JPS5841887A - Novel cephem compound, its preparation and preventive or remedy for microbism - Google Patents

Abstract

NEW MATERIAL:A compound of formulaI(R<1> is amino, protected amino; R<2> is lower alkyl, carboxy(lower)alkyl, lower alkenyl; R<3> is amino, lower alkanoylamino, lower alkyl; R<4> is H, lower alkyl]and its salt. EXAMPLE:7-[2-Methoxyimino-2-( 5-amino-1, 2, 4-thiadiazol-3-yl )acetamide]-3-( 3- formamide-1-pyridiniomethyl)-3-cephem-4-carboxylate. USE:Preventive or remedy for microbisms: it inhibits proliferation of microorganisms including gram-positive and -negative bacteria. PREPARATION:The reaction of a compound of formula II (R<5> is group of formula IV) or its salt with another compound of formula III or its salt gives the objective compound of formulaI.

Description

Detailed Description of the Invention [In the formula, R is amino or a protected amine, R2 is lower alkyl, carboxy(lower)alkyl, lower alkenyl, lower alkynyl or cyclo(lower)alkenyl, R3 is amino, lower alkanoylamino , lower alkyl, and droxy (lower) alkyl, carboxy, chloro, lower alkanoyl, hydroxyimino (lower) alkyl, oxaloamino or lower alkanoylamino (lower) y fi7kyl, R means hydrogen or lower alkyl, respectively] The present invention relates to novel cephem compounds represented by the above, salts thereof, methods for producing them, and agents for preventing and treating bacterial infections containing these as active ingredients.

According to the present invention, the novel cephem compound (1) can be produced by the method described below.

Method 1 or its salts; or its salts (+); or its salts; Method 2; (Ia) or its salts (1b) or its salts; R3-lower alkanoylamino, Hs
b, meaning amino respectively] target compound (,1),
(la') and [If)"l, and the starting compound (
Regarding 1], the target compound and starting compound include syn isomer, anti isomer, and mixtures thereof.

For example, regarding the target compound [1], the syn isomer means a geometric isomer having a partial structure represented by the formula: [wherein R and R have the same meanings as before], and the anti-isomer means the formula: [In the formula, R and R have the same meanings as above] means other geometric isomers having the partial structure.

Regarding the other compounds mentioned above, their syn and anti isomers refer to the same geometric isomers as the syn and anti isomers explained for compound [1].

Preferred salts of the target compound [l] are conventional non-toxic salts, such as alkali metal salts such as sodium salts and potassium salts, metal salts such as alkaline earth metal salts such as calcium salts and magnesium salts, and ammonium salts. L such as trimethylamine salt, triethylamine salt, pyridine salt,
Picoline salt, dicyclohexylamine 4, N, N'
- organic amine salts such as dibenzylethylenediamine salts, organic acid salts such as acetates, trifluoroacetates, maleates, tartrates, methanesulfonates, benzenesulfonates, formates, toluenesulfonates; Included are inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate, and salts with amino acids such as arginine, aspartic acid, and glutamic acid.

In the foregoing and following descriptions of this specification, preferred examples and explanations of the various definitions falling within the scope of this invention are set forth in detail below.

"Lower" means 1 to 6 carbon atoms unless otherwise specified.

Preferred "protected amino" refers to an amino group substituted with a conventional protecting group such as acylamino or al(lower)alkyl which may have at least one substituent such as benzyl or trityl. include.

Preferred acyl moieties in "acylamino" and "acyloxy" may include carbamoyl, aliphatic acyl groups, and acyl groups containing aromatic or heterocycles. Preferred examples of the acyl include lower alkanoyl such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl; for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethate; lower alkoxycarbonyl having 2 to 7 carbon atoms, such as pyropropyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl; arenesulfonyl, such as benzenesulfonyl, tosyl; e.g. benzoyl; Examples of aroyl such as toluoyl, xyloyl, naphthoyl, phthaloyl, and indancarbonyl; t is a) V (lower) alkanoyl such as phenylacetyl and phenylpropionyl; for example, al (lower) alkoxycarbonyl such as benzyloxycarbonyl and phenethyloxycarbonyl; can be mentioned. The acyl moieties may be substituted with at least one suitable substituent such as halogen (chlorine, bromine, fluorine and iodine), lower alkanoyl, and the like.

Preferred acyls having substituents include lower alkanoyl (lower) alkyl/yl (e.g. acetoacetyl, acetopropionyl, etc.), suitable "lower alkyl" and carboxy (lower) alkyl, hydroxy (
The "lower alkyl" moiety of lower)alkyl, hydroxyimino(lower)alkyl and loweralkanoylamino(lower)alkyl is an alkyl having 1 to 6 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl. Examples include , t-butyl, pentyl, -pentyl, hexyl, etc., which are alkyl having 1 to 4 carbon atoms.

Suitable [lower alkenyls] are those having 2 to 6 carbon atoms, including vinyl, allyl, isopro9benyl, 1-
It includes propenyl, 2-butenyl, 3-pentenyl, etc., and preferably has 2 to 4 carbon atoms.

Suitable "lower alkynyl" has 2 to 6 carbon atoms, and examples include ethynyl, 2-propynyl, 2-butynyl, 6-pentynyl, 6-hexynyl, etc., but preferably 2 to 6 carbon atoms. ~4 pieces.

Suitable "cyclo(lower) alkenyls" have 5 to 6 carbon atoms.
These include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc., and preferably have 5 to 6 carbon atoms.

Preferred "lower alkanoyl 4 moieties" in "lower alecanoyl", "lower alkanoylamino" and "lower alkanoylamino (lower) alkyl" include:
An example of the acyl group is "fcr lower alkanoyl".

Suitable examples of R include the above-mentioned acyloxy, halokene (e.g., tJf, chloro, fluoro, bromata is iodo),
Examples include acid residues such as and.

A preferred specific example of the target compound (1) is R is amino R
2 is lower alkyl, carboxy(lower) alkyl, lower alkenyl, lower arginyl tI/i td cyclo(lower) alkenyl, R is amino, lower alkanoylamino,
Lower alkyl, hydroxy (lower) alkyl, carboxy, chloro, lower alkanoyl, hydroxyimino (lower) alkyl, carboxycarbamoyl or lower alkanoylamino (lower) alkyl, a compound in which R4 is hydrogen or lower alkyl.

The method for producing the object compound of the present invention will be explained in detail below.

Method 1 The target compound (1) or its salts can be produced by reacting the compound [1] or its salts with the compound [1] or its salts. Preferred salts of the compound [1] and [Rin] The same compounds as those exemplified for compound (1) can be used.

This reaction is typically carried out in a solvent such as water, phosphate buffer, acetone, chloroform, a7tonitrile, nitrobenzene, methylene chloride, ethylene chloride, formamide, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethyl sulfoxide. Although the reaction can be carried out in any other solvent as long as it does not adversely affect the reaction, it is preferable to carry out the reaction in a strongly polar solvent. Among these solvents, hydrophilic solvents may be used in combination with water. This reaction is preferably carried out in a neutral solvent. When compound [■] is used in the free form, this reaction can be carried out using, for example, inorganic bases such as alkali metal hydroxides, alkali metal carbonates, alkali metal hydrogen carbonates, organic bases such as trialkylamines, etc. It is desirable to carry out the reaction in the presence of a base. The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature, under heating, or under heating. This reaction is preferably carried out in the presence of an alkali metal halide such as sodium bowrate or potassium iodide, or an alkali metal thiocyanate salt such as sodium thiocyanate or potassium thiocyanate.

Method 2 The target compound (IbH or its salts) can be prepared by subjecting the compound CIa or its salts to an elimination reaction of the lower alkanoyl group.

As preferred salts of compounds (Ial and (Ib'l), the same salts as exemplified for compound [1] can be used.

This elimination reaction is carried out by hydrolysis; a conventional method such as a method in which compound [1a] is reacted with an iminohalogenating agent, then reacted with an iminoetherifying agent, and if necessary, the product is subjected to a hydrolysis treatment. This is done by For hydrolysis, a method using an acid, a base, etc. can be used.

Among these methods, hydrolysis with acids is one of the preferred methods, suitable acids include organic or inorganic acids such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p
-Toluenesulfonic acid, hydrochloric acid, etc. are mentioned, and preferred acids are, for example, formic acid, trifluoroacetic acid, hydrochloric acid, etc.

When performing an elimination reaction using an acid, the reaction may be performed in the presence of a solvent or without using a solvent. Suitable solvents are customary organic solvents, water or mixtures thereof. When using trifluoroacetic acid, it is desirable to carry out the elimination reaction in the presence of anisole.

Suitable bases used for hydrolysis with bases include, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, sodium carbonate, and potassium carbonate. Alkali metal carbonates such as magnesium carbonate, alkaline earth metal carbonates such as potassium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate,
Inorganic bases such as alkali metal acetates such as sodium acetate and potassium acetate; organic bases such as trialkylamines such as trimethylamine and triethylamine; picoline, N-methylpyrrolidine, N-methylmorpholine and the like. Hydrolysis with bases is often carried out in water, customary organic solvents or mixtures thereof.

The reaction temperature is not particularly limited, but it is preferable to carry out the reaction under mild conditions such as cooling, room temperature, or slight heating.

The compounds thus obtained according to Methods 1 and 2 above can be converted into pharmaceutically acceptable salts by conventional methods.

The object compound (+) of this invention exhibits high antibacterial activity and inhibits the growth of numerous microorganisms, including Gram-positive and Gram-negative pathogenic bacteria.

When the target compound (1) is used as a medicine, it may be used in the form of a pharmaceutically acceptable salt.

When the cephem compound (1) of the present invention or its salts are administered for therapeutic purposes, the compound may be administered in a pharmaceutically acceptable medium, such as an organic or inorganic solid or It is used in the form of a preparation mixed with liquid excipients. Such preparations include solid preparations such as capsules, tablets, granules, ointments, and suppositories, and liquid preparations such as solutions, suspensions, and emulsions.

Furthermore, if desired, the preparation may contain adjuvants, stabilizers, wetting agents or emulsifiers, buffers, and other conventional additives.

Although the amount of active compound administered will vary depending on the age and condition of the patient, an average single dose of the compounds of this invention is approximately 50! , 100~. 250 Cape and 500
The amount of cho is effective in treating infections induced by many pathogenic bacteria. Generally, the daily dose is 1 to about 110
0ON or more stars may be administered.

Next, in order to demonstrate the usefulness of the target compound (1), test data regarding the antibacterial activity of representative compounds according to the present invention will be shown.

, Shie Kouhiro - In vitro antibacterial activity was determined by the agar plate dilution method described below.

Heart Infusion Agar (Hl-agar) was inoculated with a loopful of each test strain cultured overnight in trypticase soy broth (10'?bacterial count/gi!'').This medium contained antibacterial Contains various concentrations of agents at 37℃
After culturing for 20 hours, the minimum inhibitory concentration (MIC'
) was measured. (Unit: μf/Ml) Test compound (1) 7-(2-methoxyimino-2-(5-amino 1,2.4-thiadiazole/L/-3-yl)acetamide)-3-(3 ,5-dimethy/L/-1
-pyriciniomethyl)-3-mer-4-carboxylate (synisomer).

(2) 7-t'2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-(3,4-dimethytv-1-pyridiniomethy/L /)-3-cephem-4-carboxylate (
syn isomer).

Trial driving results M, 1. C (μf/me) This invention will be explained below with reference to production examples and examples.

Production Example 7-[2-methoxyimino-2-(5-amino-1,2
,4-Thiadiazo-)v-3-I/L/)acetamide]cephalosporanic acid (synisomer) K sodium acetate was reacted in a conventional manner to form 7-(2-methoxyimino-
2-(5-amino-1,2,4-thiadiazole-3-
acetamido]cephalosporanic acid sodium salt (syn isomer) is obtained.

mpl 85-190℃ (decomposition) IR (nujo I): 3150.1765, 1745
,1670°1550.1400.1555.1290
．． 125CI, 1055-01" υ view (L 6-formamidopyridine (5, IP), thorium iodide (565 g), phosphoric acid (1,24F), water (6 l/)
A mixture of 7-[2-methoxyimino-2-(5-amino-1,2,4-guadiazol-5-yl) → acetonitrile (18 ml) was heated to 65-70°C with stirring and F amide] Cef 10 Sodium salt of sporanic acid (syn isomer) (10)) is added. The mixture was stirred at 70-72 °C for 1,5 h and water (50+wl
).

Cool the aqueous solution, adjust the pH to 3 with 6N hydrochloric acid, and dilute to 200111 with water. The aqueous solution was washed five times with a mixed solvent of chloroform and ethanol (2:1) (15011t), and concentrated to 300 ml under reduced pressure.

Insoluble materials were removed, and the p-liquid was treated with nonionic adsorption resin 1 Diaion HP20' (registered trademark: manufactured by Mitsubishi Chemical Industries, Ltd.) (
Subjected to column chromatography at 300 l). After washing the column with water, it is eluted with 100% aqueous methanol. The eluates containing the target compound were combined, methanol was distilled off under reduced pressure, and lyophilized to give 7-[2-methoxyimino-2-
(5-amino-1,2,4-thiadiazol-3-yl)acetamide)-1-(3-formamido-1-pyridiniomethyl)-5-cephem-4-carboxylate (syn isomer) (5,20F) get.

mI), 158-163°C (decomposition).

IR (nuji, -A/): 3400-3100,177[
1,1670,1600゜1530c11 N old (p2o, δ): 3.20o! Hi 3.73 (2H
, ABq , J-18Hz), 4f13(5H,s),
528 (IH, d, J=5Hz).

530 and 5.67 (2H, ABq, J=14Hz)
, 5.88 (IH, d, J=5Hz), 7.9-8.2
(IH, m), 8.3-8.6 (IH, m), 8.45
(IH, s), 8.6-8.8 (IH, m).

9.5 (IH, m) ・Example 2 7・-[2-methoxyimino-2-(5niamino-1,
2,4-thiadiazol-/L/-3-yl)acetami)
) 3- < 5-formamide-1-pyridiniomethyl #)-3-cephem-4-carboxylate (syn isomer) (4,48F) in methano-/L' (45 pH 4 to 4 with an aqueous solution of sodium bicarbonate) 5 and subjected to column chromatography using a nonionic adsorption resin 1 Diaion HP20" (registered trademark: manufactured by Mitsubishi Chemical Industries, Ltd.) (135 m). After washing with columnar water, elution was carried out with 15 aqueous isopropyl alcohol. The eluates containing the target product were combined, the isoforopyl alcohol was distilled off under reduced pressure, and lyophilized to give 7-[2-methoxyimino-2-(5-amino-1,
2,4-'f-7diazo)v-3-yl)acetamido)-3-(3-amino-1-pyridiniomethyl)-3
-cephem-4-carboxylate (syn isomer) (3
, 10y). mp177-182'C (degraded).

Engineering R (nuji * zlz): 3350.3200.17
70.1640-1590.1510cM' NMFi (D20, δ): 5.15o and 3A5 (2H
, ABq , J=18H2), 4.04(3H,s),
52-5.4 (2H, m).

523 (IH, d, J = 5Hz), 5.85 (IH, d
, J=5H2).

7.6-7.7 (2H, m), 8.0-8.1 (IH
, m), 8.2NH, m) Example 3 7-[2-methoxyimino-2-(5-amino-1,2
,4-thiadiazole-/1/-3-i/L/)acedore,
Mido] Cephalonuporanic acid sodium salt (syn isomer)
(12,0ri), 6-methylpyridine (468F), sodium iodide (44,42), phosphoric acid (1,4°8y)
, water (7.6 g/) and acetonitrile (22.4 l) are stirred for 1 hour at 72-76°C. The reaction mixture was diluted to 300 g/ml with water, adjusted to pH 3 with 6N hydrochloric acid, and washed with ethyl acetate. Separate the aqueous solution,
Nonionic adsorption resin 1 Diaion HP-20” (36
0 g/) and subjected to column chromatography. After washing the column with water, it is eluted with 25 cm aqueous methanol, and the eluates containing the target compound are combined and concentrated to 20 l under reduced pressure.

N,N-dimethylformamide (20g+/) in aqueous solution
Add and mix, and add acetone (470 l) while stirring.
). The resulting precipitate was filtered and washed with acetone;
dry. The precipitate was dissolved in water (80s+t), passed through acidic alumina (22,55F), and lyophilized to give 7-[2
-methoxyimino-2-(5-amino-1,2,4-thiadiazol-6-yA/)acetamide)-3-(3
-Methyl-1-pyridiniomethy/1/)-5-cephem-4-carboxylate (syn isomer) (4,815r
).

m9150-154°C (decomposition).

IP (nuji r gore): 3650-31 Do, 1770
,16711°1640~1610.1520m' NMR (D20.δ):252(3H,S),3
．． 15 and 3.65 (2H, ABq, J=18Hz)
, 4.02 (3H, s), 527 (1B, d, J=5H
z), 525 and 5.55 (2H.

ABq, J = 14Hz), 5.87 (IH, d, J = 5
Hz).

7.73-8.10 (IH, m), 823-850 (I
H, m).

8.63~a83 (IH, m) ”91 Ward 1 The following compounds are obtained in analogy to the above examples.

(1) 7-(2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-A/-5-yl)acetamide)-3-(4-methyl-1-pyridiniomethyl #)
-3-cephem-4-carboxylate (syn isomer)
. mp, 155-160°C (decomposition).

Engineering R (nuji g-/v): 365[h”3100.177
0.1660°1640.1610, 1520rM NMR (D20.δ), 2.63(3H,S), 3.
15 and 367 (2H, ABq, J=18Hz),
4.03(!IH,S), 5.27(IH,d,
J=5Hz), 522 and 5.55 (2H.

ABq, J=14Hz), 5B5(IH, d, J=5H
z).

7.83 (2H, d, J=7Hz), 8.73 (2H
, d, J=7Hz) (2) 7-(2-methoxyimino-2-(5-ami/-1,2,4-+7cy7zol-3
-Ilv) Acetamide) -3-(3-Ethyl-I-pyridiniomethy/L') -3-7Femu 4-carboxylate (Syn isomer) 1mp160-165°C (
Disassembly).

, LR (Nujol): 3! +00.3150.177
0.1670,1610°1530.1285,114
0.101040cIRN? (D20.δ): 1.30
(3H, t, J=7Hz) , 2.92 (2H, q,
J=7Hz), 3.22 and 3.68 (2H, Ad
q.

, T=18Hz), 4.05(3H,S), 528
(IH, c, J=5Hz), 5.28 and 55
8 (2H, ABq, J=14Hz).

5.88 (IH, d, J=5Hz), 7J32-8.1
3 (IH, m).

830-857 (I H, m), 8.63-8.90
(2H,m)(3)7-(2-ethoxyimino-2-(
5-amino-1,2,4-thiadiazol-)v-3-yl)acetamide)-3-(3-ethy/L/-1-pyridiniomethyl)-6-cephem-4-carboxylate (
syn isomer), mp 150-155°C (decomposition).

Engineering R (nuji w #): 3250, 3150, 1770.
1670°1610.1530,1510.1290.
1150.104 Kano 11NMP (D 20 , δ):
1.30 (6H, t, J=7H2), 2.93 (2H.

q, J=7Hz), 3.17 and 3.68
(2H, ABq, J=18Hz), 4.37 (2H
, q, J=7Hz), 51 (IH, d.

J = 5Hz) , 528 5.58 (2H,
ABq, J=14Hz), 5.88(IH,d, J=
5Hz), 7.8 to 8.15 (I H, m), 8.
30A-8,60(IH,m), 8.65-8.92
(2H, m) (4) 7-(2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-)v-3-yl)acetamido)-5-[2-(2-hydroxy ethyl)-1-
pyridiniomethyl)-3-hfemu-4-carboxylate (syn isomer).

mp, 150-155°C (decomposition).

Engineering R (nuji v-#): 3650-3100.1770.
1660, 1620° 1530.1280.1180.
1140.1040x 1NMR (D20.δ): 1.
32 (3H, t, J=7Hz), 3.15 and 3.6
2 (2H, ABq, J=18Hz), 3.43 (2
H,t.

J=6Hz), 407 (2H, t, J=6Hz), 4.
40 (2H.

q, J=7Hz), 530 (IH, d, J=5Hz)
, 5.57 (2H, m), 5.90 (IH, d, J=5
Hz), 7.65-8.30 (2H, m), 8.33
~8.70 (IH, m), , 8J35NH, d, J=6
Hz) (5) 7-(2-methoxyimino-2-(5-amino-
1,2,4-thiadiazol-5-yl)acetamide)-'3-(2-(2-hydroxyethyl/L/)-1-
Pyridiniomethyl]-3-cephem-4-carboxylate (syn isomer), mp 16o-165°C (bunch).

IR (nuji = s-#): 365 to 3100.1770
．． 1660°1620.1520.1280;1170
．． 1140.1040cIr'NMR (D20, δ
): 3.15o [)" 3.58 (2H, ABq, J=1
8H2), 3.43 (2H, t, J=6H2), 4.0
7 (3H, S').

4rJ7(2H,t,,T=6Hz) ,5.27(1
H, d'; J=5Hz).

557 (2H, m), 5.90 (IH, d, J=5Hz
), 7.70-8.13 (2H, m), 8.23-8.
63 (IH, m), 8.80 (IH, d, J=6Hz
) (6) 7-(2-Methoxyimino-2-(5-amino-1,2,4-thiadiazol-tL/-3-yl)acetamide)-3-(2-methy/l/-1-pyridiniomethyl /L/)-3-cephem-4-carboxylate (cy isomer), mpl 50-154°C (decomposition).

1R (Nujol): 3650-5100.1770.
1670°1630.1610.1530.1290.
1150.1040cy 'NMR (D20.δ): 2
．． 83 (3H, s), 3.15 and 3.57 (2H,
ABq, J=18Hz, ), 4.05(3H,
s), 5.27 (IH, d, J=5Hz), 528
Oh! and 5.57 (2H.

Station ABq, J = 14HzL5.87 (IH, d, J = 5H
z).

7.68-8.00 (2H, m), 8.17-8.5
7 (1'H, m).

8.72 (IH, d, J=6Hz).

(7) 7-(2-ethoxyimino-2-(5-amino-
1,2,4-Thiadiazo-)Lt-3-I/L/)acetamido)-5-(5-(3-hydroxypropyl)-
1-Hiriciniomethyl]-3-7fem-4-carboxylate (syn isomer). m9160-165°C (decomposition).

Engineering R (Nujo 1): 3250, 5150.1770
．． 1670°1530.1280,1140,1060
．． 1040cl1040clIN, δ): 1.30(3
H, t, J = 7Hz), 1.73-2.27 (2H, m
), 2.70-3.13 (2H, m), 3.15 and 3.65 (2H, ABq, J=18Hz), 3.63 (
2H,t.

J=7Hz), 4.33(2H,q, J=7Hz)
), 5.30 (IH.

d, J=5Hz), 5.28 and 5.58 (2H, A
Bq.

J=14Hz), 5.88(IH,d, J=
5Hz), 7.77-8.10 (IH, m), 8.
40 (IH, y'o--do d, J==8Hz).

8.75 (IH, d, , T = 5Hz), 8.80 (tH
,s).

(8) 7-(2-ethoxyimino-2-(5-amino-1,2,4-thiasifuso/L/-3-i/I/)
7) Amido)-3-(4-(1-hydroxyethyl)
-1-Pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer). mp160-165°C (decomposition).

Engineering R (Nujol): 3250.3150.1770.
1660°1640.1610.1520,1280.
1150.1100°1040cf1 040cf1N, δ): 1.33 (3H, t, J=7H
zL1.60 (3H, d, J=7Hz), 3.
20 and 3.73(2H,AB(1°J=18I(Z
), 4.40 (2H,q, J=7Hz), 5.0
3-550 (IH, m), 5.33 (IH, d, J=
5Hz), 5.30 and 5.62 (2H, ABq,
J=147), 5.93 (1H.

d, J=5Hz), 8.08(2H, d, J=7H
z) ,8.93(2H,d,,T=7Hz) (9)7-(2-ethoxyimino-2-(5-amino-
1,2,4-1diazol-5-yl)acetamide']-3-(3-(2-hydroxyethyl,)-1-t
'Rijiniomethi/L',] -]3-cephemu4-
carboxylate sin isomer]. rnp155-160
°C (decomposition).

:[R(nuji*-/u)=5250.3170.177
0.1660°1610.1530m' NMR (D20.δ): 1.28 (3H, t, J=7H
z), 3.07 (2H, t, J==6Hz), 3.23
O and 3.57 (2H, ABq.

J = 18Hz), 3.90 (2H, t, J = 6Hz),
4.32 (2H, q, J=7Hz), 527 (IH
, d, J=5Hz).

5.35 o! and 5.53 (2H, ABq,, r=14H
z), 5.87 (IH, d, J=5Hz), 7.85
-8.17 (1H, m).

8.33-8.60 (IH, m), 8.70-8.9
7(2H,m)6 of 7-[2-methoxyimino-2-
(5-amino-1,2,4-thiadiazol-3-yl)acetamide)-3-(3-chloro-1-pyridiniomethyl/I/)-3-cephem-4-carboxylate (syn isomer), mpl 45-150°C (decomposition).

IR (nuji-i, ρ): 3270.3170.177L
1.1660゜1610.1525,1490α N strike (D20.δ): 5.25 and 3A8 (2H
,ABq, J=18Hz), 4.07(3H,s)
, 528 (IH, d, J=5Hz).

537 and 5.62 (2H, ABq, J-14H2)
, 5.88 (IH, d, J=5Hz), 7.90-8
．． 23 (IH, m), 8.50-8.77 (IH, m)
, 8.8! y-9 sword 8 (IH, m), 918 (1H, broad 5) (11) 7-(2-methoxyimino-2-(5-amino-1,2,4-thiadiazole-)v-5-y /I/) Acetamide)-3-(3,5-dimethyl-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), mpl 46-150°C (decomposition).

IR (nuji! 1-jv): 5400, 35oO, 520
0,1770,1665゜1610.15301ff Shimatan (D20.δ): 2.48 (6H, S), 3
, 22 and 355 (2H, Aaq, J=18Hz),
4.03 (3H, 8), 5.25 (IH, d, J=5H
2)', 528 and 5.43 (2F(.

ABq, J=14Hz), 5B5CIH,d,
, T=5Hz).

8.115(IH,S), 8,60(2H,s)0~7-[2-methoxyimino-2-(5-amino-1
,2,4-thiadiazol-1v-3-yl]acetamide J-3-(3-(3-hydroxypropyl)-1-pyridiniomethyl]-3-cephem-4-carboxylate (syn isomer), mp166-167 °C (decomposition).

IR (Nujiwo/L/): 3250.3150,177
0.1660°1610.1525m' NMR (D20.δ): 1.7-223 (2H, m)
, 2.75-3.17 (2E(,m), 3.23 and 3.60 (2H, ABq, J=18Hz), 3.6
3 (2H, t, J=7Hz), 4.05 (3H, s)
.

527 (IH, d, J=5Hz), 5.37 and 5.
53 (2FT.

ABq, J=14Hz), 5.87(IH,d, J
=5Hz).

7.80-8.17 (IH, m), 8244.60 (
IH, m).

8.67-8.93 (2H, m) 6→ 7-[2-ethoxyimino-2-(5-amino-
1,2,4-Thiadiazo-)V-3-I/L/)acetamide]-3-(3-oxaloamino-1-hyridiniomethyl/I/)-3-7femu-4-carboxylate (synisomer body), mp 108.5-117.5°
c, -IR (Nujol'): 3250,1770.1
660.1590°1530.1180,1145.1
040cII1040cIIN, δ): 1.33 (3H
,t, ,T=7Hz), 333 and 5.75(2H,
ABq, J=18Hz), 435 (2H.

q, J=7Hz), 522 (IH, d, J=5Hz)
, 5.32 Oyobi 5.70 (2H, ABq, J=14H
2), 5.92 (IH, d, J = 5Hz), 8.05 (
'It(, m), 8.45 (IH.

m) , 8.75 (IH, m) , 953 (IH, m)
(147-(2-ethoxyimino-2-(5-amino-
1,2,4-Thiadiazo-/L/-3-y/1/)acetamide)-3-(5-formamidomethyl-1-pyridiniomethy/l/)-3-cephem-4-carboxylate (syn isomer ), mp157-161”C (disassembly?.

Engineering R (nuji * *): 3250.3200, 3050
．． 1775°1660.1610.1550.1350
．． 1285,1140°1060.1035103 5cIiN D'20 , δ): 1.30 (3H, t,
J=7Hz), 3.18 and 3.62 (2H, ABq
,,T=18H2), 4.30(2H,q.

J=7Hz), 4.62 (2H, s), 525 (IH,
d, J=5Hz), 5.30 and 5.57 (
2H, AB'q, J=14Hz).

5.85 (IH, (i, J=5H2), 8J) 0 (IH
, dd, J = 6 and 8 Hz), 8.20 (IH, S
), 8.45(1)I, d, J=8Hz), 8.8
5 (IH, d, J=6Hz), 8.89 (IH, s)6
Moan 7-[2-ethoxyimino-2-(5-amino-1
,2,4-thiadiazole-/l/-'3-i)v)acetamido)-3-(4-amino-1-pyridiniomethyA/
)-3-t! Fuemu 4-carboxylate (syn isomer), mpi 65-175°C (decomposed).

Engineering R (Meji 1 Koya): 3300, 315D, 1770.
1650°1600.1530.1160.10103
5cIIN (D2 starvation δ): 1.32 (3H,t,,
T=7Hz), 3.15 and 5.65 (2H, ABq
, J=18Hz), 4.35(2H,q.

J=7Hz), 5.00 (2H, %-t's), 5.
26 (IH.

d, J=5H2), 5.88 (I H, d,
J=5Hz), 6.94(2H,a,,T=7Hz
), 8j18 (2H, d, J=7Hz) (147-(
2-allyloxyimino-2-(5-amino-1,2,
4-thiadiazole-3-i/I/)acetamide)-
,5-(3,5-dimethyA7-1-hydrinio)thi)
v)-3-cephem-4-carboxyv-) (y7R form), mp 198-203°C (decomposition).

Engineering R (Nujiwo/I/): 3250, 3160.177
0.16s5゜1610.1525, 1290.117
0.1150.1060°1010cn+ NMR (D20.δ): 2.48 (6H,S),! 1.
15 and 6.60 (2H, ABq, J=18H
z), 4.7-4.9 (2H, m).

5.25 (I H, d, J=5Hz), 4.9
-5.7 (4H, m>.

5.75-6.40 (IH, m), 5.87 (IH, d
, J==5Hz).

8.15 (IH, s), 8.57 (21H, s) Ono
7-(2-(2-Brohi~Ogishiimino)~2-(5-
Amino-1,2,4-thiadiazole-IL/-5-i/L
/) Acetamide '33-(3,5-dimethyl-1-pyridiniomethylv)-5-cephem-4-carboxylate (syn isomer), mp175-180°C (decomposition)
.

I'R (nujo-/l/): 3400, 3250.30
50.2110°1775.1660,1610,15
30cIr'NMR (DMSO-d6+D20.δ)
:2.47(6H,S),3.43(IB,'t,J
=2Hz), 5:'12o and 3.45(2H,ABq
.

J=18I-Tz), 4.73(IH,d, J=2H
z), 5j13 (IH.

d, J=5Hz), 5.17 and 552 (2
H,ABq, J=14Hz), 5.68(IH,d
, J=5Hz), 8.26 (IH,S).

9.00 (2H, s) 0 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-1L/-3-yl)acetamide)-3-(3-ethyl /l/-1-pyridiniomethy/I/)-5-cephem-4-carboxylate (syn isomer), mp 195-200°C (decomposition).

fR (nuji! l #): 3270, 3160.1770
．． 1665°1610.1530.1280,1145
, 1060αNMFt ('D 20', δ): 1
．． 28(3H,t, J=7HI, 2.86(2H.

q, J=7Hz),! 1.17 and 3.5
8 (2H, ABq,, T-18Hz), 4A ~ 4.8 (
2H, m), 5,1!5 (IH, d, J=5Hz), 5
．． 1-5.8 (4H, m), 5.90 (IH, d, J=
5T(z).

5.8-65 (IH, m), 7.8-J8.1 (
IH, m), 8.2-8.6 (IH, m), 8.7
~8.9 (IH, m), 8.80 (IH, s)0n
7-(2-(2-prohynereoximino)-2-(5
-amino-1,2,4-thiadiazole-3-i/I/
) Acetamide-3-(3-ethyl-1-pyridiniomethy/L/)-3-cephem-4-carboxylate (syn isomer), mIN 65-170'C (degraded).

IR (nuji = l #): 3400, 3250, 3450
,2090°1770.1660,1610.1520
c* 'NMR (DMSO-4, +D20.δ): 1
．． 33 (3H, t, J=7Hz).

2.90 (2H, q, , T=7Hz), 3.17
and 555 (2H.

ABq, J=18Hz), 3.50(IH,t,J=
2Hz).

4.80 (2H, d, J-2Hz), 5.12 (IH,
d, J=5Hz).

525 and 5.67 (2H, ABq,, r=14Hz
), 5.75 (IH, d, J=5Hz), 7.93-8
．． 23 (IH, m), 8.37-8.67 (IH, m)
, 9.17-J? , 40(2B, m)) 7-(2
-(2-cyclopenten-1-yloxyimino)-2
-(5-amino-1,2,4-thiadiazol-3-yIL/)acetamide]-3-(3,5-dimethyl-1
-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer).

IF7 (Nujol): 3300.3170,1770
．． 1670, 1610° 1525.1290, 1170
．． 1060.1030a++NME? (D20.δ):
1. t2J6 (4H, 111), 2.42 (6H, s)
.

308 and 3.50 (2H, ABq, J=17Hz)
, 4.95 (IH, m), 5f15-562 (2H, m
), 5.15 (IH, d.

J=5Hz) , 5.77(IH,d, ,T=5Hz
), 5J35-6.12 (2H, m), 8.10 (
IH, y"o-t' S), 8.50 (2H.

) Seed 5) 91) 7-C2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazole-3-i/I/)acetamide]-3-( 3
-Ethyl-1-pyridiniomethy/L/)-3-cephem-4-carboxyle) (C: 'isomer).

mp151-158°C (decomposition).

Engineering R (nuji r-1v): 3300j200, 1765.
1660.

1610.1525.1280.1140,1060.
1030c11NMP1030c11N Seven M6. δG
1.50 (IH, t, J=7Hz).

1.80-2.60 (4H, m), 2.92 (2H,
q, J=7Hz).

3.17 and 3.63 (2H, ABq, J=18
Hz), 4.67-6.27 (5H, m),
5.21 (IH, d, J=5Hz), 5.85 (I
H, d, J = 5Hz), 8.02 (IH, dd, J
= 6 and 8H2), 8.47 (IH, d, J = 8Hz
), 8.95(2H,m)H7-(2-ethoxyimino-2-C'5-amino-1,2,4-thiadiazole-#
-3-yl)acetamide) -3-(4-acetyl A/-
1-pyridinio) f) v) -3-cephem-4-carboxylate (syn isomer), m9 150-155 °C (
Disassembly).

IP (Nujo #): 3300.1780, 1700.
1660-1610.1530 ax ” NMR (D20.δ) two 130 (3H, t,, T=7H
z), 2.80 (3H,s).

5.27 and 3.63 (2H, ABq, J=18H2
), 4.5+3 (2H,q, J=7Hz), 5.28
(IH, d, J=4Hz).

5.45 and 5.67 (2H, ABq, J=14Hz
).

5.90 (I H, d, J = 4Hz), 8.47 (2
H, d, J = 7Hz).

9.20 (2H, d, J=7Hz) Q fathom 7-
[2-Ethoxyimino-2-(5-amino-1,2,4
-thiadiazole-3-i/L/)acetamide)l-
(,4-Hydroxyiminomethyl-1-pyridiniomethy/I/)-3-7femu-4-carboxylate (syn isomer).

IR (Nujol): 3300.3150,1775.
1670°1610.1520cII IME(:p2O-)-DC/, δ): 1.38
(3H, t, J=7Hz).

4.45 (2H, q, J=7Hz), 5.40 (IH,
d, J=4Hz).

5.47 and 5.87 (2H, ABq, J=14Hz
), 5.97NH,d, J=4Hz), 8.25(2H
, d, J=7Hz).

8.40 (IH, s), 8.95 (2H, d, J=7H
z)94 7-(2-allyloxyimino-2-(5-
7 minnow 1.2.4-thiadiazol-tL/-3-yl)
Acetamide)-3-(2,4-dimethyl-1-pyridiniomethy) I/)5-cephem-4-carboxylate (syn isomer), mpl 15-117°C (decomposition)
.

Engineering R: 3280.3180,1760.
1675.1635°1610.1520cM NME? (D20.δ) :259(3H,s), 2
．． 78 (3H, s), 3.20 and 350 (2H, A
Bq, J=18Hz), 4.81 (2H.

cl, J=6Hz), 5.27 o and 5.
55 (2H, ABQ.

J=14Hz), 5.28(1H, d,, T=5H
z), 5.93 (1H, d, J=5Hz), 5.1
-5.6 (2H, m), 5.7-6.5NH, m), 7
．． 5-7.9 (2H, m), 8.60 (IH, d,, T
=7Hz) 9!97-(2-allyloxyimino-2-(5-amino-1,2,4-thiadiazole-)v-5-i/1/)acetamide)-3-(1-noti/L /-i-pyridiniomethyAz) -5-h fuemu 4-carboxylate (syn isomer), mp 115-117°C (decomposition).

IR: 3300.3160, 1770.
1670.1610°15303' N strike (D20.δ): 256 (3H, S), 320
and 5.40 (2H, ABq, J=18Hz), 4.
80 (2H, d, J=6Hz).

5.30 (IH, d, J = sHz), 5.1 to 5.8 (
4H, m).

5.92 (IH, d, J = 5Hz), 5.8-65 (I
H, m).

7.8-8.9 (4H, m) (c) 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazole-6-i/1/)acetamide)-3- (3,4-dimethy1v-1-pyridiniomethy/I/)-3-cephem-4-carboxylate (
syn isomer), mpl 17-122°C (decomposition).

■'B (5<ji w #): 3280, 3150.177
0.1665°1635.1610, 1525CM NMR (D20.δ): 2.43 (3H, s), 2.5
5(3H,s), 320 and 3.60(2H,AEi
q, J==18Hz), 4.05 (3H, s).

5.26 (IH, d, J = 5Hz), 522 and 5.47 (2H0ABq, J = 14H2), 5.87 (
IH, d, J = 5Hz).

7.6-8.0 (IH, m), 8.3-8.8 (2H,
m) (b) 7-[2-7 lyloxyimino 2-(5-
amino-1,2,4-thiadiazol-1L/-3-yl)
Acetamide)-3-(3,4-dimethy/I/-1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer), mp 157-161°C (decomposition).

Engineering R(, (Jen-/L/):5270,3160.17
7 (J, 1670°1655, 1610, 1520
cmNMR (D20, δ), 233 (3H, s),
254 (5H, s).

5.20 and! 1.63 (2H, 'ABQ, J=18
Hz).

4.80 (2H, d, J=6Hz), 51 (IE(
, d, J=5Hz).

5.1-5J3 (4H, m), 5.92 (IH, d, J
=5Hz).

5, Ejx6.5 (IH, m), 7.81 (IH, d
, J=7Hz).

8.60 (II-T, d, J=, 7Hz), 8.68 (
IH, 5) H7-(2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-/L/-5-yl)acetamide)-3-(4-acety/L/-1- Pyridiniomethy/L/)-3-7femu 4-carboxylate (syn isomer), m9 155-160°C (decomposition).

Engineering R (Nujol): 3300.5150.3100.
1775°1700.1670,1610.1530c
NNMR (D20.δ): 2.80 (5H, S), 3.
28 and 3.67 (2H, ABq, J=18Hz
), 4.07(3H,s), 5.28(IH
, d, J=5Hz), 5.47 and 5.68 (2H,
ABCl.

J=14Hz), 5.87(IH,d, J=5Hz
), 8.47 (2H, d, J=7Hz), 925
(2H, cl,, T=7Hz) @7-(2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-5-yl)acetamide)-3-(5-formamide-1-pyridiniomethyl A/)-3-cephem-4-carboxylate (syn isomer), mp 158-165°C
(Disassembly) Engineering R (Nujol): 3250, 3100.1760,
1670°1600.1540CM NME? (DMSO-d6+D20.δCt20(3H
, t, J=-7Hz).

3.0-3.6 (2H, m), 4.18 (2H, q, J
=7Hz), 5.1-5.9 (2H, m), 5.1BI
H, d, J=5Hz), 5.77(1) Ld, J=sH
z), 7.9-8.2 (tH, m), 8.48 (IH,
S).

8.5-8.7 (IH, m), 8.9-9.
1 (IH, m), 9.4-9.7 (IH, m
) (to) 7-(2-(2-propynyloxyimino)-
2-(5-amino-1,2,4-thiadiazole-5-
yl)acetamido)-3-(5-formamide-1-
Pyridiniomethy/L/)-3-cephem-4-carboxylate (syn isomer), m9163-168°C (decomposition).

Engineering F (Nujime Koshi): 3400 Hero 100.1770.
1670°1610, 1560~1500cyxN
MR (DMSO-d6+D20.δ): 3.05 (IH
, t, J=2H2).

5.15 and 3.70 (2H, ABq, J=18Hz
).

4.87 (2H, d, J=2Hz), 523 (IH
, d, J==5Hz).

5.27 and 5A5 (2H, ABq, J=14Hz)
, 5.84 (IH, d, , T=5Hz) , 7.9~8
．． 1 (IH, m) , 8.42 (1) T, s) , 8
．． 3-8.8 (2H, m), 9.4-9.5 (IH,
m) (sl) 7-(2-(2-glovinyloxyimino)-2-(5-amino-1,2,4-thiadiazol-5-yl)acetamide]-3-(3-amino-1
-Pyridiniomethylto 5-cephem-4-carboxylate (syn isomer), mp 158-170°C (decomposition).

IP (nuuchi-/l/): 3350-3150.1770
．． 1660-1590°1510a' NMFt (D20.δ): 3.15 and 3.67 (
2H,ABq,J=-18Hz4.90(2H,S)
, 5.0-5.6 (2H, m), 5.28 (IH, d
.

J=5Hz), 5.88 (IH, d, J=5Hz)
, 7.6~7.7(2H,m), 8.0~B2(
2H,m)6'47-('2-carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazole-A/
-5-i/I/)acetamido)-3-(5-formamido-1-pyridiniomethy/l/)-3-tfemu-4-carboxylate (syn isomer), m9165-1
70°C (decomposition).

Engineering R (Nujol): 3400-31 Do, 177
0, 1670.

1630-1590, 1560.1530.1505m
NMR (D20.δ): 3.15 and 5.71
(2H, ABq, , J=18Hz), 4.73 (2
H,s), 5.26 (IH,d, J=5Hz).

527 and 5.65 (2H, ABq, J=14Hz)
, 5.87 (IH, d, J=5Hz), 7.9-8.1
(IH, m), 8.42 (IH, s), 8.3-8.8
(2H, m), 9.4-95 (IH, m) (c) 7-
(2-carboxymethoxyimino-2-(5-amino-
1,2,4-thiadiazol-)v-5-yl)acetamido)-3-(5-amino-1-pyridinyF)f-3
-cephem-4-carboxylate (syn isomer), m
p175-185°C (decomposed).

IR (Nujol'): 3350, 3200.1770
．． 1670-1590.1510.1230cII NMR (D20+NaHCO3, δ): 3.17
and 3.61 (2H.

ABq, J = 18H, z), 4.68 (2H, s), 5
．． 25 (28°71 seed S), 5.0 (1'H, d
, J=5Hz), 5.90 (IH, d, J==5Hz)
, 7.7 (2H, m), 8.1 (IH, m).

821 (IH, m) (b) 7-[2-methoxyimino-2-(5-amino-1,2,4-guadiazol-6-i/L/)acetamide)-3-(3-hydroxymethy/ Ly-1-pyridiniomethyl-5-cephem-4-carboxylate (sz-isomer), mpl 64-168°C (decomposition)
.

IR (Nujo #): 5650~31[]0.1770
．． 1660° 1610, 1550, 15103 N (D20.δ>: 3.18 and 5.72 (
2H, ABq・J=18Hz), 4J)7(3H,s)
, 4.70 (2H, s), 532 (IH, d, J=5H
z), 532 and 5.65 (2H.

ABq, J=14Hz), 5.92(IH,d
, J==5Hz).

8.13 (IH, m), 8.57 (IH, m), 8.7
0(IH, m).

8.95 (IH, Broad S) 7-[2-methoxyimino-2-(5-amino-
1,2,4-thiadiazole-6-y/I/)acetamido)-5-(4-(5-hydroxypropyl)-1-
Pyridiniomethyl/l/)-5-cephem-4-carboxylate (syn isomer), m915-120°C (decomposition).

IP (Nuzir): 6400-3100.1770j
660°1630, 1605, 152DrINM1
1t (D20.δ): 2.00 (2H, m), 3.00
(2H, t, J=6.5Hz), 3.0 to 3.8 (2H
, m), 3.62 (2H, t.

J = 65Hz), 4.02 (3H, s), 521 and 556 (2H, AB (1, J = 15) Tz), 5.23
(IH, d, J=5Hz), 5.84 (IH, d, J=
5Hz), 7.87 (2H.

d, J=7Hz), 8.74(2Ld, J=7Hz)(
547-(2-ethoxyimino-2-(5-amino-1
,2,4-thiadiazol-)v-6-yl)acetamyl
')-3-(3-carboxy-1-hydriniomethyl
)-5-cephem-4-carboxylate (syn isomer), mpl 59-166°C (decomposition) IR (nujirol): 3300, 3150.3050.1770°167
0.1650.1520z NMR (D20.δC1,27(3B, t, J=7Hz
), 3.25 and 3.70 (2H, ABq , J=1
8Hz), 4.32(2H,q.

J=7E(Z) −, 5,28(IH, d, J=5
Hz), 53B and 5.73(2H,ABq,
J=14Hz), 5.88 (IH, d, J=5Hz)
, 8.15 (IH, m) , 9.03 (2H, m)
, 9.40 (1H1) Seed S) 0-7-[2-ethoxyimino-2-(5-amino-
1,2,4-thiadiazol-6-yl)acetamido)-3-(4-formamido-1-pyridi-niomethyl)-6-cephem-4-carboxylate (syn isomer), r1158-165°C (decomposition) ).

IR: 3280.3160-1770
,1710°1660.1630.1600.1530
, 1515cIr'NMR(D20.δ)': 1.30
(3H, t, J=7Hz), 3.13 and 3.67 (
2H,ABq, J=18&), 4AO(2H,q.

J=7Hz), 5.1 to 5.5 (3H, m), 5.
83 (IH, d.

J=sHzL 7.97 (2H, d, J=7Hz), 8
．． 67 (1H, Broad S), 8.75C2H, d,
J=7Hz) Example 5 7-[2-methoxyimino-2-(5-amino-1,2
,4-thiadiazol-3-yl)acetamide)-3
-(3,5-dimethyl-1-pyridiniomethyl→-6-
Heptafemu 4-carboxylate (syn isomer) (50
Dissolve the powder of 'P) in water (25 m/m) and leave it in the refrigerator for several days. The resulting crystals are collected and used as crystal seeds.

7-[2-methoxyimino-2-(5-amino-1,2
,4-Thiadiazo-A/-3-i/L/)acedo"mido)-3-<↓5-dimethyA/-1-pyridiniomethyl)-5-cephem-4-carboxylate (syn isomer) (1 , 58F) in water (1.6 m+/), add the crystals of the standard product obtained earlier as crystal seeds, and leave it in the refrigerator overnight.The resulting crystals are taken out of the oven and washed with cold water. , dried to form colorless crystals of 7-[2-methoxyimino-2
-(5-amino-1,2,4-thiadiazo-)v-3-
yl)acetamido)-3-1,5-dimethyzlz-1
-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (370~) is obtained.

Similar to Example 5, crystal forms of other compounds of the above examples are also obtained.

Applicant: Fujisawa Pharmaceutical Co., Ltd.

Claims (2)

[Claims] (1) General formula [wherein R is λ] or protected amino, R2 is lower alkyl, carboxy (lower) alkyl, lower alkenyl, lower alkynyl or cyclo (lower) alkenyl, R is amino 1, lower alkanoyl Amino, lower alkyl, hydroxy (lower) alkyl, carboxine, 2 talol, lower alkanoyl, hydroxyimino (lower) alkyl, oxaloamino or lower alkanoylamino (
(lower) alkyl R4 means hydrogen or lower alkyl, respectively] and salts thereof. (2)) General formula R is lower alkyl, carboxy(lower)alkyl, lower alkyl, hydroxy(lower)alkyl, carboxy, chloro, lower alkanoyl, roximino(lower)alkyl, oxaloamino or lower alkanoylamino(lower) alkyl, R4 means hydrogen or lower alkyl, respectively] (in which R3 and R4 each have the same meanings as above) or a salt thereof. to obtain a novel cephem compound or a salt thereof represented by the general formula (wherein R1, R2, R3 and R4 each have the same meaning as before) or (wherein R1, R2 and R4 each have the same meaning as before). , R5a means lower alkanoylamino, and E3b means amino, respectively) or salts thereof. A method for producing cephem compounds and their salts. [Wherein, B1 is amine or protected amino, R2 is lower alkyl, carboxy (lower i) alkyl, lower alkenyl, lower alkynyl or cyclo (lower) alkenyl, and R3 is amino, lower alkanoylamino, lower alkyl, hydroxy (lower ) alkyl, carboxy, chlor, lower alkanoyl, hydroxyimino (lower) alkyl, oxaloamino or lower alkanoylamino (
A prophylactic/therapeutic agent for bacterial infections containing a novel cephem compound and its salts as active ingredients.