JPH0830068B2 - 3-propenyl-3-cephem derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Object of the Invention] The present invention relates to a 3-propenyl-3-cephem derivative useful as an antibacterial agent.

Conventionally, in JP-A-59-172493 and JP-A-61-5084, a cephem derivative having an ammoniopropenyl group at the 3-position is known. However, a compound having a cyano-substituted lower alkoxyimino group at the side chain at the 7-position is not shown. The present inventors have found that a cephem derivative having an ammoniopropenyl group at the 3-position and a cyano-substituted lower alkoxyimino group at the side chain at the 7-position has excellent antibacterial activity, and completed the present invention. is there.

Therefore, 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 compounds of the present invention have the general formula: [In the formula, R ₁ is a cyano-substituted lower alkyl group, and A is a cyclic or acyclic ammonio group.] A 3-propenyl-3-cephem derivative or a non-toxic salt thereof.

Examples of the cyano-substituted lower alkyl group for R _{1 in} the general formula (I) include cyanomethyl, 2-cyanoethyl, 3-cyanopropyl and the like.

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

[Wherein R ₂ , R ₃ and R ₄ are the same or different, and are 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 alkylcarbonylamido-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, carbonyl lower alkylaminocarbonyl-substituted lower alkyl group, hydroxy lower alkyl group Roh carbonyl-substituted lower alkyl group,
Lower alkylamino-substituted lower alkyl group, (carboxylate lower alkyldi-lower alkylammonio) -substituted lower alkyl group, lower alkylamino-substituted lower alkyl group, lower alkylamino- and hydroxy-substituted lower alkyl group, ureido group, hydroxy group, carboxy-substituted lower Alkyl group, hydroxy- and carbamoyl-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 heterocycle Substituted lower alkyl group (5-membered heterocycle represents a group selected from pyrazolyl, imidazolyl, oxadiazolyl, tetrazolyl, etc.)],
Further, examples of the cyclic ammonio group represented by A in the general formula (I) include the groups shown below.

[Wherein 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) aminocarbamoyl group, hydroxy lower alkylaminocarbamoyl group,
It may have a substituent selected from an amino group, a morpholinocarbonyl group, a carboxy lower alkyloxy-substituted lower alkyl group, a carboxy lower alkylthio-substituted lower alkyl group, and a lower alkyl group.] Also, in the general formula (I), A (R _{2 to} R ₅ ) as a lower alkyl group in the definition, 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.

The steric moieties of the following moieties of the compounds 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 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 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. Also, use a silylating agent such as N, O-bis (trimethylsilyl) acetamide, N-methyl-N- (trimethylsilyl) acetamide, N-methyl-N- (trimethylsilyl) trifluoroacetamide, or N- (trimethylsilyl) acetamide. 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) 2- (5-tritylamino-1,2,4-thiadiazole-
3-yl)-(Z) -2-cyanomethoxyiminoacetic acid N-Cyanomethoxyphthalimide 8.00g ethanol 50m
The mixture was suspended in 1 l, hydrazine monohydrate (1.93 ml) was added at room temperature, and the mixture was stirred for 1 hour and 45 minutes. Saturated saline and ethyl ether were added to this, the solution was made basic with concentrated ammonia water, and then extracted with ethyl ether. The ethyl ether layer was washed with saturated brine, anhydrous sodium sulfate was added and dried, and the solvent was evaporated.

To the residue were added 350 ml of methanol and 6.50 g of 2- (5-tritylamino-1,2,4-thiadiazol-3-yl) guloxylic acid, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, the residue was dissolved in ethyl acetate and washed with 0.1N hydrochloric acid and then saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain 7.64 g of the desired product.

Experimental Example 2 (Synthesis of raw material compound) p-methoxybenzyl 7β- [2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-
2-Cyanomethoxyiminoacetamide] -3-
[(Z) -3-Chloro-1-propen-1-yl] -3
-Cephem-4-carboxylate Dimethylformamide (1.51 ml) and tetrahydrofuran (18 ml) were cooled to -10 ° C, phosphoryl chloride (1.82 ml) was added, and the mixture was stirred under ice cooling for 40 minutes. A solution of 7.64 g of the compound of Experimental Example 1 in 24 ml of tetrahydrofuran was added thereto, 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 (6.00 g), N-trimethylsilylacetamide (12.8 g) and ethyl acetate (60 ml) were cooled to -25 ° C in this solution. The reaction solution was added to and the temperature was raised to 0 ° C. with stirring for 40 minutes. The reaction solution was extracted with ethyl acetate, the organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the desired product 7.80.
got g.

Experimental Example 3 (Synthesis of Starting Compound) p-methoxybenzyl 7β- [2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-
2-Cyanomethoxyiminoacetamide] -3-
[(E) -Iodo-1-propen-1-yl] -3-cephem-4-carboxylate To a solution of 7.80 g of the compound of Experimental Example 2 in 120 ml of acetone, 6.9 g of sodium iodide was added under ice cooling, the mixture was stirred for 10 minutes, then returned to room temperature and further stirred for 1 hour 30 minutes. The solvent was distilled off, and the mixture was extracted with ethyl acetate. This was washed with a dilute aqueous solution of sodium thiosulfate and then with saturated saline, and then dried over anhydrous sodium sulfate. The solution was concentrated, and this was added dropwise to an isopropyl ether-ethyl ether mixed solution. The resulting precipitate was removed to obtain 6.50 g of the desired product.

Example 1 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-cyanomethoxyiminoacetamido] -3-[(E) -3-[(1S-carbamoyl-
2-Hydroxyethyl) dimethylammonio] -1-propen-1-yl] -3-cephem-4-carboxylate 1.0 g of the compound of Experimental Example 3 was dissolved in 2 ml of dimethylformamide, 210 mg of (1S-carbamoyl-2-hydroxyethyl) dimethylamine was added at room temperature, and the mixture was stirred for 1 hour.
The reaction solution was diluted by adding 10 ml of ethyl acetate, and this solution was added dropwise to 100 ml of ethyl ether to obtain 710 mg of a brown precipitate.

The precipitate was stirred in a mixed solution of 6 ml of anisole and 6.5 ml of trifluoroacetic acid under ice cooling for 1 hour. Ethyl ether was added to the reaction solution to obtain 430 mg of a brown precipitate. 10 ml of this precipitate in water
And suspended in sodium chloride and adjusted to pH 7.0 with sodium acetate. The insoluble material was removed, and the liquid was purified by reverse-phase silica gel column chromatography to obtain 50 mg of the desired product.

Example 2 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-cyanomethoxyiminoacetamido] -3-[(E) -3- (1-methyl-2R-hydroxymethyl-4R-hydroxy-1-pyrrolidinio)-
1-propen-1-yl] -3-cephem-4-carboxylate 1.0 g of the compound of Experimental Example 3 was dissolved in a mixed solution of 10 ml of ethyl acetate and 8 ml of ethyl ether, and N-methyl-4R-hydroxy-
167 mg of D-prolinol was added and the mixture was stirred overnight. The reaction solution was added to 100 ml of ethyl ether and the resulting precipitate was collected to obtain 840 mg of yellow powder.

To this powder was added 6 ml of anisole, 8 ml of trifluoroacetic acid was added dropwise over 30 minutes with stirring under ice cooling, and the mixture was further added for 3 hours.
It was stirred for 0 minutes. 100 ml of ethyl ether was added to the reaction solution and the resulting precipitate was collected. This was suspended in 4 ml of water and adjusted to pH 7.0 with sodium acetate. The insoluble material was removed, and the liquid was purified by reverse-phase silica gel column chromatography to obtain 24 mg of the desired product.

The following compounds of Examples 3 to 10 were produced in the same manner as in Examples 1 and 2.

A plurality of isomers may be produced due to the portion of the ammonio group of A, but when they were separated, the yield was shown for each isomer.

Example 11 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-cyanomethoxyiminoacetamido] -3-[(E) -3- (carbamoylmethyldimethylammonio) -1-propen-1-yl] -3-
Cephem-4-carboxylate To a solution of 390 mg of the compound of Experimental Example 3 in 15 ml of ethyl acetate was added 64 mg of dimethylglycinamide, and the mixture was stirred at room temperature for 1 hour. Ethyl ether was added to the reaction solution, and the resulting precipitate was collected and dried to obtain 260 mg of yellowish brown powder.

Add 2 ml of trifluoroacetic acid and anisole under ice cooling.
1.5 ml of the mixed solution was added and stirred for 1 hour. Ethyl ether was added to the solution, the resulting precipitate was collected, and washed with ethyl ether. The precipitate was suspended in 5 ml of water, adjusted to pH 5.5 to 6.5 with sodium acetate, and then the insoluble matter was removed. The liquid was purified by reverse phase silica gel column chromatography to obtain 37 mg of the desired product.

Example 12 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-cyanomethoxyiminoacetamido] -3-[(E) -3- (1-methyl-4-sulfamoyl-1-piperazinio) -1-propene-1-
Ill] -3-cephem-4-carboxylate 500 mg of the compound of Experimental Example 3 was dissolved in a mixed solution of 5 ml of dichloromethane and 1 ml of methanol, 145 mg of N-sulfamoyl-N'-methylpiperazine was added, and the mixture was stirred at room temperature for 4 hours. The solution was concentrated and ethyl ether was added. The resulting precipitate was collected and dried to obtain 450 mg of yellowish brown powder.

Under ice cooling, a mixed solution of 3.5 ml of trifluoroacetic acid and 3 ml of anisole was added and stirred for 1 hour. Ethyl ether was added to the solution, the resulting precipitate was collected, and washed with ethyl ether. The precipitate was suspended in 5 ml of water, adjusted to pH 5.5 to 6.5 with sodium acetate, and then the insoluble matter was removed. The liquid was purified by reverse-phase silica gel column chromatography to obtain 39 mg of the desired product.

Example 13 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-cyanomethoxyiminoacetamido] -3-[(E) -3- (1,4-diazabicyclo [2,2,2] octane-1-io) -1-propene- 1-
Ill] -3-cephem-4-carboxylate 500 mg of the compound of Experimental Example 3 was mixed with 6 ml of ethyl acetate and methanol.
The solution was dissolved in 0.5 ml of a mixed solution, 90 mg of 1,4-diazabicyclo [2,2,2] octane was added, and the mixture was stirred at room temperature for 20 minutes. Ethyl ether was added to the solution and the resulting precipitate was collected and dried to obtain 330 mg of yellowish brown powder.

Add 3 ml of trifluoroacetic acid and anisole under ice cooling.
A 2.5 ml mixture was added and stirred for 1 hour. Ethyl ether was added to the solution, the resulting precipitate was collected, and washed with ethyl ether. The precipitate was suspended in 5 ml of water, adjusted to pH 5.5 to 6.5 with sodium acetate, and then the insoluble matter was removed. The liquid was purified by reverse phase silica gel column chromatography to obtain 48 mg of the desired product.

The compounds of the following Examples 14 to 17 were obtained in the same manner as in Examples 11 to 13.

Example 14 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-cyanomethoxyiminoacetamido] -3-[(E) -3- (4-carbamoylpyridinio-1-propen-1-yl] -3-cephem-4
-Carboxylate 600 mg of the compound of Experimental Example 3 and 4-carbamoylpyridine 2
35 mg was reacted and the protecting group was removed to obtain 37 mg of the desired product.

Example 15 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-cyanomethoxyiminoacetamido) -3-((E) -3-[(1,3,4-oxadiazol-2-yl) methyldimethylammonio] -1-
Propen-1-yl] -3-cephem-4-carboxylate The compound of Experimental Example 3 (600 mg) was reacted with 2-dimethylaminomethyl-1,3,4-oxadiazole (163 mg), and the protective group was eliminated to obtain 54 mg of the desired product.

Example 16 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-cyanomethoxyiminoacetamido] -3-[(E) -3-[(1,2-dimethyl-1
-Pyrazolidinio) -1-propen-1-yl] -3-
Cephem-4-carboxylate (isomers: A and B) 510 mg of the compound of Experimental Example 3 and 1,2-dimethylpyrazolidine
0.4 ml was reacted and the protecting group was removed to obtain the desired isomer A 20 mg and isomer B 20 mg.

Example 17 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-cyanomethoxyiminoacetamido] -3-[(E) -3- (1,5-diazabicyclo [3,3,0] octane-1-io) -1-propene- 1-
Ill] -3-cephem-4-carboxylate 600 mg of the compound of Experimental Example 3 and 1,5-diazabicyclo [3,3,
0] Reaction with 220 mg of octane, elimination of the protective group
Obtained 39 mg.

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 five 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 1,2,6,7,10,11 (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.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Yoshimasa Machida 500-81 Sakuramura Shimooka, Shinji-gun, Ibaraki 500-81 (72) Inventor Seiichiro Nomoto 1-1-344-2 Kariya, Ushiku-cho, Inashiki-gun, Ibaraki (72) Inventor Katsu Kama Masa 672-165 Koshirashi, Yatabe-cho, Tsukuba-gun, Ibaraki Prefecture (72) Inventor Hiroshi Yamauchi 500-105 Shimohirooka, Sakuramura, Shinji-gun, Ibaraki Prefecture Masato Ikeda Examiner

Claims (8)

[Claims] 1. A general formula: [Wherein, R ₁ represents a cyano-substituted lower alkyl group and A represents a cyclic or acyclic ammonio group], or a 3-propenyl-3-cephem derivative or a non-toxic salt thereof. 2. The compound according to claim _{1, wherein} R ₁ is a cyanomethyl group. 3. A is the following acyclic ammonio group: [Wherein R ₂ , R ₃ and R ₄ are the same or different and are a lower alkyl group, a hydroxy substituted lower alkyl group, a carbamoyl substituted lower alkyl group, a hydroxy and a carbamoyl substituted lower alkyl group, an oxo substituted lower alkyl group, an oxadiazolyl substituted lower group A group selected from an alkyl group] or A is a cyclic ammonio group as follows: [Wherein R ₅ represents a lower alkyl group, and the cyclic ammonio group further has a substituent selected from a lower alkyl group, a sulfamoyl group, a carbamoyl group, a hydroxy group and a hydroxy-substituted lower alkyl group on the ring. The propionyl-3-cephem derivative or the non-toxic salt thereof according to claim 1 or 2, represented by the formula: 4. β- [2- (5-Amino-1,2,4-thiadiazol-3-yl)-(Z) -2-cyanomethoxyiminoacetamido] -3-[(E) -3- [ (2-Oxopropyl) dimethylammonio] -1-propene-
The compound according to claim 3, which is 1-yl] -3-cephem-4-carboxylate. 5. β- [2- (5-Amino-1,2,4-thiadiazol-3-yl)-(Z) -2-cyanomethoxyiminoacetamide] -3-[(E) -3- [ The compound according to claim 3, which is (1S-carbamoylethyl) dimethylammonio] -1-propen-1-yl] -3-cephem-4-carboxylate. 6. β- [2- (5-amino-1,2,4-thiadiazol-3-yl)-(Z) -2-cyanomethoxyiminoacetamido] -3-[(E) -3- [ The compound according to claim 3, which is (1R-carbamoylethyl) dimethylammonio] -1-propen-1-yl] -3-cephem-4-carboxylate. 7. A general formula: [Wherein R ₁ represents a cyano-substituted lower alkyl group and A represents a cyclic or acyclic ammonio group], in the production of a 3-propenylcephem derivative or 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: 8. A general formula: An antibacterial agent comprising a 3-propenylcephem derivative represented by the formula: wherein R ₁ represents a cyano-substituted lower alkyl group, and A represents a cyclic or acyclic ammonio group, or a non-toxic salt thereof.