylphosphine and diethyl azodicarboxylate, etc. It can be obtained by reacting with a reagent to obtain a compound represented by Formula 9, and then treating this compound with hydrazine or hydrochloric acid.

Also, compounds where R6 in the structure of Ra is hydrogen [Notification]
After carrying out a reaction to introduce a protecting group, R6 can be treated with, for example, hydrazine, so that R6 can be converted to trityl, pormyl,
Corresponding compounds such as tertiary butoxycarbonyl [
■] can be obtained.

The compound of the present invention exhibits a broad antibacterial spectrum and high antibacterial activity, but in particular Ps.
, it also has the feature of showing antibacterial activity against P. aeruginosa.

The following table compares the antibacterial activity of some compounds of the present invention with that of cefotagime.

Antibacterial Spectrum Minimum Inhibitory Concentration Compound Ania β-(2-(2-aminothiazole-4-
yl)-2-(:(11214-triazole-8-
Compound B nia β-[2-(2-aminothiazole-4-
yl)-g-((1,,2,a-triazol-4-yl)methoxyimino)acetamide)-8-(]-pipyridinismethyl-8-cephem-4-carboxilade (
syn isomer) Example] 7β-(2-(2-aminothiazol-4-yl)-2
-(1,2,4-)lyazol-8-yl)methoxyimino)acetamide)-8-(1-pyridiniomethyl)-
8-cephem-4-carboxilade (syn isomer) [Step 1] Ethyl N-trityl-1,,2,4-)riacee 18
- Suspending 0.869 of lyazole-3-carboxilade (ethyl 1,2.4-) in methylene chloride,
Trityl chloride 1°67 and triethylamine 1
．． 04 was added dropwise and stirred at room temperature for 1 hour. 10% citric acid solution 9 Then washed with saturated saline and anhydrous sulfuric acid) I
Dry with Jum.

The solvent was distilled off to obtain 2.69 g of the title compound as a pale yellow electric oil.

OW-NM 几 (0DCJIs + Ao) 1.87 (8H, t, J-7) IZ, 0H20B
3) 4.46 (2H,q, J-7Hz, OHg
OHa ) 7.1-7.4 (15H, m, ) Riazole) 8.02 (IH, s, ) Riazole H at position 5) [
Step ■〕 8-(Hydroxymethyl)-N-) Reasy 1.2.4
-) Add 0.289 g of lithium aluminum hydride of lyazole to 80 g of tetrahydrofuran to this suspension.

Compound 2.65914- obtained in [Step I] under water-cooling and stirring A 10-solution of tetrahydrofuran is added dropwise.

After heating under reflux at 80°C for 1 hour, cool. Add water, filter, reduce the filtrate to 1 ml (dry to dryness, and wash the residue with ether to obtain 1830 ml of the title compound, melting point 208-212°C.

OW -N M R (CI) C13, all) 4゜78 (
2H, +1. -0 town OTT )7.0~7.4 (15
] f, m, trityl) 7.95 (IH, 11,) H at the 5th position of lyazole) Elemental analysis Calculated value for 022H19N30 C77,3Sl, I+ 5.61. N
12.31 Actual value 077.20. ](5,85,N
12.12 [Step ■] 8-(7talimidoxymethyl)-N-trityl-1
,,2,4-) Riazole [Step 1] 1.02 ml of the compound obtained in step 1 was wetted and dissolved in 8 ntnl of tetrahydrofuran, and 0.419 ml of N-hydroxyphthalimide and 0.419 ml of triphenylphosphine were added.
79 g and ethyl azodicarboxylate o, rrq9 were added sequentially at room temperature and stirred overnight. After distilling off the solvent, the product is purified twice by column chromatography using silica gel as a carrier (first time, chloroform:methanol-19:1β, second time, ethyl acetate:benzene-1:4).

0.562 of the title compound is obtained, melting point 254-257°C.

1780.1780, 1490.14400W-NM
R(0DO13,ppH1)5.28 (2H,s,
N0OH2) 7.0~? . 4 (15I(+1711
) real) 7.75 (4H, a, phthalimide) 7
, f)? (IH, s, ) Riazole 5th position ■) [
Step ■] 8-(ami/oxymethyl)-N-trityl-1,2,
0.559 of the compound obtained in 4,-triazole [Step 1] was added to 2 Qt of ethanol.
After adding an ethanol solution of 0.0 μl of hydrazine hydratro, the mixture was heated and stirred at 80° C. for 1.5 hours. The precipitated crystals were removed by filtration, the solvent was distilled off, chloroform was added to the residue, insoluble matter was removed by filtration again, and the filtrate was washed with saturated brine. Dry with anhydrous sodium sulfate.

After distilling off the solvent, if the remaining liquid is washed with ether, the melting point is 105 ~
0.40 ml of the title compound is obtained at 110°C.

OW - N M R (0DOls + l'rfl'
)4.80 (zn, s, Noarh-)5.60
(2H, br, H2N0-)7.1~7.4 (
15I1. m, ) real) 7.03 (IH, g,
)H at the 5th position of lyazole) [Step ■] 2-(2-)rithylaminothiazol-4-yl)-2
-((N-trityl-1,2,4-triazole-8-
・Methoxyimino)acetic acid [Step 1] Dissolve 0.409 of the compound obtained in 15 va/ml of ethanol, (2-)
Add 0.409 glyoxylic acid (cutylaminothiazole-4-I/I/) and stir at room temperature for 1 hour. After evaporating the solvent.

The residue is dissolved in chloroform and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue is washed with ether 17- to obtain the title compound with a melting point of 128-185°C.
Get 89.

OW-NMR (0DCIs, IIP) 5.50 (2
H, s, NOOIi-) 6.75 (LH, a, ■ at thiazole 5th position) 7.0-7.4 (15H, m, )
real) 8.08 (IH, s, )H at the 5th position of lyazole) [Step ■] 7β-C2-(2-aminothiazol-4-yl)-2
-((1,2,4-triazol-8-yl)methoxyimino)acetamide)-8-(1-pyridiniomethyl)
-8-cephem-4-carboxilade (syn isomer) in methylene chloride under water cooling, dimethylformamide 0.77
Add phosphorus oxychloride Q, 91w+t to fnl.

■ Prepare a total of 10-reaction mixtures. Dissolve 0.76 ml of the compound obtained in [Step M] in 8fILt of methylene chloride,
Add the reaction mixture 2.0- while cooling with water.

Stir for 45 minutes. This reaction solution was converted into 7β-ami18-no8-(1-pyridiniomethyl)-8-cephem-
0.75 g of 4-carboxyl-1...dihydrochloride and bis(
The mixture was added to a solution of 0.9-(trimethylsilyl)acetamide in 8-acetonitrile under water cooling, and then returned to room temperature and stirred for 1.5 hours. The reaction solution was diluted with chloroporum, washed with water and then with saturated saline, and dried over anhydrous sulfuric acid.

After distilling off the solvent, washing the remaining liquid with ether yields a light brown powder 7.
Get 80 ■.

This powder is added to a water-cooled mixture of 98% formic acid (8-) and concentrated hydrochloric acid (0.4-), and after 10 minutes the mixture is returned to room temperature and stirred for 1 hour. The precipitated solid is removed by filtration, and the filtrate is concentrated under reduced pressure. Dissolve the residue in water and perform column chromatography using Diaion HP-20 as a carrier (2.5% tetrahydrofuran).
1. High performance liquid chromatography, - (Carrier: Partsil (manufactured by Whatman); Medium: 10% methanol)
Purification to give the title compound.

1770.1flflO, 1610 F T -N M R (D20 + pl”, 200
MHz) 8.14 (IH, d, J-18Hz,
02-H) 8.68 (IH, d, J-18Hz,
02-H)'6.25 (IH, d, J-5Hz,
Ca-H)5.86 (2H, a, N-0-0, &
) 5.59 (Rule d, J-14Hz, CHzNDO)
5.87 (IH, d, J-5Hz, 07-H)7
．． 04 (IH,s, H at 5-position of thiazole) 8.12
(211,t, J-7Hz, H at position 8.5 of pyrimidine
)8.137 (1N!, s, )H at position 5 of lyazole) 8.62 (IH, t, J-7Hz, H at position 4 of pyrimidine) 8.99 (2H, d, J-7Hz, pyrimidine 2, 6th place ■) Elemental analysis 0211 (to l058
Calculated value for 2.2+H2o 042.99. ,H
4,12,N 21.49 Actual value C48,21,H4
,04,N 21.10 Example 2 7β-(2-(2-aminothiazol-4-yl)-2
-((1,2,8-triazol-4-yl)methoxyimino)acetamide)-a-(+-pyridiniomethyl)-8-cephem-4-carboxyl-1.(synMt
t/l form) [Step I] Ethyl N-)lythyl-1.2.8-)lyazole-
4-carboxylic toethyl 1. ．． 2.8-) Riazole-4-carboxylar) 8.4.77 and 5J and trityl chloride7.
Dissolve 552 in 100ml of chloroporm.

,=h under water cooling and stirring, 1.Liedylamine 877- was added dropwise to the solution, and the mixture was stirred at room temperature for 80 minutes. After distilling off the chloroform,
The residue was dissolved in ethyl acetate, washed with brine, and dried over anhydrous sulfuric acid.

Ethyl acetate is distilled off to obtain a crystalline solid. This was subjected to column chromatography (silica gel = 10og, MW:
If purified with benzene and then chloroform), the melting point is 2.
The title compound (8,879) is obtained at 01-208°C.

OW-NMR ((JT)0/3.ppm) 1.87
(BIT, t, J-7, FiT(z, 0H20H
s)-21-4,89(2H,q, J-7,5Hz, 0H20H
3) 8.01 (IH, 8,) Riazole 5th position ■) [
Step ■] 4-(Hydroxymethyl)-N-)rityl-1.2.8
-) Liazole Lithium aluminum hydride 1.29 g was suspended in tetrahydrofuran 10 (1@/), and then compound 13.Qg obtained in water-cooled stirring [Step I] was prepared using 800 tn of tetrahydrofuran.
t solution (partial suspension) was added dropwise and stirred at room temperature for 8 hours.

Add 1.8 frLt of water to the reaction solution, then 15% hydroxide)
Carefully add 1.8 ml of IJum aqueous solution and 8.0 mL of water. After filtration, the filtrate is dried under reduced pressure to precipitate a pale yellow solid. Add ro-hexane to this, collect the solid by filtration, wash with ro-hexane, and dry under reduced pressure to obtain a melting point of 205~
11.4 of the title compound is obtained at 207°C.

OW-NMR (CDO/3.ppm) 4.78 (2
H, s, 0OH2) [Step ■] 4-(phthalimidoxymethyl)-N-)22-rityl-1.2.8-triazole [Compound obtained in Step ■], 7.59. 8.49 g of N-human p-xyphthalimide and 14° El of triphenylphosphine were dissolved in 700 g of tetrahydrofuran, and 9.8 g of diethyl azodicarboxylate was added under stirring at room temperature.
Stir for 1 hour at room temperature. After distilling off the solvent, chloroform was added to the residue and the mixture was dried under reduced pressure to precipitate a slight solid. A large plate of solid precipitates out when diethyl ether is added. This is collected by filtration, dried under reduced pressure, and then methylene chloride is added. Insoluble matter is filtered and dried under reduced pressure to obtain 24.5 gft of powder. This was subjected to column chromatography (silica gel: 5oO).
Solvent: If purified with chloroporum), the melting point is 195-2.
14.2 g of the title compound 00''C are obtained.

Ill vKB"cm-': 1790.1.780
ax OW -NM It (01)O7a, 4)5.86
(2H,n, 0OH2) [Step ■] 4-(acetoxymethyl)-N-)real-1,2,8
Compound 16.17 obtained in -1-lyazole [Step 1] was mixed with methanol 300 ml.
-, add 1.7 g of hydrazine hydrogen chloride, and stir at room temperature for 1.5 hours. After filtration, the solvent is distilled off. After adding chloroform to the residue and filtering off insoluble matter, the filtrate is dried under reduced pressure (this operation is repeated 8 to 4 times). The residue is purified by column chromatography (silica gel = 200, solvent: chloroform) to obtain the title compound 9.57 having a melting point of 144-145°C.

OW-NMR (CD0Is, fall) 4.79 (2T(,'s, 00H2) 4.80~
5.80 (2H,br, NH2)7.45 (L
H, s, ) 5-position ■) of lyazole [Step V] 2-(2-)ditylami/thiazol-4-yl)-2
-((N-)Rithyru1.2.8-)Riazole-4
-yl) methoxyimino) acetic acid [Step 1] was dissolved in methanol 100-, and (2-) IJ thylaminothiazol-4-yl) glyoxylic acid 2.48!7 was dissolved in methanol 100-. Add and stir for 16 hours. The solvent residue was dissolved in ethyl acetate, washed with a pH 4 aqueous hydrochloric acid solution and brine, and dried over anhydrous sulfuric acid. The solvent is distilled off. The residue is dissolved in a small amount of chloroform, leuhexane is added thereto, and the precipitated solid is collected by filtration.

After washing with luhexane and drying under reduced pressure, the melting point is 138-145.
C. (decomposition) to obtain the title compound 4.059.

8600-2700.1720 0W-NMR (CI) 0/3. 4) 5.27 (2H,n, 001T2 )6.55 (
IIL 8. ■) at the 5th position of thiazole [Step ■] Sodium 7β-1:2-(2-aminothiazole-4-
yl)-z-((t,2.a-)lyazol-4-yl)methoxyimino)acetamide]-3-acetoxymethyl-8-cephem-4-carboxylate (syn isomer) -2ii + [Step ■ ] Compound 2.269 obtained in
Dissolve 0.629% of dicyclohexylcarbodiimide in water and stir at room temperature. N-Hydroxybenztriazole 0.
41.9 and tertiary butyl 7-amino-8-acetoxymethyl-3-cephem-4-carboxylate 0.9
After adding 8 g, stir at room temperature for 2 hours. After filtering off insoluble materials, the solvent is distilled off.

The residue was subjected to column chromatography (silica gel: 459
．． Solvent: chloroform) to obtain foam 2.409. This was dissolved in anisole Cod>, and trifluoroacetic acid 24- was added while stirring under water cooling, and the mixture was stirred at room temperature for 1.5 hours. Dry under reduced pressure. Formic acid 25- is added to the residue and stirred at room temperature for 1 hour. Dry under reduced pressure. Diethyl ether was added to the residue and the precipitated solid was collected by filtration. After washing with diethyl ether and drying under reduced pressure, 0.88 g of powder was obtained.

This powder was used in the next [Step 1] without further purification. Part (0,29) is 5% hydrogen carbonate) IJ
The title compound is obtained by dissolving the product in an aqueous solution of 100% and purifying it by high performance liquid 26-chromatography (1H form: Vertsil (manufactured by Whatman), solvent: 2% methanol).

IRvI(I"cm-': 8650~2600°a
x 1760.1655.1600 F T -NMR (D20.) 2.1.0 (8H, s, δC! difference) 8.82 (IE,, d, J-1,8Hz, 02
-H) 8.64 (1, H, d, J-], 8Hz,
02-H) 5.17 (11:T, d, J-5H
z, 0s-H)5.4], (2H+s, 0
OH2) 5.80 (1) T, d, , T-5Hys
, 0? -I() 7.06 (ITJ, s, 5th position ■ of thiazole) 8.04 (IH, s, ) riazole 5
Position l [Step ■] 7β-(2-(2-aminothiazol-4-yl)-2
4(1,2,8-triazol-4-yl)methoxyimino]acetamide)-a-(l-pyridiniomethyl)
-8-cephem-4-carboxilade (syn isomer) 688 m9 of the compound obtained in [Step 1] was added to 0.4 m of pyridine.
5w+l, sodium bicarbonate 93+719 and water 0
．． 75 fi/, add 2.84 g of sodium iodide, and stir for 1.5 hours at a bath temperature of 70 to 75°C in a nitrogen atmosphere. After cooling, acetone is added and the precipitated solid is collected by filtration. After washing with acetone and drying under reduced pressure, 47 omg of powder was obtained. Dissolve this in a small amount of water and use Diaion ■P-20 (80ml).
) with support (5% tetrahydrofuran, then 20% tetrahydrofuran).

Furthermore, high performance liquid chromatography (carrier: 01s Micro Bonder Back (manufactured by Waters)).

Purification using a solvent solution (5% MeOH) gives the title compound.

IRvK"cm': 3600-2500°ax 1770.1610 FT-NM Dan (D201 Lord) 8.18 (IH, d, J-18H2,02-H)8.
60 (II(,d, J-18Hz, C2-H)5
．． 23 (IH, d, J-5Hz, 06-H)5,
s s (u■, d, J-1,4Hz, 0II2
-N ■) 5.39 (2L s + 0OH2) 5.5
8 (IH, d, , T-14:Hz, 09N■)
5.84 (LH, d, J=-5Hz, a7-H)
7.04 (], H, B, H at thiazole 5th position)8.0
2 (11(,n, )lyazole 5th position ■)8.1.
8 (2H, t, J-7Hz, H at 3 and 5 positions of pyridine
)8.68 (IH, t, J-7:tIz, H at the 4th position of pyridine) 8.98 (2H, d, J-?lIz, H at the 2nd and 6th positions of pyridine) Elemental analysis Oz IIt eNe
Calculated value for OS 82/8H20 042.34.
H4, 28, N 21.17 Actual value 042.88.
H8,80,N 21.0829-

Claims (3)

[Claims] Cephalosporin derivatives represented by the formula (1) or lower argyl; R3: hydrogen or lower alkyl) and salts thereof (2) 7β-(2-(2-ami/thiazol-4-yl)-2-((1,,2,4-)lyazol-3-yl)
methoxyimino)acetamido]-5-(l-pyridiniomethyl)-8-cephem-4-carboxylad syn isomer or a salt thereof; the compound according to claim 1; (3) 7β-(2-(2-aminothiazol-4-yl)-2-((l,2.a-triazol-4-yl)methoxyimino)acetamide] = 8-(1-pyridiniomethyl)-8 -The compound according to claim 1, which is a syn isomer of cephem-4-carboxilade or a salt thereof.