JPH0742292B2 - Cefalosporin derivative - Google Patents

Description

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

Conventionally, JP-A-58-174387, JP-A-58-198490, JP-A-59-130295, JP-A-59-219292,
In JP-A-60-97983 and JP-A-60-197693, cephalosporin derivatives having a quaternary ammonio group similar to the compound of the present invention are known. However, it cannot be said that a sufficiently satisfactory compound has been obtained in terms of a compound effective against both Gram-positive bacteria and Gram-negative bacteria (particularly Pseudomonas aeruginosa).

The present inventors have found that the compound of the present invention has excellent antibacterial activity against both Gram-positive bacteria and Gram-negative bacteria (Pseudomonas aeruginosa), and completed the present invention.

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

[Structure of Invention]

The present invention has the general formula: [In the formula, R ₁ represents a lower alkyl group, and A is the following group: (R ₂ and R ₃ are the same or different lower alkyl groups, R ₄ is a lower alkyl group substituted with a group selected from a carbamoyl group, a carboxyl group, a lower alkyl-substituted amino group, a mercapto group, a lower alkanoyl group and a hydroxyl group. ); Or the following groups optionally substituted with a group selected from a carboxyl group, a carbamoyl group and a lower alkyldithio group: (R ₅ represents a lower alkyl group); or the following groups: (R ₅ is the same as defined above, R ₆ is a hydroxy lower alkyl group or a carboxyl group)]] or a non-toxic salt thereof.

Examples of the lower alkyl group for R ₁ in the above general formula (I) include C _{1 to} C ₄ groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl and t-butyl. To be

Further, examples of the lower alkyl group in the definition of A in the general formula (I), the lower alkyl-substituted amino group, the hydroxy lower alkyl group, and the lower alkyl group in the lower alkyldithio group include the lower alkyl group in R ₁ above. The same as the example is given.

Examples of the lower alkanoyl group for R ₂ , R ₃ and R ₄ include acetyl and propanoyl.

More specific groups represented by A include, for example, the following groups.

The non-toxic salts of the compound of the general formula (I) include pharmaceutically acceptable salts, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; hydrochloride salt and odor. Inorganic acid salts such as hydrohydrate, hydroiodide, sulfate, carbonate, bicarbonate; organic carboxylates such as acetate, maleate, lactate, tartrate; methanesulfonate, Benzene sulfonate,
Organic sulfonates such as toluene sulfonate; amino acid salts such as arginine salt, lysine salt, serine salt, aspartate salt, and glutamate salt; trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, Examples include amine salts such as N, 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 isomers (Z) and anti isomers (E). Although both isomers are included in the present invention, the syn isomer is preferable from the viewpoint of antibacterial activity.

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

General formula: [In the formula, R ₁ is a lower alkyl group, and X is a halogen atom]
A compound represented by the formula (1), 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 general formula: A '(III) [A' is represented by the following general formula: (R ₂ and R ₃ are the same or different lower alkyl groups, R ₄ is a lower alkyl group substituted with a group selected from a carbamoyl group, a carboxyl group, a lower alkyl-substituted amino group, a mercapto group, a lower alkanoyl group and a hydroxyl group. ); Or the following formula, which may be substituted with a group selected from a carboxyl group, a carbamoyl group and a lower alkyldithio group: (R ₅ represents a lower alkyl group); or the following formula: (R ₅ is the same as the above definition, R ₆ is a hydroxy lower alkyl group or a carboxyl group)] or a salt thereof is reacted, and if necessary, the protecting group is eliminated to give the compound of the general formula (I) And a non-toxic salt thereof can be obtained.

Examples of the halogen atom represented by X in the general formula (II) include iodine atom, bromine atom and chlorine atom. A'is a tertiary amine corresponding to A in the general formula (I).

The above reaction is carried out at a reaction temperature of -10 ° C to 60 ° C, preferably 0 ° C to 40 ° C.
It can be performed at ° C. Further, the reaction solvent is preferably an anhydrous organic solvent. Organic solvents that can be used include lower alkyl nitriles such as acetonitrile and propionitrile; halogenated lower alkyls such as chloromethane, dichloromethane and chloroform; ethers such as tetrahydrofuran, dioxane and ethyl ether; N, N-dimethylformamide. And amides; esters such as ethyl acetate; ketones such as acetone; hydrocarbons such as benzene; and mixed solvents thereof.

The removal of the protecting group can be carried out by a conventional method such as hydrolysis or reduction depending on the kind of the protecting group used.

Salts of the compounds of the general formulas (II) and (III), the general formula (I
As the protecting group for the amino group and the carboxyl group of the compound of I), those commonly used can be used as long as they do not interfere with the above reaction.

For example, as a protecting group for amino group, formyl group, acetyl group, chloroacetyl group, dichloroacetyl group, t-butoxycarbonyl group, benzyloxycarbonyl group, trityl group, p-methoxybenzyl group, diphenylmethyl group, etc .; The protecting group for the group includes p-methoxybenzyl group, p-nitrobenzyl group, t-butyl group, methyl group, 2,
Examples thereof include 2,2-trichloroethyl group, diphenylmethyl group, pivaloyloxymethyl group. Also, bis (trimethylsilyl) acetamide, N-methyl-N-
It is convenient to use a silylating agent such as (trimethylsilyl) acetamide or N-methyl-N-trimethylsilyl-trifluoroacetamide because the amino group and the carboxy group can be protected at the same time.

Examples of the salts of the compounds of the general formulas (II) and (III) include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; hydrochloride salts, hydrobromic acid salts. Inorganic acid salts such as salts, sulfates, carbonates, hydroiodides and bicarbonates; organic carboxylates such as acetates, trifluoroacetates, maleates, lactates and tartrates; methanesulfonic acid Salts, organic sulfonates such as benzene sulfonate and toluene sulfonate; trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, N-methyl Glucamine salt, diethanolamine salt, triethanolamine salt, tris (hydroxymethylamino) methane salt, phenethylbenzyl Amine salts such as amine salts; arginine salt, aspartate, lysine, glutamate, can be appropriately selected from among salts such as amino acid salts such as serine salt.

Next, the present invention will be described in more detail by showing experimental examples and examples.

Experimental Example 1 (Synthesis of raw material compound) p-methoxybenzyl 7β- [2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-
2-Methoxyiminoacetamido] -3-chloromethyl-3-cephem-4-carboxylate 2- (5-tritylamino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetic acid 100 g was dissolved in dimethylformamide 1 and p-methoxybenzyl 7β-amino-3-chloromethyl-3-cephem-4-carboxylate p- was dissolved under ice cooling. Toluenesulfonate 121.7 g, triethylamine 22.77 g and N-ethyl-
139.6 g of N'-3-dimethylaminopropylcarbodiimide hydrochloride was added, and the mixture was stirred at the same temperature for 8 hours. After adding ethyl acetate 4l to the reaction liquid, it wash | cleaned one by one by water, saturated salt solution, saturated sodium hydrogencarbonate aqueous solution, saturated salt solution, 1N hydrochloric acid, and saturated salt solution. Anhydrous magnesium sulfate was added to this and dried, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution; chloroform) to obtain 115 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-Methoxyiminoacetamido] -3-iodomethyl-3-cephem-4-carboxylate 60 g of the compound of Experimental Example 1 was dissolved in 1.2 l of methyl ethyl ketone, and 56.5 g of sodium iodide was added to
Stir for hours. The solvent was evaporated, the residue was dissolved in ethyl acetate, washed with water, saturated aqueous sodium thiosulfate solution and saturated brine in that order, and anhydrous magnesium sulfate was added to dry the residue. This was concentrated under reduced pressure, n-hexane was added, and the resulting precipitate was collected to obtain 61.0 g of the desired product.

Experimental Example 3 (Synthesis of raw material compound) p-methoxybenzyl 7β- [2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-
2-Methoxyiminoacetamido] -3-triphenylphosphoniomethyl-3-cephem-4-carboxylate iodide 9.54 g of the compound of Experimental Example 2 was dissolved in 190 ml of benzene, 5.64 g of triphenylphosphine was added, and the mixture was stirred at room temperature for 1 hour. 100 ml of n-hexane was added dropwise to this reaction solution and the resulting precipitate was collected. This is benzene-n-hexane (1:
1) The mixture was washed with n-hexane to obtain 11.30 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-Methoxyiminoacetamide] -3-[(Z) -3
-Chloro-1-propen-1-yl] -3-cephem-
4-carboxylate 30.0 g of the compound of Experimental Example 3 was dissolved in a mixed solution of 250 ml of chloroform and 300 ml of ethyl acetate, and 78.3 ml of a 1N sodium hydroxide aqueous solution was added under ice cooling and the mixture was stirred. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and dried. A solution of 6.15 g of chloroacetaldehyde in 10 ml of chloroform was added to this organic layer under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated and 300 ml of ethyl acetate was added to remove the resulting precipitate. The liquid is concentrated to give the crude product 29.3
got g. This was purified by silica gel column chromatography (elution; chloroform) to obtain 7.73 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-Methoxyiminoacetamide] -3-[(E) -3
-Iodo-1-propen-1-yl) -3-cephem-
4-carboxylate 7.97 g of the compound of Experimental Example 4 was dissolved in 167 ml of acetone, 4.37 g of sodium iodide was added thereto, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, the residue was dissolved in 150 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, n-hexane and petroleum ether were added to the residue to solidify it, and the desired product (8.42 g) was obtained.

Experimental Example 6 (Synthesis of raw material compound) p-methoxybenzyl 7β- [2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-
2-Ethoxyiminoacetamide] -3-chloromethyl-3-cephem-4-carboxylate In the same manner as in Experimental Example 1, 2- (5-tritylamino-1,2,
4-thiadiazol-3-yl)-(Z) -2-ethoxyiminoacetic acid 21.5 g and p-methoxybenzyl 7β-amino-3-chloromethyl-3-cephem-4-carboxylic acid p-toluenesulfonate 19.8 g Was reacted to obtain 13.4 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-Ethoxyiminoacetamido] -3- (3-chloro-1-propen-1-yl) -3-cephem-4-carboxylate 13 g of the compound of Experimental Example 6, 3 g of sodium iodide, and 8.5 g of triphenylphosphine were suspended in 80 ml of acetone and stirred. Two
Precipitate formed by adding 300 ml of isopropyl ether after 1 hour
I took 8.8g. Suspend this in 100 ml of chloroform and
46 ml of aqueous sodium hydroxide solution was added. Take the organic layer,
Anhydrous magnesium sulfate was added to this and dried. Next, 3.6 g of chloroacetaldehyde was added and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, 300 ml of ethyl acetate was added to the residue, and the formed precipitate was removed. The liquid was concentrated and purified by silica gel column chromatography to obtain 3.46 g of the desired product.

Experimental Example 8 (Synthesis of raw material compound) p-methoxybenzyl 7β- [2- (5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-
2-Ethoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3-cephem-4-carboxylate In the same manner as in Experimental Example 5, 1.7 g of the compound of Experimental Example 7 was reacted with 600 mg of sodium iodide to obtain 1.1 g of the desired product.

Example 1 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3- (carbamoylmethyldimethylammonio) -1-propen-1-yl] -3-cephem-4-carboxylate 600 mg of the compound of Experimental Example 5 was suspended in 60 ml of ethyl ether,
Add 87.3 mg of N, N-dimethylglycinamide at room temperature for 10
Stir for minutes. To this solution, 43 ml of ethyl acetate was added dropwise over 30 minutes. Then, after stirring for 12 hours, ethyl ether
20 ml was added and the resulting precipitate was removed. This was dissolved in 1 ml of tetrahydrofuran, 10 ml of ethyl acetate was added, and the resulting precipitate was collected to obtain 279 mg of a yellow powder.

This was added to a mixed solution of 3.32 ml of trifluoroacetic acid and 1.75 ml of anisole, and the mixture was stirred under ice cooling for 3 hours. The reaction solution was added to a mixed solution of 50 ml of ethyl ether and 50 ml of isopropyl ether, and the resulting precipitate was collected and washed with ethyl ether.
This precipitate was added to 1.8 ml of water, and the pH of the solution was adjusted to 6.0 with sodium acetate. The insoluble material was removed, and the solution was purified by reverse-phase silica gel column chromatography to obtain 51 mg of the desired product.

Example 2 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3- (1-methyl-3-pyrrolinio) -1-propen-1-yl] -3-cephem-4-
Carboxylate 500 mg of the compound of Experimental Example 5 was suspended in 50 ml of ethyl ether,
A solution of 59.2 mg of N-methyl-3-pyrroline in 5 ml of ethyl acetate was added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate in this solution
32 ml was added dropwise over 3 hours and 30 minutes, 20 ml of ethyl ether was added after 4 hours, and stirring was continued for 13 hours. The formed precipitate was taken and dissolved in 0.88 ml of tetrahydrofuran. To this was added 9 ml of ethyl acetate and the precipitate was removed to give a yellow powder 283
to obtain mg.

This yellow powder was added with 3.3 ml of trifluoroacetic acid and 1.8 ml of anisole.
A mixed solution of ml was added, and the mixture was stirred under ice cooling for 3 hours. The reaction solution was added to a mixed solution of 50 ml of ethyl ether and 50 ml of isopropyl ether, and the resulting precipitate was collected. Add 1.8 ml of water to this,
After adjusting the pH of the solution to 6.8 with sodium acetate, the insoluble matter was removed. The liquid was purified by reverse-phase silica gel column chromatography (elution; 5.5% methanol water, 6.5% methanol water) to obtain 47 mg of the desired product.

Example 3 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3-((2S) -2-hydroxymethyl-1-methylpyrrolidinio) -1-propene-1
-Yl] -3-cephem-4-carboxylate 900 mg of the compound of Experimental Example 5 was suspended in 90 ml of ethyl ether,
N-methyl-L-prolinol 147.6 mg ethyl acetate 9 ml
The solution was added at room temperature, and 10 minutes later, 57.6 ml of ethyl acetate was added dropwise over 2 hours. After stirring this solution for 1 hour, a solution of 73.8 mg of N-methyl-L-prolinol in 3 ml of ethyl ether was added, and the mixture was further stirred for 14 hours. 10 ml of ethyl ether was added and the resulting precipitate was collected. This is tetrahydrofuran 1.
It was dissolved in 3 ml, 13 ml of ethyl acetate was added, and the resulting precipitate was collected to obtain 546 mg of yellow powder.

This yellow powder was mixed with 3.9 ml of trifluoroacetic acid and 3.3 ml 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 90 ml of ethyl ether and 90 ml of isopropyl ether, and the resulting precipitate was collected. Water (1.8 ml) was added to this precipitate, the pH of the solution was adjusted to 5.7 with sodium acetate, and the insoluble material was removed. The liquid was purified by reverse-phase silica gel column chromatography (elution; 5.5% methanol water, 6.5% methanol water, 7.5% methanol water) to obtain 19 mg of the desired product.

Example 4 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3- (4-carbamoylquinuclidinio) -1-propen-1-yl] -3-cephem-
4-carboxylate 500 ml of the compound of Experimental Example 5 was suspended in 50 ml of ethyl ether,
4-Carbamoylquinuclidine (110 mg) was added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. 50 ml of ethyl acetate was added dropwise over 2 hours, and the resulting precipitate was collected after stirring for another 22 hours. This was dissolved in 0.9 ml of tetrahydrofuran, 9 ml of ethyl acetate was added, and the resulting precipitate was collected to obtain 318 mg of a yellow powder.

This yellow powder was mixed with 2.3 ml of trifluoroacetic acid and 2.8 of anisole.
It was added to the mixed solution of ml and stirred at room temperature for 2 hours and 30 minutes. The reaction solution was added to 100 ml of ethyl ether and the resulting precipitate was collected. This was suspended in 1.8 ml of water, the pH of the solution was adjusted to 5.3 with sodium hydrogen carbonate, and then the insoluble matter was removed. The liquid was purified by reverse-phase silica gel column chromatography (elution; 5% aqueous methanol) to obtain 50 mg of the desired product.

Example 5 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3- (1-methyl-1-piperazinio) -1-propen-1-yl] -3-cephem-4
-Carboxylate trifluoroacetate 984 mg of the compound of Experimental Example 5 was suspended in 98 ml of ethyl ether,
115 μl of 1-methylpiperazine was added, and the mixture was stirred at room temperature for 1 hour. Then 49 ml of ethyl acetate was added dropwise over 2 hours, 20
After stirring for a period of time, the resulting precipitate was collected. This was dissolved in 1.6 ml of tetrahydrofuran, 16 ml of ethyl acetate was added and reprecipitation was repeated twice, to obtain 411 mg of a yellow powder.

This yellow powder was mixed with 2.9 ml of trifluoroacetic acid and 2.5 of anisole.
It was added to the mixed solution of ml and stirred at room temperature for 30 minutes. The reaction solution was added to a mixed solution of 50 ml of ethyl ether and 50 ml of isopropyl ether, and the resulting precipitate was collected. Add 3 ml of water to this precipitate,
The insoluble matter was removed. The liquid was purified by reverse phase silica gel column chromatography (elution; 5.5% methanol water, 7.5% methanol water) to obtain 19 mg of the desired product.

The compounds of the following Examples 6 to 18 were synthesized in the same manner as in Examples 1 to 5.

Example 6 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyacetamide] -3
-[(E) -3- (4-Carboxyquinuclidinio)-
1-propen-1-yl] -3-cephem-4-carboxylate 800 mg of the compound of Experimental Example 5 and 4-carboxyquinuclidine 1
76.8 mg was reacted and the protective group was removed to obtain 15 mg of the desired product.

Example 7 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido-3-[(E) -3-[(2S) -2-carboxy-1-
Methylpyrrolidinio] -1-propen-1-yl] -3
-Cephem-4-carboxylate 800 mg of the compound of Experimental Example 5 and N-methyl-L-proline 317
mg was reacted and the protecting group was removed to obtain two types of isomers (related to the conformation of the methyl group bonded to the nitrogen atom of the pyrrolidine ring) as the desired product.

Isomer A 12 mg Isomer B 20 mg Example 8 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3- (carboxymethyldimethylammonio) -1-propen-1-yl] -3-cephem-4-carboxylate 800 mg of the compound of Experimental Example 5 and 117.5 m of N, N-dimethylglycine
g was reacted and the protecting group was removed to obtain 12 mg of the desired product.

Example 9 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3- (3-carboxypyridinio) -1-propen-1-yl] -3-cephem-4-
Carboxylate Reacting 1.0 g of the compound of Experimental Example 5 with 405 mg of nicotinic acid,
The protective group was removed to obtain 35 mg of the desired product.

Example 10 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3- (1,5-tetramethylene-2
-Pyrazolio) -1-propen-1-yl] -3-cephem-4-carboxylate 600 mg of the compound of Experimental Example 5 was reacted with 0.6 ml of 1,5-tetramethylenepyrazole and the protecting group was eliminated to obtain 11 mg of the desired product.

Example 11 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3- (carbamoylmethyldiethylammonio) -1-propen-1-yl] -3-cephem-4-carboxylate 500 mg of the compound of Experimental Example 5 and N, N-diethylglycinamide
93 mg was reacted and the protecting group was removed to obtain 6 mg of the desired product.

Example 12 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3- (2-dimethylaminoethyldimethylammonio) -1-propen-1-yl] -3
-Cephem-4-carboxylate 800 mg of the compound of Experimental Example 5 and 1,2-bis (dimethylamino)
React with 172 μl of ethane and remove the protecting group to give the desired product 14 m
got g.

Example 13 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3- (2-mercaptoethyldimethylammonio) -1-propen-1-yl] -3-cephem-4- Carboxylate 2.5 mg of the target compound was obtained by reacting 500 mg of the compound of Experimental Example 5 with 200 mg of 2-dimethylaminoethanethiol to eliminate the protecting group.
Got

Example 14 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3- (1-morpholino [4,3-
b] Pyrazolio) -1-propen-1-yl] -3-cephem-4-carboxylate The compound of Experimental Example 5 (1.0 g) was reacted with morpholino [4,3-b] pyrazole (408 mg) to remove the protecting group to obtain 11 mg of the desired product.

Example 15 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-ethoxyiminoacetamide] -3-[(E) -3- (carbamoylmethyldimethylammonio) -1-propen-1-yl] -3-cephem-4-carboxylate 1.0 g of the compound of Experimental Example 8 and N, N-dimethylglycinamide 2
30 mg was reacted and the protecting group was removed to obtain 90 mg of the desired product.

Example 16 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3- [4- (methyldithio) quinuclidinio] -1-propen-1-yl] -3-cephem-4-carboxy rate 28 mg of the desired product was obtained by reacting 500 mg of the compound of Experimental Example 5 with 350 mg of 4- (methyldithio) quinuclidine to eliminate the protecting group.
Got

Example 17 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3- (2-oxopropyldimethylammonio) -1-propen-1-yl] -3-cephem-4- Carboxylate 500 mg of the compound of Experimental Example 5 and N, N-dimethylaminoacetone
100 mg was reacted and the protecting group was removed to obtain 36 mg of the desired product.

Example 18 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3- [N, N-dimethyl-N- (2
-Carbamoylethyl) ammonio] -1-propene-
1-yl] -3-cephem-4-carboxylate The compound of Experimental Example 5 (500 mg) and 3-dimethylaminopropionamide (127 mg) were reacted with each other to remove the protective group and to obtain the target compound (12 m).
got g.

Example 19 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3- (2-hydroxyethyldimethylammonio) -1-propen-1-yl] -3-
Cephem-4-carboxylate (Compound A) 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(Z) -3- (2-hydroxyethyldimethylammonio) -1-propen-1-yl] -3-
Cephem-4-carboxylate (Compound B) 500 mg of the compound of Experimental Example 4, 142 mg of sodium iodide and 10 ml of 2-butanone were stirred at room temperature for 1 hour. The solvent was distilled off, the residue was dissolved in ethyl acetate, washed with a 10% aqueous sodium thiosulfate solution and saturated saline, dried over anhydrous magnesium sulfate, and dried. The solvent was distilled off, and the residue was dissolved in a mixed solution of 30 ml of ethyl acetate and 10 ml of ethyl ether. to this
Add 112 mg of N, N-dimethylaminoethanol, and add 1 at room temperature.
The mixture was stirred for 30 minutes. 20 ml of ethyl ether was added and the resulting precipitate was removed. This was washed with isopropyl ether to obtain 370 mg of a yellow powder.

This yellow powder was added to a mixed solution of 0.8 ml of anisole and 8 ml of trifluoroacetic acid under ice cooling and stirred at the same temperature for 1 hour.
20 ml of isopropyl ether was added to the reaction solution and the resulting precipitate was collected. 30% methanol water was added to this and the insoluble matter was removed. The pH of the solution was adjusted to 5 with sodium acetate.
The solvent was distilled off, and the residue was purified by reverse-phase silica gel column chromatography (elution; 5% aqueous methanol) to obtain the desired compound A 25 mg and compound B 17 mg.

Example 20 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(Z) -3- (carbamoylmethyldimethylammonio) -1-propen-1-yl] -3-cephem-4-carboxylate 1.031 g of the compound of Experimental Example 3 was dissolved in a mixed solution of 20 ml of ethyl acetate and 6 ml of chloroform, and 20 ml of a 10% potassium carbonate aqueous solution was added to this solution, followed by shaking. The organic layer was separated, dried over anhydrous potassium carbonate and then washed with 6 ml of ethyl acetate. Chloroacetaldehyde 85 ml ethyl acetate 0.
The 25 ml solution was added under ice cooling and stirred for 4 hours. Then, N, N-
Dimethylglycinamide 137mg and sodium iodide 5
A solution of 0 mg of acetone in 1 ml was added, and the mixture was stirred at room temperature overnight.
The precipitate was removed and dried. This was dissolved in 1.4 ml of anisole, 1.9 ml of trifluoroacetic acid was added under ice cooling, and the mixture was stirred for 1 hour. 100 ml of an isopropyl ether-ethyl ether (1: 1) mixed solution was added to the reaction solution, and the resulting precipitate was collected. This precipitate was washed with ethyl ether and dried to 20 mg.
To give a solid. This was dissolved in a mixed solution of 1.5 ml of water-1.0 ml of a saturated aqueous sodium acetate solution, and the insoluble matter was removed. The liquid was subjected to reverse phase silica gel column chromatography (elution; water-
Purified with 6% methanol water gradient)
Obtained 5 mg.

〔The invention's effect〕

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hiroshi Yamauchi 500-105 Shimohirooka Sakuramura, Shinji District, Ibaraki Prefecture Masato Ikeda Examiner

Claims (6)

[Claims] 1. A general formula: [In the formula, R ₁ represents a lower alkyl group, and A is the following group: (R ₂ and R ₃ are the same or different lower alkyl groups, R ₄ is a lower alkyl group substituted with a group selected from a carbamoyl group, a carboxyl group, a lower alkyl-substituted amino group, a mercapto group, a lower alkanoyl group and a hydroxyl group. ); Or the following groups optionally substituted with a group selected from a carboxyl group, a carbamoyl group and a lower alkyldithio group: (R ₅ represents a lower alkyl group); or the following groups: (R ₅ is the same as defined above, R ₆ is a hydroxy lower alkyl group or a carboxyl group)]] or a non-toxic salt thereof. 2. A group represented by the following A in general formula (I): The compound according to claim 1, which is a compound which is: or a non-toxic salt thereof. 3. β- [2- (5-Amino-1,2,4-thiadiazol-3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3- (carbamoyl) Methyldimethylammonio) -1-propen-1-yl]
The compound according to claim 1, which is -3-cephem-4-carboxylate or a non-toxic salt thereof. 4. 7β- [2- (5-Amino-1,2,4-thiadiazol-3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3- (1) -Methyl-1
A compound according to claim 1, which is -piperazinio) -1-propen-1-yl] -3-cephem-4-carboxylate or a non-toxic salt thereof. 5. β- [2- (5-Amino-1,2,4-thiadiazol-3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3- (2) -Hydroxyethyldimethylammonio) -1-propen-1-yl] -3-cephem-4-carboxylate or a non-toxic salt thereof, according to claim 1. 6. A general formula: [In the formula, R ₁ is a lower alkyl group, and X is a halogen atom]
A compound represented by the formula (1), 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 general formula: A '(III) [A' is the following formula: (R ₂ and R ₃ are the same or different lower alkyl groups, R ₄ is a lower alkyl group substituted with a group selected from a carbamoyl group, a carboxyl group, a lower alkyl-substituted amino group, a mercapto group, a lower alkanoyl group and a hydroxyl group. ); Or the following formula, which may be substituted with a group selected from a carboxyl group, a carbamoyl group and a lower alkyldithio group: (R ₅ represents a lower alkyl group); or the following formula (R ₅ is the same as defined above and represents R ₆ hydroxy lower alkyl group or carboxyl group)] or a salt thereof, and a protecting group is eliminated as necessary: A method for producing a compound represented by the formula: wherein R ₁ is as described above, and A is a quaternary ammonio group corresponding to A ', or a non-toxic salt thereof.