JPH0717654B2 - 7-thiadiazolylacetamide-3-cefm 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, JP-A-60-97983, and JP-A-60-97983 In 60-197693, etc., a cephalosporin derivative having a quaternary ammonio group similar to the compound of the present invention is 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: 7-thiadiazolylacetamide-3 represented by the formula: wherein R ₁ , R ₂ and R ₃ are lower alkyl groups, and R ₄ is a 5-membered heterocyclic lower alkyl group which may have a substituent. -Cephem derivatives and their non-toxic salts.

Examples of the lower alkyl group represented by R ₁ , R ₂ and R _{3 in} the above general formula (I) include C ₁ ~ such as methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl and t-butyl. C ₄ group can be mentioned.

5-membered heterocycle optionally having a substituent of R _{4 is} a 5-membered heterocycle in the lower alkyl group, which is thiazolyl, pyrazolyl, oxadiazolyl, imidazolyl, furyl, isothiazolyl, isoxazolyl, thiadiazolyl, thienyl, pyrrolyl, tetrazolyl, triazolyl. And so on. Substituents for these 5-membered heterocycles include amino groups; carboxyl groups; methyl, ethyl, n-propyl, i-
Lower alkyl groups such as propyl, n-butyl, sec-butyl, i-butyl; carboxy lower alkyl groups such as carboxymethyl, carboxyethyl; carbamoyl groups; hydroxyl groups; lower alkyl substituted amino groups such as dimethylamino, diethylamino; hydroxymethyl And hydroxy lower alkyl groups such as hydroxyethyl. The lower alkyl group in the 5-membered heterocyclic lower alkyl group includes methyl, ethyl, n-propyl, i-propyl, n-
Butyl, sec-butyl, t-butyl, etc. may be mentioned.

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, glutamate salt; trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, Examples thereof include N, N'-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, tris (hydroxymethylamino) methane salt, phenethylbenzylamine salt, and other amine salts.

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 atine 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 the compound represented by the general formula: [Wherein R ₂ , R ₃ , and R ₄ are the same as defined above] or a salt thereof is reacted, and a protecting group is optionally removed to remove the compound of the general formula (I) or its nontoxicity. A salt can be obtained.

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

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 salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt;
Ammonium salts; inorganic salts such as hydrochloride, hydrobromide, sulfate, carbonate, hydroiodide, bicarbonate; acetate, trifluoroacetate, maleate, lactate, tartrate Organic carboxylic acid salts such as methanesulfonic acid salts, benzenesulfonic acid salts, and toluenesulfonic acid salts; trimethylamine salts, triethylamine salts, pyridine salts, procaine salts, picoline salts, dicyclohexylamine salts, N, N Amine salts such as ′ -dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, tris (hydroxymethylamino) methane salt, phenethylbenzylamine salt; arginine salt, asparaginate salt, lysine salt, It can be appropriately selected from salts such as amino acid salts such as glutamate and serine salts.

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 ethyl acetate 4 was added to the reaction solution, it was washed successively with water, saturated saline, saturated aqueous sodium hydrogen carbonate solution, saturated saline, 1N hydrochloric acid, and saturated saline. 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),
115 g of the target product was obtained.

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 of methyl ethyl ketone, and 56.5 g of sodium iodide was added thereto, and
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 The compound of Experimental Example 2 (9.54 g) was dissolved in benzene (190 ml), triphenylphosphine (5.64 g) was added, and the mixture was stirred at room temperature for 1 hr. 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 under ice cooling, 78.3 ml of a 1N sodium hydroxide aqueous solution was added 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, and n-hexane and petroleum ether were added to the residue to solidify it, and the desired product (8.42 g) was obtained.

Example 1 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3-[(1,3,4-oxadiazol-2-yl) methyldimethylammonio] -1-propene -1-yl] -3-cephem-4-carboxylate 500 mg of the compound of Experimental Example 5 was suspended in 10 ml of ethyl ether,
2-dimethylaminomethyl-1,3,4-oxadiazole 12
0 mg was added and the mixture was stirred at room temperature for 1 hour. 50 ml of ethyl ether was added to the reaction solution and the precipitate was collected to obtain 510 mg of a yellow powder.

2.5 ml of this yellow powder was added to trifluoroacetic acid and anisole 2.5.
It was added to the mixed solution of ml and stirred for 3 hours under ice cooling. 50 ml of isopropyl ether was added to the reaction solution and the resulting precipitate was collected.
This was suspended in 2 ml of water, sodium hydrogen carbonate was added to adjust the pH of the solution to 7-8, and then the insoluble matter was removed. The liquid was purified by reverse-phase silica gel chromatography to obtain 13 mg of the desired product.

Example 2 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3-[(1,2,4-oxadiazol-3-yl) methyldimethylammonio] -1-propene -1-yl] -3-cephem-4-carboxylate 500 mg of the compound of Experimental Example 5 was suspended in 10 ml of ethyl ether,
3-dimethylaminomethyl-1,2,4-oxadiazole 12
0 mg was added and the mixture was stirred at room temperature for 1 hour. 50 ml of ethyl ether was added to the reaction solution and the precipitate was collected to obtain 480 mg of yellow powder.

2.5 ml of this yellow powder was added to trifluoroacetic acid and anisole 2.5.
The mixture was added to the mixed solution of ml and stirred under ice cooling for 3 hours. 50 ml of isopropyl ether was added to the reaction solution, and the resulting precipitate was collected.
This was suspended in 2 ml of water, and sodium hydrogencarbonate was added to adjust the solution to pH 7-8. The insoluble material was removed, and the liquid was purified by reverse phase silica gel chromatography to obtain 34 mg of the desired product.

Example 3 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3-[(imidazol-4-yl) methyldimethylammonio] -1-propen-1-
Ill] -3-cephem-4-carboxylate 500 mg of the compound of Experimental Example 5 was suspended in 10 ml of ethyl ether,
125 mg of 4- (dimethylaminomethyl) imidazole was added and stirred for 1 hour. 50 ml of ethyl ether was added to the reaction solution, and the resulting precipitate was collected to obtain 382 mg of yellow powder.

2.5 ml of this yellow powder was added to trifluoroacetic acid and anisole 2.5.
The mixture was added to the mixed solution of ml and stirred under ice cooling for 3 hours. 50 ml of isopropyl ether was added to the reaction solution and the precipitate was collected. This was suspended in 2 ml of water, sodium hydrogen carbonate was added, and the solution was adjusted to pH 7-
Adjusted to 8. The insoluble material was removed, and the solution was purified by reverse-phase silica gel chromatography to obtain the desired product (23 mg).

The compounds of the following Examples 4 to 7 were produced in the same manner as in Examples 1 to 3.

Example 4 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3-[(thiazol-4-yl)
Methyldimethylammonio] -1-propen-1-yl] -3-cephem-4-carboxylate The compound of Experimental Example 5 (500 mg) was reacted with 4-dimethylaminomethylthiazole (126 mg), and then the protecting group was removed to obtain 33 mg of the desired product.

Example 5 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3-[(pyrazol-4-yl)
Methyldimethylammonio] -1-propen-1-yl] -3-cephem-4-carboxylate The compound of Experimental Example 5 (500 mg) was reacted with 3-dimethylaminomethylpyrazole (120 mg), and then the protecting group was removed to obtain 20 mg of the desired product.

Example 6 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3-[(2-aminothiazole-
4-yl) methyldimethylammonio] -1-propen-1-yl] -3-cephem-4-carboxylate The compound of Experimental Example 5 (500 mg) was reacted with 2-amino-4-dimethylaminomethylthiazole (140 mg), and then the protecting group was removed to obtain 58 mg of the desired product.

Example 7 7β- [2- (5-amino-1,2,4-thiadiazole-
3-yl)-(Z) -2-methoxyiminoacetamido] -3-[(E) -3-[(furan-3-yl) methyldimethylammonio] -1-propen-1-yl]-
3-cephem-4-carboxylate The compound of Experimental Example 5 (500 mg) was reacted with 3-dimethylaminomethylfuran (125 mg), and then the protecting group was eliminated to give the desired compound 3
Obtained 5 mg.

〔The invention's effect〕

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Isao Sugiyama 29-4 Higashiarai, Yatabe-cho, Tsukuba-gun, Ibaraki Prefecture (72) Inventor Hiroshi Yamauchi 500-105 Sakuramura Shimooka, Shinji-gun, Ibaraki Examiner Masato Ikeda

Claims (7)

[Claims] 1. A general formula: 7-thiadiazolylacetamide-3 represented by the formula: wherein R ₁ , R ₂ and R ₃ are lower alkyl groups, and R ₄ is a 5-membered heterocyclic lower alkyl group which may have a substituent. -Cephem derivatives and their non-toxic salts. 2. A 5-membered heterocyclic ring which may have a substituent for R ₄ , wherein the 5-membered heterocycle in the lower alkyl group is thiazolyl, pyrazolyl, oxadiazolyl, imidazolyl or furyl. Compounds and their non-toxic salts. 3. The compound according to claim 1 or 2, wherein the substituent in the optionally substituted 5-membered heterocyclic lower alkyl group for R ₄ is an amino group, and its nontoxicity. salt. 4. R ₁ is a methyl group, R ₂ is a methyl group, R ₃ is a methyl group, and R ₄ is a (1,3,4-oxadiazol-2-yl) methyl group. A compound according to item 1 and a non-toxic salt thereof. 5. A method according to claim 1, wherein R ₁ is a methyl group, R ₂ is a methyl group, R ₃ is a methyl group, and R ₄ is a (1,2,4-oxadiazol-3-yl) methyl group. A compound according to item 1 and a non-toxic salt thereof. 6. The compound according to claim 1, wherein R ₁ is a methyl group, R ₂ is a methyl group, R ₃ is a methyl group, and R ₄ is a (imidazol-4-yl) methyl group. Toxic salt. 7. 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 the compound represented by the general formula: [Wherein R ₂ and R ₃ are lower alkyl groups, and R ₄ is a 5-membered heterocyclic lower alkyl group which may have a substituent] or a salt thereof is reacted and optionally protected. General formula characterized by leaving a group: A method for producing a compound represented by the formula: wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as defined above, or a non-toxic salt thereof.