JPH085897B2 - 3-propenyl cephem derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Object of the Invention] The present invention relates to a novel cephem derivative useful as an antibacterial agent.

Conventionally, a cephem derivative having an ammoniopropenyl group at the 3-position is known in JP-A-59-172493 and JP-A-61-5094.

The present inventors have found that a cephem derivative having an ammoniopropenyl group at the 3-position and a fluorine-substituted lower alkoxyimino group at the side chain at the 7-position has excellent antibacterial activity, and completed the present invention. is there.

Accordingly, an object of the present invention is to provide a novel compound useful as an antibacterial agent, a method for producing the same, and an antibacterial agent comprising the same.

[Structure of Invention]

The present invention has the general formula: [In the formula, R ₁ represents a fluorine-substituted lower alkyl group, A represents a cyclic or acyclic ammonio group] and a 3-propenyl cephem derivative and a non-toxic salt thereof.

Examples of the fluorine-substituted lower alkyl group for R _{1 in} the general formula (I) include fluoromethyl, difluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-fluoroethyl, 2-fluoropropyl, 1- (fluoromethyl) -2-fluoroethyl, 3-fluoropropyl and the like can be mentioned, with fluoromethyl being particularly preferred.

Examples of the acyclic ammonio group represented by A in the general formula (I) include the groups shown below.

[In the formula, R ₂ , R ₃ and R ₄ are the same or different, and a lower alkyl group, a hydroxy-substituted lower alkyl group, a carbamoyl-substituted lower alkyl group, a cyano-substituted lower alkyl group, an amino group, a lower alkylcarbonylamino-substituted lower alkyl group , Aminosulfonylaminocarbonyl-substituted lower alkyl group, lower alkylsulfonylaminocarbonyl-substituted lower alkyl group, lower alkylaminocarbonyl-substituted lower alkyl group, hydroxy and carbamoyl-substituted lower alkyl group, hydroxy and hydroxy lower alkylaminocarbonyl-substituted lower alkyl group, lower Alkyloxyaminocarbonyl-substituted lower alkyl group, hydroxyaminocarbonyl-substituted lower alkyl group, carbamoyl lower alkylaminocarbonyl-substituted lower alkyl group, hydroxy lower alkyl Aminocarbonyl-substituted lower alkyl group, (carboxylate lower alkyldi-lower alkylammonio) -substituted lower alkyl group, lower alkylamino-substituted lower alkyl group, di-lower alkylamino and hydroxy-substituted lower alkyl group, ureido group, hydroxy group,
Carboxy-substituted lower alkyl group, lower alkyloxy-substituted lower alkyl group, di-lower alkylaminocarbonyl-substituted lower alkyl group, dicarbamoyl-substituted lower alkyl group, bis (hydroxy lower alkyl) aminocarbonyl-substituted lower alkyl group, dihydroxy-substituted lower alkyl group, Trihydroxy-substituted lower alkyl group, bis (hydroxy lower alkyl) amino-substituted lower alkyl group, amino-substituted lower alkyl group, oxo-substituted lower alkyl group, di-lower alkylamino-substituted lower alkyl group, 5-membered heterocyclic-substituted lower alkyl group (5 Member heterocycles include groups selected from pyrazolyl, imidazolyl, oxadiazolyl, tetrazolyl, etc.), and examples of the cyclic ammonio group of A in general formula (I) include the groups shown below. it can.

[In the formula, R ₅ is a lower alkyl group, a carbamoyl-substituted lower alkyl group, an amino-substituted lower alkyl group, a hydroxy-substituted lower alkyl group, a carboxy-substituted lower alkyl group, a cyano-substituted lower alkyl group, a dihydroxy-substituted lower alkyl group, a ureido-substituted lower alkyl group. A group selected from alkyl groups, wherein the cyclic ammonio group further has a hydroxy-substituted lower alkyl group, a hydroxy group, a formyl group, a sulfonic acid group, a carboxy-substituted lower alkyl group, a carbamoyl group, a sulfamoyl group, a carboxyl group on the ring. , Hydroxyimino-substituted lower alkyl group, imino-substituted lower alkyl group, bis (hydroxy lower alkyl) aminocarbonyl group, hydroxy lower alkylaminocarbonyl group, amino group, morpholinocarbonyl group, carboxy lower alkyloxy substituted lower alkyl group Kill group, carboxy lower alkylthio group, sulfo-substituted lower alkyl group, which may have a substituent selected from a lower alkyl group].

Further, the lower alkyl group in the definition of A (R _{2 to} R ₅ ) in the general formula (I) includes methyl, ethyl, n-propyl, i.
It includes an alkyl group having 1 to 4 carbon atoms such as -propyl, n-butyl, i-butyl, sec-butyl, t-butyl.

Non-toxic salts of the compound of the formula (I) include pharmaceutically acceptable salts, for example, alkali metal salts such as sodium salt and potassium salt; ammonium salts; quaternary ammonium salts such as tetraethylammonium salt and betaine salt; Alkaline earth metal salts such as salts and magnesium salts;
Inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, carbonate, bicarbonate; acetate, maleate,
Organic carboxylates such as lactate and tartrate; organic sulfonates such as methanesulfonate, hydroxymethanesulfonate, hydroxyethanesulfonate, taurine, benzenesulfonate and toluenesulfonate; arginine salts , Lysine salt, serine salt, aspartate,
Amino acid salts such as glutamate and glycine; trimethylamine, triethylamine, pyridine, procaine, picoline, dicyclohexylamine, N,
And amine salts such as N'-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, tris (hydroxymethylamino) methane salt and phenethylbenzylamine salt.

Concerning the configuration of the following moiety of the compound of the present invention of the general formula (I), There are syn isomer (Z) and anti isomer (E). Although both isomers are included in the present invention, syn isomers are preferred from the viewpoint of antibacterial activity.

The compound of the present invention can be produced by the following method.

General formula: [Wherein R ₁ is a fluorine-substituted lower alkyl group, X is a halogen atom], a compound in which an amino group and / or a carboxyl group is protected with a protecting group, or a salt of these compounds is represented by the formula: A '(III) [A' represents an amine corresponding to the above A], a compound whose functional group is protected by a protecting group,
Alternatively, salts of these compounds can be reacted and, if necessary, the protecting group can be removed to obtain the compound of the general formula (I) or a non-toxic salt thereof.

Examples of the halogen atom represented by X in the general formula (II) include iodine atom, bromine atom and chlorine atom.

The reaction temperature is -10 ° C to 60 ° C, preferably 0 ° C to
Can be performed at 40 ° C. Further, as the reaction solvent, an anhydrous organic solvent is desirable. Examples of the organic solvent which can be used include lower alkyl nitriles such as acetonitrile and propionitrile; lower alkyl halides such as chloromethane, dichloromethane and chloroform; ethers such as tetrahydrofuran, dioxane and ethyl ether; amides such as dimethylformamide; Esters such as ethyl acetate; ketones such as acetone; hydrocarbons such as benzene; alcohols such as methanol and ethanol; sulfoxides such as dimethyl sulfoxide; and mixed solvents thereof.

The elimination of the protecting group can be performed by a conventional method such as hydrolysis or reduction depending on the type of the protecting group used.

As the salts and protecting groups of the compounds of the general formulas (II) and (III), those usually used can be used as long as they do not hinder the above reaction.

For example, as a protecting group for amino group, formyl group, acetyl group, chloroacetyl group, dichloroacetyl group, phenylacetyl group, thienylacetyl group, t-butoxycarbonyl group, benzyloxycarbonyl group, trityl group, p
-Methoxybenzyl group, diphenylmethyl group, benzylidene group, p-nitrobenzylidene group, m-chlorobenzylidene group and the like; protective groups for carboxyl group include p-methoxybenzyl group, p-nitrobenzyl group, t-butyl group, Examples include a methyl group, a 2,2,2-trichloroethyl group, a diphenylmethyl group, and a pivaloyloxymethyl group. In addition, silylating agents such as N, O-bis (trimethylsilyl) acetamide, N-methyl-N- (trimethylsilyl) acetamide, N-methyl-N- (trimethylsilyl) trifluoroatamide, N- (trimethylsilyl) acetamide are used. This is convenient because the amino group and the carboxyl group can be protected at the same time.

As salts of the compounds of the general formulas (II) and (III),
For example, alkali metal salts such as sodium salt and potassium salt,
Alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; quaternary ammonium salt such as triethylammonium salt and betaine salt; hydrochloride, hydrobromide, sulfate, carbonate, hydroiodide, Inorganic acid salts such as bicarbonates; Acetates, trifluoroacetates, maleates, lactates, tartarates and other organic carboxylates; methanesulfonates, hydroxymethanesulfonates, hydroxyethanesulfonates, Taurine salt, benzene sulfonate,
Organic sulfonates such as toluene sulfonate; trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, N, N '
-Dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt,
Amine salts such as tris (hydroxymethylamino) methane salt and phenethylbenzylamine salt; arginine salt, asparaginate salt, lysine salt, glutamate salt, serine salt,
It can be appropriately selected from salts such as amino acid salts such as glycine salts.

The compound of the present invention has a strong antibacterial activity against Gram-negative bacteria and Gram-positive bacteria and is useful as an antibacterial agent.

When the compound of the present invention is used as an injection, it is usually 1
The daily dose of 100 mg to 10 g can be administered intravenously or intramuscularly in 1 to 4 times. The dose may be adjusted according to age and symptoms.

An injection can be produced by a conventional method. For example,
The compound of the present invention can be dissolved in distilled water in the presence of an isotonic agent, a solubilizing agent, and the like, if necessary, to give an injection solution.
In addition, it can be filled in a vial or the like in the form of a powder to obtain a dissolvable injection at the time of use. This injection is used by dissolving it in distilled water for injection, physiological saline, glucose injection, amino acid infusion and the like at the time of administration.

Next, the present invention will be described in more detail with reference to experimental examples and examples.

Experimental Example 1 (Synthesis of raw material compound) Ethyl 2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluorylomethoxyiminoacetate 60.4 g of ethyl 2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z) -2-hydroxyiminoacetate was dissolved in 210 ml of dimethyl sulfoxide, and 96.48 g of potassium carbonate was dissolved under ice cooling. The mixture was stirred for 10 minutes. Then, 19 g of bromofluoromethane was added, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate 1 was added to the reaction solution, which was washed with water and then saturated brine, dried over anhydrous magnesium sulfate, and dried. The solvent was distilled off, and 120 ml ethanol was added to the residue.
Was added. The precipitated crystals were collected by filtration and washed with ethanol to obtain 58.2 g of the desired product.

Experimental Example 2 (Synthesis of raw material compound) 2- (5-tritylamino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetic acid Sodium hydroxide 2.04g, ethanol 146ml and water 29m
17.87 g of the compound of Experimental Example 1 was added to the mixed solution of 1 and stirred under reflux for 20 minutes. The reaction mixture was concentrated under reduced pressure, and 200 ml of ethyl acetate and 77 ml of 1N hydrochloric acid were added. The ethyl acetate layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and dried. The solvent was distilled off to obtain crystals. Petroleum ether was added to the crystals, and the crystals were pulverized and collected by filtration to obtain 16.55 g of the desired product.

Experimental Example 3 (Synthesis of Starting Compound) p-methoxybenzyl 7β- [2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-
2-Fluoromethoxyiminoacetamide] -3-
[(Z) -3-Chloro-1-propen-1-yl] -3
-Cephem-4-carboxylate Dimethylformamide (348 μl) and tetrahydrofuran (4.1 ml) were cooled to −10 ° C., phosphorus oxychloride (418 μl) was added, and the mixture was stirred under ice cooling for 90 minutes. Experimental Example 2 was added to this solution.
A solution of 1.73 g of the compound of Example 1 in 5.5 ml of tetrahydrofuran at -10 ° C.
After cooling, the mixture was stirred for 90 minutes under ice cooling. -2
It was cooled to 0 ° C. and p-methoxybenzyl 7β-amino-3-[(Z) -3-chloro-1-propene-1-
Il] -3-cephem-4-carboxylate hydrochloride 1.
A mixture of 78 g, N- (trimethylsilyl) acetamide 2.95 g, ethyl acetate 18 ml and tetrahydrofuran 5.5 ml was added, and the mixture was stirred at -10 ° C for 1 hour. Ethyl acetate 10 in the reaction solution
0 ml was added, and the mixture was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and dried. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 2.65 g of the desired product.

Experimental Example 4 (Synthesis of raw material compound) p-methoxybenzyl 7β- [2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-
2-Fluoromethoxyiminoacetamide] -3-
[(E) -3-Iodo-1-propen-1-yl] -3
-Cephem-4-carboxylate 10.11 g of the compound of Experimental Example 3 was dissolved in 212 ml of acetone,
Under ice cooling, 9.03 g of sodium iodide was added, and the mixture was stirred for 15 minutes and then at room temperature for 90 minutes. The solvent was distilled off, and the residue was extracted with 500 ml of ethyl acetate. The extract was washed with saturated aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and dried. This was concentrated under reduced pressure, and n-hexane was added. The resulting precipitate was collected by filtration to obtain 10.92 g of the desired product.

Experimental Example 5 (Synthesis of raw material compound) p-methoxybenzyl 7β- [2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-
2-difluoromethoxyiminoacetamide] -3-
[(Z) -3-Chloro-1-propen-1-yl] -3
-Cephem-4-carboxylate In the same manner as in Experimental Example 3, 2- (5-tritylamino-1,
2.00 g of 2,4-thiadiazol-3-yl)-(Z) -2-difluoromethoxyiminoacetic acid and p-methoxybenzyl 7β-amino-3-[(Z) -3-chloro-1-propen-1-yl ] -3-Cephem-4-carboxylate hydrochloride 1.795 g was reacted to obtain 3.17 g of the desired product.

Experimental Example 6 (Synthesis of raw material compound) p-methoxybenzyl 7β- [2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-
2-difluoromethoxyiminoacetamide] -3-
[(E) -3-Iodo-1-propen-1-yl] -3
-Cephem-4-carboxylate In the same manner as in Experimental Example 4, 3.00 g of the compound of Experimental Example 5 was reacted with 2.62 g of sodium iodide to obtain 2.92 g of the desired product.

Experimental Example 7 (Synthesis of raw material compound) p-methoxybenzyl 7β- [2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-
2- (2,2,2-Trifluoroethyl) oxyiminoacetamido] -3-[(Z) -3-chloro-1-propen-1-yl] -3-cephem-4-carboxylate A mixed solution of 0.247 ml of dimethylformamide and 3 ml of tetrahydrofuran was cooled to -10 ° C, and 0.297 ml of phosphorus oxychloride was added.
ml was added, and the mixture was stirred under ice cooling for 40 minutes. In this solution,
(5-Tritylamino-1,2,4-thiadiazole-3-
Yl)-(Z) -2- (2,2,2-trifluoroethyl)
A solution of 1.36 g of oximinoacetic acid in 4 ml of tetrahydrofuran was added, and the mixture was further stirred at the same temperature for 1 hour. p-methoxybenzyl 7β-amino-3-[(Z) -3-chloro-1
-Propen-1-yl] -3-cephem-4-carboxylate hydrochloride 1.145 g, N- (trimethylsilyl) acetamide 2.09 g, and ethyl acetate 10 ml were added to the mixture by cooling to -20 ° C. Then, the temperature was raised to 0 ° C. with stirring for 1 hour. After adding ethyl acetate to the reaction solution, washing with water,
Anhydrous sodium sulfate was added and dried. Evaporate the solvent,
The residue was purified by silica gel column chromatography to obtain 1.43 g of the desired product.

Example 1 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (carbamoylmethylethylmethylammonio) -1-propen-1-yl]
-3-Cephem-4-carboxylate 550 mg of the compound of Experimental Example 4 was dissolved in a mixed solution of ethyl acetate (20 ml) and ethyl ether (10 ml), 117 mg of ethylmethylaminoacetamide was added, and the mixture was stirred at room temperature for 4 hours and 30 minutes. Isopropyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration and dried to obtain 400 mg of yellowish brown powder.

Trifluoroacetic acid (4.5 ml) -anisole (4 m
After stirring for 1 hour under ice-cooling in the mixed solution of l), ethyl ether was added. The resulting precipitate was collected by filtration and washed with ethyl ether. Suspend this precipitate in 5 ml of water and adjust the pH with sodium acetate.
Adjusted to 5.5-6.5. The insoluble material was filtered off, and the filtrate was purified by reverse-phase silica gel column chromatography to give the desired compound 49.
to obtain mg.

Example 2 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- [1- (2-hydroxyethyl) -4-carbamoyl-1-piperidinio]-
1-propen-1-yl] -3-cephem-4-carboxylate 700 mg of the compound of Experimental Example 4 was dissolved in 3 ml of dimethylformamide to prepare 1- (2-hydroxyethyl) isonipecotamide.
A solution of 194 mg of dimethylformamide in 0.5 ml was added, and the mixture was stirred overnight. The reaction solution was added to 120 ml of ethyl ether, and the resulting precipitate was collected by filtration and 680 mg of yellow powder was added.

4.5 ml of anisole was added to this powder, and 5.3 ml of trifluoroacetic acid was added dropwise over 30 minutes under ice-cooling stirring, and the mixture was further stirred for 1 hour and 30 minutes after the completion of dropping. 50 ml of isopropyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration. Water this 30
It was suspended in ml and adjusted to pH 7.0 with sodium acetate. The resulting insoluble matter was filtered off, and the filtrate was purified by reverse phase silica gel column chromatography to obtain the following two isomers of the title compound.

Isomer (2-1) 21 mg Isomer (2-2) 20 mg 1: 1 mixture of the above isomers 50 mg Example 3 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3-[(1S-carbamoylethyl) dimethylammonio] -1-propen-1-yl] -3-cephem -4-carboxylate (3-1) 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3-[(1R-carbamoylethyl ) Dimethylammonio] -1-propene-1-
Il] -3-cephem-4-carboxylate (3-
2) 600 mg of the compound of Experimental Example 4 was dissolved in a mixed solution of ethyl acetate (20 ml) and ethyl ether (10 ml), 2-dimethylaminopropylamide (150 mg) was added, and the mixture was stirred at room temperature for 3 hours.
Isopropyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration and dried to obtain 550 mg of yellowish brown powder.

Add this powder to trifluoroacetic acid (5.5 ml) anisole (5
ml), and after stirring for 1 hour under ice cooling, ethyl ether was added. The precipitate formed was collected by filtration and washed with ethyl ether. Suspend this precipitate in 5 ml of water and pour with sodium acetate.
Adjusted to H5.5-6.5. The insoluble material was filtered off, and the filtrate was purified by reverse-phase silica gel column chromatography to obtain the target (3-1) 8 mg, (3-2) 7 mg, (3-1) and (3).
2 mg of the mixture (-2) (1: 1) was obtained.

Example 4 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3-[(2-hydroxypropyl) dimethylammonio] -1-propen-1-yl] -3-cephem -4-carboxylate 550 mg of the compound of Experimental Example 4 was dissolved in a mixed solution of ethyl acetate (20 ml) and ethyl ether (10 ml), 3-dimethylamino-2-propanol (0.124 ml) was added, and the mixture was stirred at room temperature for 1 hour 30 hours.
Stir for minutes. Isopropanol was added to the reaction solution, and the resulting precipitate was collected by filtration and dried to obtain 530 mg of yellowish brown powder.

This powder was stirred in a mixed solution of trifluoroacetic acid (5.5 ml) and anisole (5 ml) under ice cooling for 1 hour, and ethyl ether was added. The precipitate formed was collected by filtration and washed with ethyl ether. The precipitate was suspended in 5 ml of water and the pH was adjusted with sodium acetate.
Adjusted to 5.5-6.5. The insoluble material was filtered off, and the filtrate was purified by reverse-phase silica gel column chromatography to give the desired product 70
to obtain mg.

Example 5 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamide] -3-[(E) -3-[(1R-carbamoyl-2-hydroxyethyl) dimethylammonio] -1-
Propen-1-yl] -3-cephem-4-carboxylate 1.00 g of the compound of Experimental Example 4 was dissolved in 2 ml of dimethylformamide. 590 mg of N, N-dimethyl-D-serinamide trifluoroacetate was dissolved in 5 ml of methanol, 2.4 ml of 1N-sodium hydroxide aqueous solution was added, the solvent was distilled off under reduced pressure, and extracted with 2 ml of acetonitrile to extract N, N-dimethyl-D-
A serinamide solution was prepared. This N, N-dimethyl-D
-The serinamide solution was added to the dimethylformamide solution of the compound of Experimental Example 4 under ice cooling, and the mixture was stirred for 30 minutes.
The reaction solution was added to ethyl ether, and the formed precipitate was collected by filtration to obtain 1.1 g of a yellow powder.

8 ml of anisole was added to this powder, and 9 ml of trifluoroacetic acid was added dropwise over 30 minutes while stirring with ice cooling, followed by 3 hours for 1 hour.
It was stirred for 0 minutes. Ethyl ether was added to the reaction solution and the resulting precipitate was collected by filtration. The precipitate was suspended in 10 ml of water and adjusted to pH 7 with sodium acetate. The insoluble material was filtered off, and the filtrate was purified by reverse-phase silica gel column chromatography to obtain 30 mg of the desired product.

Example 6 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (4R-hydroxy-2R
-Hydroxymethyl-1-methyl-1-pyrrolidinio)
-1-Propene-1-yl] -3-cephem-4-carboxylate 700 mg of the compound of Experimental Example 4 was dissolved in 4 ml of acetone, a solution of 89 mg of N-methyl-cis-4-hydroxy-D-prolinol in 2 ml of acetone was added, and the mixture was stirred overnight. The reaction solution was added to 100 ml of ethyl ether, and the formed precipitate was collected by filtration to obtain 700 mg of a yellow powder.

4.5 ml of anisole was added to this powder, and 5.3 ml of trifluoroacetic acid was added dropwise over 30 minutes while stirring with ice cooling.
The mixture was stirred for 30 minutes. 50 ml of isopropyl ether in the reaction solution
Was added and the resulting precipitate was collected by filtration. This precipitate was suspended in 30 ml of water and adjusted to pH 7 with sodium acetate. The insoluble material was filtered off, and the filtrate was purified by reverse-phase silica gel column chromatography to obtain the following two isomers (related to the nitrogen atom of pyrrolidine).

Isomer (6-1) 27 mg Isomer (6-2) 100 mg Example 7 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- [4R-hydroxy-1]
-(2-hydroxyethyl) -2S-hydroxymethyl-
1-pyrrolidinio] -1-propen-1-yl] -3-
Cephem-4-carboxylate 2.0 g of the compound of Experimental Example 4 was added to (R) -4-hydroxy-1
5 ml of dimethylformamide containing 450 mg of-(2-hydroxyethyl)-(S) -2-hydroxymethylpyrrolidine
Add to solution and stir overnight. The reaction solution was added to ethyl acetate, and the formed precipitate was collected by filtration to obtain 1.65 g of a yellow powder.

10 ml of anisole was added to this powder, 11.7 ml of trifluoroacetic acid was added dropwise over 30 minutes under ice-cooling stirring, and the mixture was further stirred for 1 hour and 30 minutes. Isopropyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration. The precipitate was suspended in 4.5 ml of water and adjusted to pH 7 with sodium acetate. The insoluble material was filtered off, and the filtrate was purified by reverse-phase silica gel column chromatography to obtain two isomers of the title compound (related to the nitrogen atom of pyrrolidine).

Isomer (7-1) 96 mg Isomer (7-2) 207 mg Example 8 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (4R-hydroxy-2S
-Hydroxymethyl-1-methyl-1-pyrrolidinio)
-1-Propene-1-yl] -3-cephem-4-carboxylate The compound of Experimental Example 4 (700 mg) was dissolved in acetone (4 ml) and N-methyl-trans-4-hydroxy-L-prolinol 89 was added.
A solution of 2 mg of acetone in 2 ml was added, and the mixture was stirred overnight. The reaction solution was added to 100 ml of ethyl ether, and the formed precipitate was collected by filtration to obtain 700 mg of a yellow powder.

4.5 ml of anisole was added to this powder, and 5.3 ml of trifluoroacetic acid was added dropwise over 30 minutes while stirring with ice cooling.
The mixture was stirred for 30 minutes. 50 ml of isopropyl ether in the reaction solution
Was added and the resulting precipitate was collected by filtration. This was suspended in 30 ml of water and adjusted to pH 7 with sodium acetate. The insoluble material was filtered off, and the filtrate was purified by reverse phase silica gel column chromatography to obtain 92 mg of the desired product.

Example 9 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (1-carbamoylmethyl-3-hydroxy-1-pyrrolidinio) -1-propen-1-yl]- 3-cephem-4-carboxylate 1.0 g of the compound of Experimental Example 4 was dissolved in 4 ml of dimethylformamide, a solution of 186 mg of N-carbamoylmethyl-3-hydroxypyrrolidine in 2 ml of dimethylformamide was added, and the mixture was stirred overnight. The reaction solution was added to 200 ml of ethyl ether, and the resulting precipitate was collected by filtration to obtain 970 mg of a yellow powder.

9.0 ml of anisole was added to this powder, and 10.6 ml of trifluoroacetic acid was added dropwise over 30 minutes while stirring with ice cooling.
The mixture was stirred for 30 minutes. 80 ml of isopropyl ether in the reaction solution
Was added and the resulting precipitate was collected by filtration. It was suspended in 50 ml of water and adjusted to pH 7 with sodium acetate. The insoluble material was filtered off, and the filtrate was purified by reversed-phase silica gel column chromatography to give various isomers of the title compound (related to the nitrogen atom and the carbon atom at the 3-position of pyrrolidine, 4 types in high performance liquid chromatography). Got

Isomer (9-1) 71 mg (mixture of two types) Isomer (9-2) 70 mg (single) Isomer (9-3) 54 mg (single) Example 10 7β- [2- (5- Amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (1-methyl-4-sulfo-1-piperazinio) -1-propen-1-yl]
-3-Cephem-4-carboxylate 2.0 g of the compound of Experimental Example 4 was added to a mixed solution of 718 mg of 4-methylpiperazinosulfonic acid sulfate, 2 ml of N-methyl-N- (trimethylsilyl) trifluoroacetamide and 6 ml of dimethylformamide, and the mixture was stirred overnight. 2 ml of methanol was added to the reaction solution, and the insoluble material was filtered off. The filtrate was added to a mixed solution of 50 ml of ethyl acetate and 50 ml of ethyl ether, and the resulting precipitate was collected by filtration to obtain 1.79 g of a yellow powder.

10.9 ml of anisole was added to this powder, and 12.7 ml of trifluoroacetic acid was added dropwise over 30 minutes while stirring with ice cooling.
The mixture was stirred for 30 minutes. 100m of isopropyl ether in the reaction solution
l was added and the resulting precipitate was collected by filtration. This was suspended in 4.5 ml of water and adjusted to pH 7 with sodium acetate. The insoluble material was filtered off, and the filtrate was purified by reverse-phase silica gel column chromatography to obtain 50 mg of the desired product.

Example 11 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (1-carbamoylmethyl-4-hydroxy-1-piperidinio) -1-propen-1-yl]- 3-cephem-4-carboxylate 1.0 g of the compound of Experimental Example 4 was dissolved in 9 ml of acetone, 206 mg of N-carbamoyl-4-hydroxypiperidine was added, and the mixture was stirred overnight. The reaction solution was added to 100 ml of a mixed solution (2: 1) of ethyl ether and isopropyl ether, and the resulting precipitate was collected by filtration to obtain 1.0 g of a yellow powder.

9.0 ml of anisole was added to this powder, and 10.6 ml of trifluoroacetic acid was added dropwise over 30 minutes while stirring with ice cooling.
The mixture was stirred for 30 minutes. 80 ml of isopropyl ether in the reaction solution
Was added and the resulting precipitate was collected by filtration. This was suspended in 50 ml of water and adjusted to pH 7.0 with sodium acetate. The insoluble material was filtered off, and the filtrate was purified by reverse-phase silica gel column chromatography to obtain 166 mg of the desired product.

Example 12 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (5-aza-1-methyl-2,8-dioxabicyclo [3,3,1] nonane -5-Io) -1-propen-1-yl] -3-cephem-4-
Carboxylate The compound of Experimental Example 4 was dissolved in 10 ml of dimethylformamide, 800 mg of 5-aza-1-methyl-2,8-dioxabicyclo [3,3,1] nonane was added at room temperature, and the mixture was stirred for 20 minutes. 25 ml of ethyl acetate was added to the reaction solution to dilute it, and this was added dropwise to ethyl ether to obtain 3.85 g of a brown precipitate.

This precipitate was dissolved in 23 ml of anisole, 26 ml of trifluoroacetic acid was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. Ethyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration. The precipitate was suspended in 40 ml of water and adjusted to pH 7.0 with sodium acetate. The insoluble material was filtered off, and the filtrate was purified by reverse-phase silica gel column chromatography to obtain 408 mg of the desired product.

The following compounds of Examples 13 to 113 were produced in the same manner as in Examples 1 to 12.

In some cases, a plurality of isomers were formed due to the portion of the ammonium group of A. When the isomers were separated, the yield was shown for each isomer.

 The following abbreviations are used.

Boc: t-butoxycarbonyl group ^t Bu: t-butyl group BH: Benzhydryl group Tr: Trityl group Example 114 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-difluoromethoxyiminoacetamido] -3-[(E) -3- (dimethylcarbamoylmethylammonio) -1-propen-1-yl]-
3-cephem-4-carboxylate 500 mg of the compound of Experimental Example 6 was dissolved in a mixed solution of 10 ml of ethyl acetate and 10 ml of ethyl ether, and dimethylglycinamide 16 was added.
0 mg was added, and the mixture was stirred at room temperature for 30 minutes. Isopropyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration and dried to obtain 400 mg of yellowish brown powder.

This powder was stirred in a mixed solution of 5 ml of trifluoroacetic acid and 4.5 ml of anisole under ice cooling for 1 hour. Ethyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration and washed with ethyl ether. Suspend this precipitate in 5 ml of water and pour with sodium acetate.
Adjusted to H5.5-6.5. The insoluble material is filtered off and the filtrate is purified by reverse phase silica gel column chromatography to obtain the desired product.
Obtained 55 mg.

The compounds of the following Examples 115 to 117 were prepared in the same manner as in Example 114.

Example 118 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (carbamoylmethyldimethylammonio) -1-propen-1-yl] -3
-Cephem-4-carboxylate 500 mg of the compound of Experimental Example 4 was dissolved in a mixed solution of 3 ml of methanol and 1 ml of dimethylformamide, 71.3 mg of N, N-dimethylglycinamide was added under ice cooling, and the mixture was stirred overnight at room temperature.
The reaction mixture was added to a mixture of 50 ml of ethyl acetate and 50 ml of ethyl ether, and the resulting precipitate was collected by filtration and dried to give a yellow powder.
2 mg was obtained.

2.7 ml of trifluoroacetic acid and anisole 2.3
The mixture was added to the mixed solution of ml and stirred for 2 hours under ice cooling. The reaction solution was added to a mixed solution of 25 ml of ethyl ether and 25 ml of isopropyl ether, and the formed precipitate was collected by filtration and washed with ethyl ether. This precipitate was suspended in 4.5 ml of water, the solution was adjusted to pH 5.5 to 6.5 with sodium acetate, and the insoluble material was filtered off. The filtrate was purified by reverse phase silica gel column chromatography to obtain 94 mg of the desired product.

Example 119 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (1-methyl-4-sulfamoyl-1-piperazinio) -1-propene-1
-Yl] -3-cephem-4-carboxylate 500 mg of the compound of Experimental Example 4 was dissolved in a mixed solution of 3 ml of methanol and 1 ml of dimethylformamide, and N-sulfamoyl-
116 mg of N'-methylpiperazine was added under ice cooling, and the mixture was stirred at room temperature overnight. The reaction solution was added to a mixed solution of 50 ml of ethyl acetate and 50 ml of ethyl ether, and the resulting precipitate was collected by filtration and dried to obtain 402 mg of a yellow powder.

This compound was mixed with 2.8 ml of trifluoroacetic acid and 2.5 of anisole.
The mixture was added to the mixed solution of ml and stirred for 2 hours under ice cooling. This reaction solution was added to a mixed solution of 25 ml of ethyl ether and 25 ml of isopropyl ether, and the resulting precipitate was collected by filtration and washed with ethyl ether. This precipitate was suspended in 4.5 ml of water, the solution was adjusted to pH 5.5 to 6.5 with sodium acetate, and the insoluble material was filtered off. The filtrate was purified by reverse phase silica gel column chromatography,
58 mg of the target product was obtained.

Example 120 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- [1,3,4-oxadiazol-2-yl) methyldimethylammonio] -1-
Propen-1-yl] -3-cephem-4-carboxylate 500 mg of the compound of Experimental Example 4 was added to 1 ml of methanol and ethyl acetate.
Dissolve it in 4.8 ml of mixed solution, and add 2-dimethylaminomethyl-1,3,4
A solution of 88.8 mg of oxadiazole in 1 ml of ethyl acetate was added under ice cooling, and the mixture was stirred overnight at room temperature. This reaction solution was added to a mixed solution of 50 ml of ethyl acetate and 50 ml of ethyl ether, and the formed precipitate was collected by filtration and dried to obtain 443 mg of a yellow powder.

This compound was treated with 3.1 ml of trifluoroacetic acid and 2.7 of anisole.
The mixture was added to the mixed solution of ml and stirred for 2 hours under ice cooling. The reaction solution was added to a mixed solution of 25 ml of ethyl ether and 25 ml of isopropyl ether, and the resulting precipitate was collected by filtration and washed with ethyl ether. The precipitate was suspended in 4.5 ml of water, the solution was adjusted to pH 5.5 to 6.5 with sodium acetate, and the insoluble material was filtered off. The filtrate was purified by reverse phase silica gel column chromatography to obtain 92 mg of the desired product.

Example 121 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (1-methyl-4-carbamoyl-1-piperazinio) -1-propene-1-
Ill] -3-cephem-4-carboxylate 500 mg of the compound of Experimental Example 4 was dissolved in a mixed solution of 3 ml of methanol and 1 ml of dimethylformamide, 100 mg of N-methyl-N'-carbamoylpiperazine was added under ice cooling, and the mixture was stirred at room temperature overnight. 50 ml of ethyl acetate and 30 ml of ethyl ether
The resulting precipitate was collected by filtration and dried to obtain 425 mg of a yellow powder.

This compound was added to trifluoroacetic acid 3.0 ml and anisole 2.6
The mixture was added to the mixed solution of ml and stirred for 2 hours under ice cooling. The reaction solution was added to a mixed solution of 25 ml of ethyl ether and 25 ml of isopropyl ether, and the resulting precipitate was collected by filtration and washed with ethyl ether. The precipitate was suspended in 4.5 ml of water, the solution was adjusted to pH 5.5 to 6.5 with sodium acetate, and the insoluble material was filtered off. The filtrate was purified by reverse phase silica gel column chromatography to obtain 107 mg of the desired product.

Example 122 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (1,2-dimethyl-1)
-Pyrazolidinio) -1-propen-1-yl] -3-
Cephem-4-carboxylate (isomers: A and B) 738 mg of the compound of Experimental Example 4 was dissolved in a mixed solution of 1.5 ml of methanol and 7.1 ml of ethyl acetate to prepare N, N′-dimethylpyrazolidine 1
A solution of 03 mg of ethyl acetate in 1.5 ml was added under ice cooling, and the mixture was stirred overnight at room temperature. 50 ml of ethyl acetate and ethyl ether
The mixture was added to 50 ml of the mixed solution, and the formed precipitate was collected by filtration and dried to obtain 631 mg of a yellow powder.

This compound was added to trifluoroacetic acid 4.5 ml and anisole 3.8
The mixture was added to the mixed solution of ml and stirred for 2 hours under ice cooling. The reaction solution was added to a mixed solution of 25 ml of ethyl ether and 25 ml of isopropyl ether, and the resulting precipitate was collected by filtration and washed with ethyl ether. The precipitate was suspended in 4.5 ml of water, the solution was adjusted to pH 5.5 to 6.5 with sodium acetate, and the insoluble material was filtered off. The filtrate was purified by reverse phase silica gel column chromatography to obtain the desired isomer A 37 mg and isomer B 27 mg.

Example 123 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (1-methyl-4-formimidoyl-1-piperazinio) -1-propene-
1-yl] -3-cephem-4-carboxylate hydrochloride 750 mg of the compound of Experimental Example 4 was dissolved in a mixed solution of 4.5 ml of methanol and 1.5 ml of dimethylformamide to give N-methyl-N'-.
Formimidoylpiperazine hydrochloride (158 mg) was added under ice cooling, and the mixture was stirred at room temperature overnight. The reaction solution was added to a mixed solution of 50 ml of ethyl acetate and 30 ml of ethyl ether, and the resulting precipitate was collected by filtration and dried to obtain 485 mg of yellow powder.

This compound was added to trifluoroacetic acid 3.4 ml and anisole 3.0
The mixture was added to the mixed solution of ml and stirred for 2 hours under ice cooling. The reaction solution was added to a mixed solution of 25 ml of ethyl ether and 25 ml of isopropyl ether, and the formed precipitate was collected by filtration and washed with ethyl ether. This precipitate was suspended in 4.0 ml of water, and the insoluble material was filtered off.
The filtrate was purified by reverse phase silica gel column chromatography to obtain 58 mg of the desired product.

The compounds of the following Examples 124 to 140 were synthesized in the same manner as in Examples 118 to 123.

Example 124 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (1-methyl-1-piperazinio) -1-propen-1-yl] -3-cephem-4 -Carboxylate 750 mg of the compound of Experimental Example 4 and 116 μ of N-methylpiperazine
l was reacted and the protecting group was removed to obtain 16 mg of the desired product.

Example 125 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (4-carboxypyridinio) -1-propen-1-yl] -3-cephem-
4-carboxylate 750 mg of the compound of Experimental Example 4 was allowed to react with 198 mg of isonicotinic acid, and the protective group was eliminated to give 143 mg of the desired product.

Example 126 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (1-methylpyrrolidinio) -1-propen-1-yl] -3-cephem-4
-Carboxylate 500 mg of the compound of Experimental Example 4 and N-methylpyrrolidine 55.8
μl was reacted and the protecting group was removed to obtain 21 mg of the desired product.

Example 127 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (4-carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4- Carboxylate 500 mg of the compound of Experimental Example 4 and 4-carbamoylpyridine 1
31 mg was reacted and the protecting group was removed to obtain 42 mg of the desired product.

Example 128 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (trimethylammonio) -1-propen-1-yl] -3-cephem-4-
Carboxylate The compound of Experimental Example 4 (500 mg) was reacted with trimethylamine (trimethylamine hydrochloride 57 mg was used after neutralization),
The protective group was removed to obtain 79 mg of the desired product.

Example 129 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (1,4-diazabicyclo [2,2,2] octane-1-io) -1-propene- 1
-Yl] -3-cephem-4-carboxylate 500 mg of the compound of Experimental Example 4 and 1,4-diazabicyclo [2,2,
2) Reaction with 72 mg of octane to eliminate the protective group
1 mg was obtained.

Example 130 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (1,5-diazabicyclo [3,3,0] octane-1-io) -1-propene- 1
-Yl] -3-cephem-4-carboxylate The compound of Experimental Example 4 (500 mg) and 1,5-diazabicyclo [3,3,
0] React with 120 mg of octane to remove the protective group and obtain the desired product.
32 mg was obtained.

Example 131 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (4-methylthiomorpholine-1,1-dioxide-4-io) -1-propen-1-yl ] -3-Cephem-4-carboxylate The compound of Experimental Example 4 (250 mg) was reacted with 4-methylthiomorpholine-1,1-dioxide (52 mg) to remove the protecting group to obtain 17 mg of the desired product.

Example 132 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (1,4-dimethyl-1)
-Piperazinio) -1-propen-1-yl] -3-cephem-4-carboxylate Compound of Experimental Example 4 (500 mg) and 1,4-dimethylpiperazine 94
μl was reacted and the protecting group was removed to obtain 35 mg of the desired product.

Example 133 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3-[(2-aminoethyl) dimethylammonio] -1-propen-1-yl]
-3-Cephem-4-carboxylate 750 mg of the compound of Experimental Example 4 was reacted with 115 μl of N, N-dimethylethylenediamine to remove the protective group, and 15 mg of the desired product.
I got

Example 134 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3-[(tetrazole-5
-Yl) methyldimethylammonio] -1-propene-
1-yl] -3-cephem-4-carboxylate The compound of Experimental Example 4 (500 mg) was reacted with 5-dimethylaminomethyltetrazole (150 mg), and the protecting group was eliminated to give 37 mg of the desired product.

Example 135 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (3-sulfopyridinio) -1-propen-1-yl] -3-cephem-4-
Carboxylate 750 mg of the compound of Experimental Example 4 and 384 of 3-pyridinesulfonic acid
mg was reacted and the protecting group was removed to obtain 68 mg of the desired product.

Example 136 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3-[(2-dimethylaminoethyl) dimethylammonio] -1-propen-1-
Ill] -3-cephem-4-carboxylate The compound of Experimental Example 4 (500 mg) was reacted with N, N, N ', N'-tetramethylethylenediamine (105 µl) to remove the protecting group, thereby obtaining 22 mg of the desired product.

Example 137 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3-[(2-oxopropyl) dimethylammonio] -1-propen-1-yl]
-3-Cephem-4-carboxylate The compound of Experimental Example 4 (500 mg) was reacted with (dimethylamino) acetone (80 μl) to remove the protecting group, to obtain 60 mg of the desired product.

Example 138 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (4-carbamoylquinuclidinio) -1-propen-1-yl] -3-cephem-4 -Carboxylate The compound of Experimental Example 4 (500 mg) was reacted with 4-carbamoylquinuclidine (107.6 mg) to remove the protective group, and the target compound (77 mg) was removed.
I got

Example 139 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- [1-methyl-2-
(2-Hydroxyethyl) pyrrolidinio] -1-propen-1-yl] -3-cephem-4-carboxylate (isomers: A and B) The compound of Experimental Example 4 (500 mg) was reacted with 1-methyl-2- (2-hydroxyethyl) pyrrolidine (83.3 mg), and the protective group was removed to obtain the desired isomer A (24 mg) and isomer B (26 mg).

Example 140 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- [4-carboxymethylpyridinio) -1-propen-1-yl] -3-cephem-4 -Carboxylate Compound of Experimental Example 4 500 mg and 4-pyridyl acetic acid hydrochloride 280
mg was reacted and the protecting group was removed to obtain 5 mg of the desired product.

Example 141 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- (1,4,4-trimethyl-1-piperazinio) -1-propen-1-yl] -3
-Cephem-4-carboxylate iodide 1.0 g of the compound of Experimental Example 4 was suspended in 100 ml of ethyl ether, to which a solution of 189 μl of 1,4-dimethylpiperazine in 40 ml of ethyl acetate was added dropwise, and the mixture was stirred overnight. The generated precipitate was collected by filtration, reprecipitated with tetrahydrofuran-ethyl acetate, and washed with ethyl acetate to obtain 492 mg of a yellow powder. This was dissolved in 2 ml of dichloromethane, 4 ml of methyl iodide was added under ice cooling, and the mixture was stirred overnight at the same temperature. The reaction mixture was added to ethyl acetate, and the formed precipitate was collected by filtration to obtain 190 mg of yellowish brown powder.

This compound was mixed with 1.35 ml of trifluoroacetic acid and 1.
The mixture was added to 16 ml of the mixed solution, and the mixture was stirred under ice cooling for 2 hours. The reaction solution was added to a mixed solution of 25 ml of ethyl ether and 25 ml of isopropyl ether, and the resulting precipitate was collected by filtration and washed with ethyl ether. The precipitate was suspended in 4.5 ml of water and the insoluble material was filtered off. The filtrate was purified by reverse phase silica gel column chromatography to obtain 23 mg of the desired product.

Example 142 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2- (2,2,2-trifluoroethyl) oxyiminoacetamido] -3-[(E) -3-
(Carbamoylmethyldimethylammonio) -1-propen-1-yl] -3-cephem-4-carboxylate 1.43 g of the compound of Experimental Example 7 was dissolved in 20 ml of acetone, and 0.927 g of sodium iodide was added under ice cooling, and the mixture was kept at the same temperature for 10 minutes.
Subsequently, the mixture was stirred at room temperature for 1 hour and 30 minutes. The solvent was evaporated, ethyl acetate was added to the residue, and the mixture was washed with dilute aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous sodium sulfate, and dried. The solvent was distilled off, the residue was dissolved in 40 ml of ethyl acetate, 237 mg of dimethylglycinamide was added, and the mixture was stirred at room temperature for 1 hour. Isopropyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration to obtain 1.07 g of yellowish brown powder.

This compound was added to a mixed solution of 8 ml of trifluoroacetic acid and 6 ml of anisole, and the mixture was stirred under ice cooling for 1 hour. Ethyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration. This precipitate in water
The solution was suspended in 10 ml, the solution was adjusted to pH 5.5 to 6.5 with sodium acetate, and the insoluble material was filtered off. The filtrate was purified by reverse phase silica gel column chromatography to obtain 268 mg of the desired product.

Example 143 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- [tris (2-hydroxyethyl) ammonio] -1-propen-1-yl]
-3-Cephem-4-carboxylate 400 mg of the compound of Experimental Example 4 was dissolved in 4 ml of ethyl acetate, a solution of 96 mg of triethanolamine in 4 ml of ethyl acetate was added, and the mixture was stirred at room temperature for 6 hours. 24 ml of diisopropyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration. This precipitate was mixed with trifluoroacetic acid and anisole (1: 1) 4.5 under ice cooling.
The mixture was added to ml and stirred at room temperature for 1 hour and 30 minutes. 18 ml of diisopropyl ether was added to the reaction solution, and the resulting precipitate was collected by filtration,
It was washed with diisopropyl ether. 3 ml of this precipitate in water
The solution was suspended in and the solution was adjusted to pH 6 by adding sodium acetate. The insoluble material was filtered off, and the filtrate was purified by reverse-phase silica gel column chromatography to obtain 17 mg of the desired product.

Example 144 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- [bis (2-hydroxyethyl) methylammonio] -1-propen-1-yl] -3 cephem -4-carboxylate In the same manner as in Example 143, 500 mg of the compound of Experimental Example 4 and N
-Methyldiethanolamine (150 mg) was reacted and the protecting group was removed to obtain 15 mg of the desired product.

Experimental Example 8 (Synthesis of Starting Compound) 2- (5-Tritylamino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetic acid chloride hydrochloride Dissolve 395 mg of phosphorus pentachloride in 2.9 ml of dichloromethane,
Cooled to 5 ° C. 627 mg of the compound of Experimental Example 2 was added to this solution, and the mixture was stirred at the same temperature for 2 hours and 30 minutes. The reaction solution was added to a mixed solution of 9.4 ml of n-hexane and 9.4 ml of n-octane. The formed crystals were collected and washed with n-octane to give the desired compound (325 mg).
I got

Melting point: 139 to 140 ° C (decomposition) Mass spectrum (m / e): M ⁺ 480 ( ³⁵ Cl), 482 ( ³⁷ Cl) Infrared absorption spectrum (cm ^-1 , Nujol): 1795,1780,1740, 1630 NMR spectrum (δ, DMSO-d ₆ ): 5.79 (2H, d, J = 54Hz), 7.31 (15H, s), 10.09 (1H, s) Experimental Example 9 (Synthesis of starting compound) 2- (5- Amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetic acid ethyl ester 2.00 g of the compound of Experimental Example 1 was stirred in trifluoroacetic acid at room temperature for 30 minutes. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 405 mg of the desired product.

Melting point: 172-173 ° C Infrared absorption spectrum (cm ^-1 , Nujol): 1730, 1615 NMR spectrum (δ, DMSO-d ₆ ): 1.28 (3H, t, J = 7.0Hz), 4.34 (2H, q, J = 7.0Hz), 5.83 (2H, d, J = 54.5Hz), 8.27 (2H, brs) Experimental Example 10 (Synthesis of starting compound) 2- (5-amino-1,2,4-thiadiazole-3- Yl)-(Z) -2-fluoromethoxyiminoacetic acid 200 mg of the compound of Experimental Example 9 was suspended in a mixed solution of 6 ml of ethanol and 2 ml of water, and 1.75 ml of 1N sodium hydroxide aqueous solution was added,
The mixture was stirred at 60 ° C for 1 hour. Ethanol was distilled off from the reaction solution, and the solution was adjusted to pH 2 with 1N hydrochloric acid. This was purified with Diaion SP207 (trademark, a nonionic adsorption resin manufactured by Mitsubishi Kasei Co., Ltd.) to obtain 30 mg of the target product.

Infrared absorption spectrum (cm ^-1 , Nujol): 1720,1620 NMR spectrum (δ, DMSO-d ₆ ): 5.74 (2H, d, J = 55Hz), 8.24 (2H, br) 7.25 ~ 7.4 (17H, m) , 9.74 (1H, d, J = 8Hz), 10.08 (1H, s) Experimental Example 11 (Synthesis of starting compound) p-methoxybenzyl 7β- [2- (5-tritylamino-1,2,4-thiadiazole- 3-yl)-(Z)
-2-Fluoromethoxyiminoacetamide] -3-
[(E) -3-Chloro-1-propen-1-yl] -3
-Cephem-4-carboxylate To a mixed solution of 37 ml of ethyl acetate, 5 ml of tetrahydrofuran and 15.7 ml of dichloromethane, 8.17 g of N- (trimethylsilyl) acetamide, p-methoxybenzyl 7β-amino-
3-[(Z) -3-chloro-1-propen-1-yl]
3.33 g of -3-cephem-4-carboxylate hydrochloride was added and dissolved. After cooling the solution to -20 ° C, 3.80 g of the compound of Experimental Example 8 was added, and the mixture was stirred at 10 ° C for 1 hour. After adding 500 ml of ethyl acetate to the reaction mixture, the mixture was washed successively with water, saturated aqueous sodium hydrogen carbonate solution, 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and dried. The solvent was distilled off, and the residue was purified by silica gel column chromatography to give the desired product.
Obtained 4.33 g.

The infrared absorption spectrum and the NMR spectrum were in agreement with those of Experimental Example 3.

Experimental Example 12 (Synthesis of Raw Material Compound) 2-Cyano-2-fluoromethoxyiminoacetamide 2-cyano-2-hydroxyiminoacetamide 22.6
Dissolve g in 100 ml of dimethyl sulfoxide and stir at room temperature.
55.2 g of potassium carbonate was added, and the mixture was further stirred for 20 minutes. Then 27 g of fluorobromomethane in dimethylformamide 2
A 0 ml solution was added, and the mixture was stirred at room temperature for 20 hours and allowed to cool. The reaction mixture was added to ice water 1 and extracted twice with 150 ml of ethyl acetate. The organic layer was washed twice with saturated saline, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was washed with ethyl ether and dried to obtain 14.4 g of the desired product.

Melting point: 124-125 ° C Infrared absorption spectrum (cm ^-1 , Nujol): 3410,3290,3150,1690,1590 NMR spectrum (δ, DMSO-d ₆ ): 5.94 (2H, d, J = 54.0Hz), 7.85-9.40 (2H, b) Experimental Example 13 (Synthesis of Starting Compound) 2-Fluoromethoxyiminopropanedinitrile A mixture of the compound of Experimental Example 12 (14.0 g), acetonitrile (15 ml), sodium chloride (15 g) and phosphoryl chloride (14 ml) was refluxed under stirring to give 2
The reaction was carried out for 2 hours, 5 ml of phosphoryl chloride was added, and the reaction was continued for 2 hours. After cooling the reaction mixture, add it to 200 ml of ice water,
Stirred at room temperature for 1 hour. It was extracted twice with 50 ml of methylene chlorand. The extract was washed with 5% aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The oily product was distilled under reduced pressure to obtain 9.1 g of the colorless oily product.

Boiling point: 69-70 ° C / 25 mmHg NMR spectrum (δ, CDCl ₃ ): 5.85 (2H, d, J = 52.0Hz) Experimental Example 14 (synthesis of starting compound) 2-cyano-2-fluoromethoxyiminoacetamidine A mixture of 50 ml of 28% aqueous ammonia, 8 g of ammonium chloride and 50 ml of ethanol was cooled to -5 ° C, 9.1 g of the compound of Experimental Example 13 was added with stirring, and the mixture was further stirred at the same temperature for 3 hours. 100 ml of water was added to the reaction solution, and the mixture was extracted 3 times with 50 ml of methylene chloride. Anhydrous magnesium sulfate was added to the extract and dried, and then the solvent was distilled off. The residue was washed with ethyl ether and dried to obtain 3.4 g of the desired product.

A part of the product was dissolved in ethanol, and glacial acetic acid was added dropwise with stirring. The resulting precipitate was collected, washed with ethanol, and dried to give the acetate salt of the title compound. The following physical properties are the values of acetate.

Melting point: 125-127 ℃ Infrared absorption spectrum (cm ^-1 , Nujol): 3200, 1670, 1570 NMR spectrum (δ, DMSO-d ₆ ): 1.90 (3H, s), 5.95 (2H, d, J = 54.0) Hz), 7.40 (3H, b) Experimental Example 15 (Synthesis of Starting Compound) 2- (5-Amino-1,2,4-thiadiazol-3-yl)-(E) -2-fluoromethoxyiminoacetonitrile 3.0 g of the compound of Experimental Example 14 was dissolved in 50 ml of methanol, and 4.2 g of triethylamine was added under ice cooling. After cooling the solution to -5 ° C, 3.5 g of bromine was added dropwise. Then, -3 ℃ ~ -5 ℃
Then, 2.1 g of potassium thiocyanate in methanol was added dropwise, and the mixture was stirred at the same temperature for 2 hours. The resulting precipitate was collected and washed with water and methanol. This was recrystallized from acetone to obtain 3.4 g of the desired product.

Melting point: 236-238 ° C Infrared absorption spectrum (cm ^-1 , Nujol): 3450,3250,3075,1610,1520 NMR spectrum (δ, DMSO-d ₆ ): 6.02 (2H, d, J = 54.0Hz), 8.38 (2H, b) Experimental Example 16 (Synthesis of starting compound) 2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetamide To 18 ml aqueous solution of 0.23 g of sodium hydroxide, 7.4 ml of 35% hydrogen peroxide solution was added, and 2.0 g of the compound of Experimental Example 15 was added under stirring at room temperature.
Was added and the mixture was stirred at 25 ° C to 30 ° C for 8 hours. The precipitated crystals were collected, washed with water and acetone, and then dried to obtain 1.3 g of the desired product.

Melting point: 210 ℃ ~ 211 ℃ Infrared absorption spectrum (cm ^-1 , Nujol): 3450,3260,3180,1690,1610 NMR spectrum (δ, DMSO-d ₆ ): 5.73 (2H, d, J = 55.0Hz) , 7.69 (2H, br), 7.98 (1H, br), 8.10 (1H, br) Experimental Example 17 2- (5-Amino-1,2,4-thiadiazol-3-yl)-(Z) -2- Fluoromethoxyiminoacetic acid A mixture of 1.1 g of the compound of Experimental Example 16 and 10 ml of 2N aqueous sodium hydroxide solution was stirred at 50 ° C. for 5 hours. The reaction mixture was cooled, adjusted to pH 1.0 with concentrated hydrochloric acid and then mixed with 20 ml of ethyl acetate.
Extracted times. Anhydrous magnesium sulfate was added to the extract and dried, and then the solvent was distilled off. The residue was washed with isopropyl ether to obtain 0.8 g of a crude product. This was purified by reverse phase silica gel column chromatography to obtain 0.4 g of the desired product.

The infrared absorption spectrum and the NMR spectrum were in agreement with those of Experimental Example 10.

Experimental Example 18 (Synthesis of starting material compound) p-methoxybenzyl 7β-phenylacetamido-3-triphenylphosphoniomethyl-3-cephem-
4-carboxylate iodide 250 g of p-methoxybenzyl 7β-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylate was suspended in 1.5 l of acetone, 200 g of triphenylphosphine and 78 g of sodium iodide were added, and the mixture was stirred at room temperature for 1 hour. . After removing the insoluble matter, the solution was diluted with ethyl acetate (6 L).
-Drop into a mixed solution of 3 liters of isopropyl ether with stirring to remove the formed precipitate. This is isopropyl ether 600m
After washing with l, it was dried to obtain 420 g of the desired product.

Infrared absorption spectrum (cm ^-1, nujol): 1780,1710,1670,1610 NMR spectrum _{(δ, DMSO-d 6)} : 3.50 (2H, s), 3.71 (3H, s), 4.3~5.3 (5H, m ), 5.56 (1H, dd, J = 5.2Hz, 7.5Hz), 6.82 (2H, d, J = 8.0Hz), 7.0 to 7.4 (7H, m), 7.4 to 8.0 (15H, m), 9.00 (1H , d, J = 7.5 Hz) Experimental Example 19 (Synthesis of starting compound) p-methoxybenzyl 7β-phenylacetamido-3-[(Z) -3-chloro-1-propen-1-yl] -3-cephem- 4-carboxylate 120 g of the compound of Experimental Example 18 was dissolved in 0.8 l of chloroform, and 1
N sodium hydroxide aqueous solution 223 ml and saturated saline solution 200 ml
Was added and stirred. The organic layer was separated, washed with water, added with potassium carbonate and dried. After removing potassium carbonate and washing with 0.4 l of chloroform, the solutions were combined. Under ice-cooling, add N, O-bis (trimethylsilyl) acetamide 18.4
After adding ml and stirring for 5 minutes, chloroacetaldehyde 67
A 150 ml solution of g in chloroform was added, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was concentrated and purified by silica gel column chromatography to obtain 32.4 g of the desired product.

Infrared absorption spectrum (cm ^-1, nujol): 1760,1720,1660,1610 NMR spectrum _{(δ, DMSO-d 6)} : 3.55 (2H, s), 3.76 (3H, s), 3.93 (1H, dd, J = 8.0Hz, 12.0Hz), 4.16 (1H, dd, J = 8.0Hz, 12.0Hz), 5.14 (2H, q, J = 12.0Hz), 5.21 (1H, d, J = 5.0Hz), 5.70 (1H , dt, J = 8.0Hz, 11.3Hz), 5.74 (1H, dd, J = 5.0Hz, 8.0Hz), 6.30 (1H, d, J = 11.3Hz), 6.94 (2H, d, J = 8.5Hz) , 7.28 (5H, s), 7.33 (2H, d, J = 8.5Hz), 9.14 (1H, d, J = 8.0Hz) Experimental Example 20 (Synthesis of starting compound) p-methoxybenzyl 7β-amino-3- [(Z)
-3-Chloro-1-propen-1-yl] -3-cephem-4-carboxylate hydrochloride Pyridine was added to a solution of 8.12 g of phosphorus pentachloride in 100 ml of methylene chloride.
3.15 ml was added, and 10 g of the compound of Experimental Example 19 was cooled to -15 ° C.
Was added. After stirring for 1 hour and 30 minutes, 1,3-butanediol
20.9 ml was added dropwise, and the mixture was further stirred at -10 ° C for 30 minutes. The reaction solution was washed 3 times with a 20% aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate and dried. Concentrate the solution,
Add 100 ml of ethyl acetate and remove the precipitate to remove the desired product.
I got 5.0g.

Infrared absorption spectrum (cm ^-1 , Nujol): 1785, 1720, 1610, 1585 NMR spectrum (δ, DMSO-d ₆ ): 3.75 (3H, s), 3.85 to 4.3 (2H, m), 5.05 to 5.45 (4H , m), 5.55 to 5.9 (1H, m), 6.35 (1H, d, J = 11.5Hz), 6.92 (2H, d, J = 8.5Hz), 7.32 (2H, d, J = 8.5Hz) 145 (Production of Injection) 10 g of the compound of Example 1 was dissolved in 50 ml of distilled water, and 5 ml of the solution was injected into one vial. This was freeze-dried to give an injection.

〔The invention's effect〕

The acute toxicity and antibacterial activity of the compound of the present invention were measured.

(1) Mouse Acute Toxicity The compound of the present invention was dissolved in physiological saline and administered intravenously to 5 ICR male, 6-week-old mice. As a result, the compounds of the following Examples all had an acute toxicity value of 2 g / kg or more.

Examples 1,2-1,2-2,3-1,3-2,5,6-1,6-2,7-1,7-
2,9-1,9-2,9-3,10,11,12,13-1,13-2,96,121,137 (2) Antibacterial activity MIC (μg / ml) is agar plate method [chemotherapy
erapy) Vol. 29, pp. 76-79, 1981]. The inoculum is 10 ⁶ CFU / ml.

CAZ (ceftazidime) and CTM (cefotiam) were selected as control drugs.

(3) Antibacterial activity The compounds of the present invention represented by the general formula (I) were compared in antibacterial activity with a control compound in which R ₁ is a methyl group. The method for measuring MIC is the same as in (2) above.

 ─────────────────────────────────────────────────── --- Continuation of the front page (72) Inventor Yoshimasa Machida 500-81 Shimohirooka, Sakuramura, Shinji-gun, Ibaraki 500-81 (72) Inventor Kyosuke Kito 1-10-8 Tokodai, Toyosato-cho, Tsukuba-gun, Ibaraki (72) Inventor Masaru Kamamasa 672-165 Koshirashi, Yatabe-cho, Tsukuba-gun, Ibaraki Prefecture (72) Inventor Hiroshi Yamauchi 500-105 Shimohirooka Shimomura, Niiji-gun, Ibaraki Examiner Masato Ikeda (56) Reference JP-A-61-5084 (JP, A) Kai 57-112396 (JP, A) JP 55-105689 (JP, A)

Claims (13)

[Claims] 1. A general formula: A 3-propenylcephem derivative represented by the formula: wherein R ₁ is a fluorine-substituted lower alkyl group, and A is a cyclic or acyclic ammonio group, and a non-toxic salt thereof. 2. A is the following acyclic ammonio group: [In the formula, R ₂ , R ₃ and R ₄ are the same or different, and a lower alkyl group, a hydroxy-substituted lower alkyl group, a carbamoyl-substituted lower alkyl group, a cyano-substituted lower alkyl group, an amino group, a lower alkylcarbonylamino-substituted lower alkyl group , Aminosulfonylaminocarbonyl-substituted lower alkyl group, lower alkylsulfonylaminocarbonyl-substituted lower alkyl group, lower alkylaminocarbonyl-substituted lower alkyl group, hydroxy and carbamoyl-substituted lower alkyl group, hydroxy and hydroxy lower alkylaminocarbonyl-substituted lower alkyl group, lower Alkyloxyaminocarbonyl-substituted lower alkyl group, hydroxyaminocarbonyl-substituted lower alkyl group, carbamoyl lower alkylaminocarbonyl-substituted lower alkyl group, hydroxy lower alkyl Aminocarbonyl-substituted lower alkyl group, (carboxylate lower alkyldi-lower alkylammonio) -substituted lower alkyl group, lower alkylamino-substituted lower alkyl group, di-lower alkylamino and hydroxy-substituted lower alkyl group, ureido group, hydroxy group,
Carboxy-substituted lower alkyl group, lower alkyloxy-substituted lower alkyl group, di-lower alkylaminocarbonyl-substituted lower alkyl group, dicarbamoyl-substituted lower alkyl group, bis (hydroxy lower alkyl) aminocarbonyl-substituted lower alkyl group, dihydroxy-substituted lower alkyl group, Trihydroxy-substituted lower alkyl group, bis (hydroxy lower alkyl) amino-substituted lower alkyl group, amino-substituted lower alkyl group, oxo-substituted lower alkyl group, di-lower alkylamino-substituted lower alkyl group, 5-membered heterocyclic-substituted lower alkyl group (5 Member heterocycle represents a group selected from pyrazolyl, imidazolyl, oxadiazolyl or tetrazolyl)], or A is the following cyclic ammonio group: [In the formula, R ₅ is a lower alkyl group, a carbamoyl-substituted lower alkyl group, an amino-substituted lower alkyl group, a hydroxy-substituted lower alkyl group, a carboxy-substituted lower alkyl group, a cyano-substituted lower alkyl group, a dihydroxy-substituted lower alkyl group, a ureido-substituted lower alkyl group. A group selected from alkyl groups, wherein the cyclic ammonio group further has a hydroxy-substituted lower alkyl group, a hydroxy group, a formyl group, a sulfonic acid group, a carboxy-substituted lower alkyl group, a carbamoyl group, a sulfamoyl group, a carboxyl group on the ring. , Hydroxyimino-substituted lower alkyl group, imino-substituted lower alkyl group, bis (hydroxy lower alkyl) aminocarbonyl group, hydroxy lower alkylaminocarbonyl group, amino group, morpholinocarbonyl group, carboxy lower alkyloxy substituted lower alkyl group Optionally substituted with a substituent selected from the group consisting of a alkyl group, a carboxy lower alkylthio group, a sulfo-substituted lower alkyl group and a lower alkyl group.] The 3-propenylcephem derivative according to claim 1 and its non-toxicity salt. 3. A 3-propenylcephem derivative and a non-toxic salt thereof according to claim 1 or 2, wherein R ₁ is a fluoromethyl group. 4. 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetamide] -3-[(E) -3- ( A compound according to claim 3 which is carbamoylmethylethylmethylammonio) -1-propen-1-yl] -3-cephem-4-carboxylate. 5. β- [2- (5-Amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetamide] -3-[(E) -3- [ 1-
The compound according to claim 3, which is (2-hydroxyethyl) -4-carbamoyl-1-piperidinio] -1-propen-1-yl] -3-cephem-4-carboxylate. 6. β- [2- (5-Amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetamide] -3-[(E) -3- [ (1S-
A compound according to claim 3 which is carbamoylethyl) dimethylammonio] -1-propen-1-yl] -3-cephem-4-carboxylate. 7. β- [2- (5-Amino-1,2,4-thiadiazole)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3-[(1R-carbamoyl) Ethyl) dimethylammonio] -1-propene-1-
The compound according to claim 3, which is yl] -3-cephem-4-carboxylate. 8. β- [2- (5-Amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetamide] -3-[(E) -3- [ (1R-
Carbamoyl-2-hydroxyethyl) dimethylammonio] -1-propen-1-yl] -3-cephem-4
A compound according to claim 3, which is a carboxylate. 9. β- [2- (5-Amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetamido] -3-[(E) -3- ( 5-Aza-1-methyl-2,8-dioxabicyclo [3,3,1] non-5-io) -1-propen-1-yl] -3-cephem-4-carboxylate The compound according to claim 3 in the range. 10. β- [2- (5-Amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetamide] -3-[(E) -3- ( Carbamoylmethyldiethylammonio) -1-propene-
The compound according to claim 3, which is 1-yl] -3-cephem-4-carboxylate. 11. β- [2- (5-Amino-1,2,4-thiadiazol-3-yl)-(Z) -2-fluoromethoxyiminoacetamide] -3-[(E) -3- [ (2
A compound according to claim 3 which is -oxopropyl) dimethylammonio] -1-propen-1-yl] -3-cephem-4-carboxylate. 12. General formula: [Wherein R ₁ is a fluorine-substituted lower alkyl group and A is a cyclic or acyclic ammonio group], in the production of a 3-propenylcephem derivative and a non-toxic salt thereof,
General formula: [Wherein R ₁ is the same as defined above, X represents a halogen atom], its amino group and / or carboxyl group is protected by a protecting group, or a salt of these compounds has the formula: A'represents a compound represented by [A 'represents an amine corresponding to A], a compound whose functional group is protected by a protecting group, or a salt of these compounds, and removes the protecting group if necessary. A manufacturing method characterized by: 13. A general formula: An antibacterial agent comprising a 3-propenylcephem derivative represented by the formula: wherein R ₁ is a fluorine-substituted lower alkyl group, and A is a cyclic or acyclic ammonio group, or a non-toxic salt thereof.