KR20020012951A - Cephalosporin derivatives having quaternary hetero compounds and process for preparation thereof - Google Patents

Abstract

PURPOSE: Provided are cephalosporin derivatives having quaternary hetero compounds and preparation process thereof. The derivatives have a broad spectrum of antibacterial activity on both gram positive and negative bacteria. Therefore, they are useful as an antibiotics. CONSTITUTION: The cephalosporin derivative is represented by the formula(1), in which X is C or N and R represents radicals of formulae or alkyl group, wherein X is preferably C. It is prepared by reacting cefotaxime and R-substituted pyridine or pyridazine in the presence of nucleophile. A pharmaceutical composition of antibiotics contains cephalosporin derivative or its pharmaceutically acceptable slat as an active ingredient.

Description

Cephalosporin compounds having quaternized hetero compounds and preparation methods thereof {Cephalosporin derivatives having quaternary hetero compounds and process for preparation etc}

The present invention relates to a cephalosporin derivative, and more particularly, a cephalosporin derivative represented by the following formula (1), which exhibits excellent antimicrobial activity in a broad antimicrobial spectrum including gram positive and gram negative bacteria, and a pharmaceutically acceptable salt thereof. It relates to a solvate, a preparation method thereof and a pharmaceutical composition for an antimicrobial agent comprising the same.

Formula 1

In the above formula,

X is C or N,

R is Or an alkyl group.

Sephaloridine (FR 1,384,197), Sephazoline (USP 3516997), Sephamandol (USP 3641021), Cythiam (Ger.Patent 2607064), and Cepu, which are classified into first and second generations of conventional cephalosporin antibiotics. Roxim (USP 1384197) mainly exhibits antimicrobial activity centered on Gram-positive bacteria, and has a weak antimicrobial activity against Gram-positive bacteria including Pseudomonas aeruginosa and very unstable against beta-lactamase (β-lactamase). Handbook of Antibiotic, Japanese Pharmaceutical Newspaper, 1992).

In order to solve the above disadvantages, third generation cephalosporins such as cytotaxin (USP 4,098888), cytotagemide (Ger.Patent 2921316), and cytotriaxone (GB 2,022,090) developed from the late 1970s to the 1980s Antibiotics significantly improved the stability of beta-lactamase and antimicrobial activity against Gram-negative bacteria compared to the first and second generation antibiotics. However, the antimicrobial activity against Gram-positive bacteria is very weak, and most of the third generation cephalosporin antibiotics, except for cytotagemite, have the disadvantage that they do not show antimicrobial activity against Pseudomonas aeruginosa (American Journal of Medicine). , 79: 14,1985). Moreover, the clinical are abusing the cephalosporin antibiotics in the third generation Sepharose weak antibacterial activity increased infections due to these resistant bacteria week for Staphylococcus aureus (Staphylococcus aureu s) and Pseudomonas aeruginosa (Pseudomonas) has become a social problem. In addition, the third generation cephalosporin antibiotics do not show the expected therapeutic effect because most of them have a short anti-half life in the blood, even if they show strong antimicrobial activity against pathogens, and thus do not continuously show antimicrobial activity in the tissue. Inevitably leads to patient pain and increased medical costs (Clinical Pharmacolinetics, 10: 101-143,1985). Some third-generation cephalosporin antibiotics have a long half-life in blood such as ceftriaxone, but still have weak antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa (Clinical Pharmacy, 3: 351-373, 1984).

Accordingly, the present inventors have shown strong antimicrobial activity in a wide range and have tried to develop a new antimicrobial agent with excellent bioavailability. As a result, the cephalosporin derivative represented by Formula 1 of the present invention has a staphylococcus aureus. Both the Gram-positive bacteria and Gram-negative bacteria including Pseudomonas aeruginosa showed excellent antimicrobial activity and were found to be safe in vivo to complete the present invention.

It is an object of the present invention to provide a cephalosporin derivative having a quaternized heterocycle, a pharmaceutically acceptable salt thereof, a preparation method thereof, and an antimicrobial pharmaceutical composition having the same as an active ingredient.

In order to achieve the above object, the present invention provides a cephalosporin compound represented by the following formula (1) and a pharmaceutically acceptable salt thereof.

The present invention also provides a method for preparing the compound.

The present invention also provides a pharmaceutical composition comprising the compound as an active ingredient.

Hereinafter, the present invention will be described in detail.

The present invention provides a cephalosporin derivative represented by the formula (1) having a quaternized hetero compound and pharmaceutically acceptable salts thereof.

Formula 1

In the above formula,

X is C or N,

R is Or an alkyl group.

Preferably, in Formula 1

X is C and R is ego;

Or X is N and R is an alkyl group.

More preferably, the compound of Formula 1 is as follows.

7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [3- (4-methylisoxazol-2-yl) -1-pyridino] Methyl-3-cepem-4-carboxylate

7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [3- (3,4-cyclohexylisoxazol-2-yl) -1- Pyridino] methyl-3-cepem-4-carboxylate

7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [3- (3,4-cyclopentylisoxazol-2-yl) -1- Pyridino] methyl-3-cepem-4-carboxylate

7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [4- (4-methylisoxazol-2-yl) -1-pyridino] Methyl-3-cepem-4-carboxylate

7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [4- (3,4-cyclohexylisoxazol-2-yl) -1- Pyridino] methyl-3-cepem-4-carboxylate

7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [4- (3,4-cyclopentylisoxazol-2-yl) -1- Pyridino] methyl-3-cepem-4-carboxylate

7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [3-methyl-2-pyridazino] methyl-3-cepem-4-car Carboxylate

The quaternized hetero compounds are known to increase the antimicrobial activity by changing the hydrophobicity of the physical properties of the material, thereby facilitating the outer membrane transmission of Gram-negative bacteria, especially Pseudomonas aeruginosa. Was prepared (35th ICAAC Symposium, Sanfransico, 1995).

In addition, the cephalosporin derivatives represented by Formula 1 may be used in the form of a pharmaceutically acceptable salt, and acid salts formed by pharmaceutically acceptable free acid are useful as salts. Inorganic acids and organic acids can be used as the free acid. Hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc. may be used as the inorganic acid, and citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, glyconic acid, succinic acid, 4-toluenesulfonic acid , Gluturonic acid, embonic acid, glutamic acid, aspartic acid, or the like can be used. The compound of formula 1 may also be a pharmaceutically acceptable metal salt, in particular an alkali metal salt, formed due to the base. Examples of these are sodium salts and potassium salts.

In addition, the present invention provides a method for producing a Sepharoserin compound represented by the formula (1).

(Wherein R and X are as defined above)

The solid compound produced by heating and refluxing a mixture of the cephataxime sodium salt and R-substituted pyridine or pyridazine in the presence of nucleophiles such as sodium iodide (NaI) and trimethylsilyl iodide (TMSI) is filtered and washed. Lyophilization yields a compound of the present invention.

The present invention also provides a pharmaceutical composition for an anticancer agent containing the compound of Formula 1 as an active ingredient.

The compound of formula 1 may be administered orally or parenterally during clinical administration and may be used in the form of a general pharmaceutical preparation.

That is, the compound of Formula 1 of the present invention may be administered in various oral and parenteral dosage forms during actual clinical administration, and when formulated, the commonly used fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. It is formulated using diluents or excipients.

Solid form preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, which form at least one excipient such as starch, calcium carbonate, It is prepared by mixing sucrose or lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. .

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As a suppository base, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

In general, in medicine, the effective dose of the compound of formula 1 according to the present invention is 0.1 to 500 mg / kg, preferably 0.1 to 50 mg / kg, and may be administered once to several times daily. However, the dosage may need to be changed, and in particular, may be changed in consideration of the constitution specificity and weight of the subject to be treated, the type and depth of the disease, the nature of the formulation, the nature of the drug administration, and the duration or interval of administration.

Minimum Inhibitory Concentration (MIC, ㎍ / ml) of the novel Sepharoseporin derivatives according to the present invention, significant antimicrobial activity compared to the existing Ceftazidime and Cefpirome (Cefpirome) Results were obtained and showed excellent antibacterial activity against Pseudomonas aeruginosa and Staphylococcus aureus.

Hereinafter, the present invention will be described in more detail with reference to Examples.

However, the following examples are illustrative of the present invention, and the content of the present invention is not limited by the examples.

Example 1 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [3- (4-methylisoxazol-2-yl)- Preparation of 1-pyridino] methyl-3-cepem-4-carboxylate

0.4 ml of 4N-HCl and 1.2 ml of acetonitrile were placed in the flask, 0.75 g (1.54 mmol) of cytotaxic sodium salt, 2.25 g (15 mmol) of sodium iodide, and 3- (4-methylisoxazol-2-yl) Pyridine 0.86 (15 mmol) was added. After refluxing at 80 degrees for about 1.5 hours, ice-cooling and acetone were added. The reaction mixture in solid form, which was precipitated by scraping with a medicine spoon, was made in suspension, filtered, and washed with acetone. The precipitate was dried in vacuo at a temperature of 40-45 degrees and subjected to tube chromatography (CH ₃ CN: H ₂ O = 4: 1) using silica gel and then lyophilized to prepare the target compound. The yield was 12.3%.

H ¹ NMR (200 MHz, DMSO-d ₆ ) δ 2.30 (3H, s) 3.2, 3.46 (2H, ABq, J = 17.4 Hz, cephem ring 2-H) 3.73 (3H, s, methoxy group) 5.04 (1H , d, J = 5.2 Hz, cephem ring 6-H) 5.18, 5.67 (2H, ABq, J = 16.2 Hz, cephem ring 3-CH2) 5.62 (1H, dd, J = 5.2 Hz, 5.9 Hz, cephem ring 7 -H) 6.64 (1H, s, thiazole ring 5-H) 7.20 (2H, s, -NH ₂ ) 8.27, 8.94, 9.65, 10.08 (each 4H, t, d, d, s, J = 14, 8.6, 5.8 Hz, pyridine ring H) 9.49 (1H, d, J = 5.9 Hz, -CONH)

Example 2 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [3- (3,4-cyclohexylisoxazole-2- I) -1-pyridino] methyl-3-cepem-4-carboxylate

0.4 ml of 4N-HCl and 1.2 ml of acetonitrile were placed in the flask, 0.75 g (1.54 mmol) of cytotaxic sodium salt, 2.25 g (15 mmol) of sodium iodide, and 3- (3,4-cyclohexylisoxazole- 2-49) pyridine 3.49 mmol was added. After refluxing at 80 degrees for about 1.5 hours, ice-cooling and acetone were added. The reaction mixture in solid form, which was rubbed with a spoon, was suspended, filtered and washed with acetone. The precipitate was dried in vacuo at a temperature of 40-45 ° C. and subjected to tube chromatography (CH ₃ CN: H ₂ O = 4: 1) using silica gel, followed by lyophilization to obtain a target compound having a yield of 10.0%.

H ¹ NMR (200 MHz, DMSO-d ₆ ) δ 1.77 (4H, s, cyclohexyl-ring) 2.71-2.92 (4H, m, cyclohexyl-ring) 3.20, 3.50 (2H, ABq, J = 17.4 Hz, cephem ring 2-H) 3.82 (3H, s, methoxy group) 5.08 (1H, d, J = 4.8 Hz, cephem ring 6-H) 5.23, 5.73 (2H, ABq, J = 13.2 Hz cephem ring 7-H) 5.66 ( 1H, dd, J = 4.6 Hz, 5.4 Hz, Cephem ring 7-H) 6.69 (1H, s, thiazole ring 5-H) 7.25 (2H, s, -NH ₂ ) 8.30, 8.86, 9.60, 9.99 (each 4H , t, d, d, s, J = 14.4, 8.4, 5.4 Hz, pyridine ring H) 9.57 (1H, d, J = 5.4 Hz, -CONH)

Example 3 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [3- (3,4-cyclopentylisoxazole-2- Yl) -1-pyridino] methyl-3-cepem-4-carboxylate

According to the preparation method of Example 1, 3- (3,4-cyclopentylisoxazol-2-yl) pyridine to be bound to the cetactaxi sodium salt was added and reacted to obtain 7.5% of the target compound.

H ¹ NMR (200 MHz, DMSO-d ₆ ) δ 1.77-2.05 (4H, m, cyclopentyl-ring) 2.57 (2H, t, J = 7.0 Hz, cyclopentyl-ring) 3.23, 3.48 (2H, ABq, J = 17.4 Hz, cephem ring 2-H) 3.88 (3H, s, methoxy group) 5.02 (1H, d, J = 4.9 Hz, cephem ring 6-H) 5.19, 5.69 (2H, ABq, J = 13.2 Hz cephem ring 3 -H) 5.61 (1H, dd, J = 4.9 Hz, 5.5 Hz, Cephem ring 7-H) 6.65 (1H, s, thiazole ring 5-H) 7.20 (2H, s, -NH ₂ ) 8.22, 8.75, 9.33, 9.82 (each 4H, t, d, d, s, J = 14.4, 8.4, 5.4 Hz, pyridine ring H) 9.59 (1H, d, J = 5.5 Hz, -CONH)

Example 4 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [4- (4-methylisoxazol-2-yl)- Preparation of 1-pyridino] methyl-3-cepem-4-carboxylate

According to the preparation method of Example 1, 4- (4-methylisoxazol-2-yl) pyridine to be bound to the cetactaxi sodium salt was added and reacted to obtain the target compound in a yield of 28.4%.

H ¹ NMR (200 MHz, DMSO-d ₆ ) δ 2.38 (3H, s) 3.15, 3.49 (2H, ABq, J = 17.4 Hz, cephem ring 2-H) 3.78 (3H, s, methoxy group) 5.06 (1H , d, J = 5.0 Hz, cephem ring 6-H) 5.12, 5.64 (2H, ABq, J = 18.4 Hz, cephem ring 3-CH2) 5.66 (1H, dd, J = 5.0 Hz, 7.8 Hz, cephem ring 7 -H) 6.70 (1H, s, thiazole ring 5-H) 7.23 (2H, s, -NH ₂ ) 7.58, 8.59, 9.66, (each 4H, s, d, d, J = 6.8, 6.6 Hz, pyridine ring H) 9.62 (1H, doublet, J = 8.0 Hz, -CONH)

Example 5 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [4- (3,4-cyclohexylisoxazole-2- I) -1-pyridino] methyl-3-cepem-4-carboxylate

According to the preparation method of Example 1, 4- (3,4-cyclohexylisoxazol-2-yl) pyridine to be bound to the cetactaxi sodium salt was added to react to obtain the target compound in a yield of 20.8%.

H ¹ NMR (200 MHz, DMSO-d ₆ ) δ 1.78 (4H, s, cyclohexyl-ring) 2.55-2.92 (4H, bd, cyclohexyl-ring) 3.10, 3.58 (2H, ABq, J = 18.0 Hz, cephem ring 2-H) 3.82 (3H, s, methoxy group) 5.05 (1H, d, J = 4.6 Hz, cephem ring 6-H) 5.12, 5.60 (2H, ABq J = 10.6 Hz cephem ring 3-CH ₂ ) 5.67 ( 1H, dd, J = 4.6 Hz, 7.8 Hz, Cephem ring 7-H) 6.69 (1H, s, thiazole ring 5-H) 7.22 (2H, s, -NH ₂ ) 8.42, 9.61 (each 4H, d, d , J = 6.6, 6.8 Hz, pyridine ring H) 9.58 (1H, d, J = 7.8 Hz, -CONH)

Example 6 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [4- (3,4-cyclopentylisoxazole-2- I) -1-pyridino] methyl-3-cepem-4-carboxylate

According to the preparation method of Example 1, 4- (3,4-cyclopentylisoxazol-2-yl) pyridine to be bound to the cetactaxi sodium salt was added to the reaction to obtain the target compound in a yield of 8.5%.

H ¹ NMR (200 MHz, DMSO-d ₆ ) δ1.81-1.96 (2H, m, cyclopentyl-ring), 2.64-2.81 (4H, m, cyclopentyl-ring), 3.14, 3.62 (2H, ABq, J = 18.0 Hz, cephem ring 2-H) 3.79 (3H, s, methoxy group) 4.98 (1H, d, J = 4.4 Hz, cephem ring 6-H) 5.05, 5.53 (2H, ABq, J = 10.2 Hz cephem ring 3- CH ₂ ) 5.61 (1H, dd, J = 4.4 Hz, 7.2 Hz, Cephem ring 7-H) 6.84 (1H, s, thiazole ring 5-H) 7.32 (2H, s, -NH ₂ ) 8.38, 9.55 (each 4H, d, d, J = 6.6, 6.8 Hz, pyridine ring H) 9.64 (1H, d, J = 7.2 Hz, -CONH)

Example 7 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [3-methyl-2-pyridazino] methyl-3- Preparation of Cefem-4-carboxylate

According to the preparation method of Example 1, 3-methylpyridazine to be bound to the cetactaxi sodium salt was added and reacted to obtain the target compound in 20.9% yield.

H ¹ NMR (200 MHz, DMSO-d ₆ ) δ 2.75 (3H, s) 3.20, 3.60 (2H, ABq, J = 16.0 Hz, cephem ring 2-H) 3.79 (3H, s, methoxy group) 5.03 (1H , d, J = 5.0 Hz, cephem ring 6-H) 5.14, 5.82 (2H, ABq, J = 14.0 Hz, cephem ring 3-CH2) 5.63 (1H, dd, J = 5.0 Hz, 8.0 Hz, cephem ring 7 -H) 6.70 (1H, s, thiazole ring 5-H) 7.22 (2H, s, -NH2) 8.45, 8.62, 10.45, (each 3H, d, q, d, J = 8.0, 14.4, 5.8 Hz, pyridazine ringH) 9.48 (1H, d, J = 8.0 Hz, -CONH)

Pharmaceutical compositions comprising the compound of formula 1 as an active ingredient of the present invention can be administered parenterally and orally, and are prepared in parenteral formulations as injections, oral formulations as syrups and tablets.

Preparation Example 1 Preparation of Injection Solution

Injection solution containing 10 mg of the active ingredient was prepared by the following method.

1 g of the compound of Example 1, 0.6 g of sodium chloride and 0.1 g of ascorbic acid were dissolved in distilled water to make 100 ml. The solution was bottled and sterilized by heating at 20 ° C. for 30 minutes.

The components of the injection solution are as follows.

Compound of Example 1 ... 1 g

Sodium Chloride ・ ・ ・ ・ 0.6 g

0.1 g of ascorbic acid

Distilled water ··················

Preparation Example 2 Preparation of Syrup

Syrups containing acid addition salts of the cephalosporin derivatives of the present invention and pharmaceutically acceptable salts thereof as an active ingredient of 2% (weight / volume) are prepared by the following method.

Acid addition salts, saccharin and sugars of the cephalosporin derivative were dissolved in 80 g of warm water. After the solution was cooled, a solution consisting of glycerin, saccharin, spices, ethanol, sorbic acid and distilled water was prepared and mixed thereto. Water was added to this mixture to 100 ml.

The components of the syrup are as follows.

Acid addition salts of the compound of Example 1 2 g

Saccharin: 0.8 g ············

25.4 g of sugar

Glycerin ... 8.0 g

Spices ··················· 0.04 g

Ethanol 4.0 g

0.4 g of sorbic acid

Distilled water ·····················

Preparation Example 3 Manufacturing Method

A tablet containing 15 mg of active ingredient is prepared by the following method.

250 g of the compound of Example 1 were mixed with 175.9 g of lactose, 180 g of potato starch and 32 g of colloidal silicic acid. 10% gelatin solution was added to the mixture, which was then ground and passed through a 14 mesh sieve. It was dried and the mixture obtained by adding 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate was made into a tablet.

The components of the tablet are as follows.

Compound of Example 1 ... 250 g

Lactose ········ 175.9 g

Potato starch ········· 180 g

Colloidal silicic acid 32 g

10% gelatin solution

Potato starch · 160 g

Talc · 50 g

Magnesium stearate ·········· 5

Experimental Example 1 Measurement of In Vitro Antimicrobial Activity

To determine whether the cephalosporin derivatives of the present invention are useful as antimicrobial agents, agar for the compounds of Examples 1, 2, 3 and 7 according to the method described in Chemotheraphy, 29 (1), 76, (1981)} Minimum Inhibitory Concentration (MIC) was measured by agar dilution. In this case was used the Gram-positive bacteria of glucose aureus (Staphylococcus) as the test organism, as gram-negative bacteria E. coli (Escherichia), Pseudomonas aeruginosa (Pseudomonas), keurep when Ella bacteria (Klebsiella), Proteus bacteria (Proteus), Enterobacteriaceae (Enterobacter), Klein Median bacteria ( Chlamydia ) and Serratia were used. As a control group, ceftazidime (CAZ) and cepirome (Cefpirome, CPR) were used, and the measurement results are shown in Table 1 below.

The compounds of the present invention exhibited strong antimicrobial activity against both Gram-negative and Gram-positive bacteria, in contrast to cytotagemide. In particular, the compounds according to Examples 2, 3, and 7 of the cephalosporin derivatives of the present invention showed significantly superior antimicrobial activity to Staphylococcus and a similar activity to cepirom. For Pseudomonas , the compound of Example 7 showed similar antimicrobial activity to that of the control group.

Standard strain ¹ CAZ ² CPR ³ Compound of Example 1 Compound of Example 2 Compound of Example 3 Compound of Example 7 S. aureus SG 511 6.25 0.39 3.13 0.78 0.78 0.78 S. aureus 209 P 25 1.56 12.5 1.56 1.56 3.13 S. aureus 285 6.25 0.39 3.13 0.78 0.78 0.78 S. aureus 5031 3.13 0.2 3.13 0.39 0.39 0.78 S. aureus smith 12.5 0.78 12.5 1.56 1.56 1.56 E. coli TEM 0.1 ≤0.025 0.39 0.39 0.1 0.05 E. coli DC 0 3.13 ≤0.025 0.39 0.05 0.05 0.05 P. aeruginosa A9027 1.56 1.56 > 100 12.5 25 3.13 P. aeruginosa 1592 E 0.78 3.13 > 100 50 12.5 12.5 P. aeruginosa 1771 0.78 1.56 > 100 50 12.5 6.25 P. aeruginosa 1771 M 0.1 1.56 6.25 50 3.13 6.25 P. aeruginosa 93 0.78 0.39 100 6.25 12.5 0.39 P. aeruginosa PAO 1 0.78 3.13 > 100 25 12.5 12.5 K. pneumoniae A0031 0.1 1.56 0.2 50 0.05 6.25 K. pneumoniae A9977 0.1 ≤0.025 0.78 0.05 0.1 ≤0.025 K. pneumoniae 477 0.05 ≤0.025 0.1 0.78 0.05 0.05 K. pneumoniae 01 0.1 ≤0.025 0.78 0.05 0.1 ≤0.025 K. pneumoniae 020 1.56 ≤0.025 12.5 0.78 3.13 0.1 P *. irabilis A 14273 0.05 0.2 0.78 6.25 0.2 3.13 P *. mirabilis 112/3 0.1 0.1 0.78 1.56 0.78 0.1 P *. mirabilis 174/3 0.05 0.2 0.39 6.25 0.1 0.78 P *. mirabilis 4 0.05 0.05 0.78 0.39 0.39 0.1 P *. vulgaris 867 0.05 0.05 0.78 1.56 0.39 0.2 P *. vulgaris 868 ≤0.025 0.05 0.2 1.56 0.05 0.2 P *. vulgaris 5 0.05 ≤0.025 1.56 0.2 1.56 ≤0.025 E *. cloacae ≤0.025 0.2 0.2 1.56 ≤0.025 0.1 E *. cloacae 417 ≤0.025 ≤0.025 0.2 0.1 ≤0.025 ≤0.025 E *. cloacae P 99 100 ≤0.025 100 0.2 12.5 ≤0.025 E *. cloacae 1321 E ≤0.025 3.13 0.2 12.5 ≤0.025 50 C. freundii A 9090 0.1 ≤0.025 0.2 0.1 ≤0.025 0.05 S *. marcescens 370 0.2 ≤0.025 1.56 0.05 0.2 0.2 S *. marcescens A 217 0.2 0.05 1.56 1.56 0.2 0.39 S *. marcescens A 216 0.2 0.05 0.78 1.56 0.1 0.39 1. S .; Staphylococcus, E .; Escherichia, P .; Pseudomonas, K .; Klebsiella, P * .; Proteus, E * .; Enterobacter, C .; Chlamydia .; S * .; Serratia 2. Ceftazidime 3. Cefpirome

Experimental Example 2 Oral Acute Toxicity Test in Rats

Acute toxicity tests were performed on the compounds according to Examples 1, 2, 3, and 7 of the present invention using a 6-week-old male SPF Sprague-Dawley rat. Five animals per group were suspended orally at a dose of 2 g / kg / 10ml, with each compound suspended in 0.5% methylcellulose solution. Hemorrhage, clinical symptoms, and body weight were examined for 2 weeks after administration of the test substance. Hematological and hematological and biochemical tests were performed, and necropsy was observed visually for abdominal and thoracic organ abnormalities.

As a result, no significant clinical symptoms or dead animals were noted in all animals treated with the test substance, and no toxic changes were observed in weight changes, blood tests, blood biochemical tests, and autopsy findings. In the above results, the minimum dose of single oral dose to the rats of the compound of the present invention was found to be more than 2g / kg.

As described above, the cephalosporin derivative represented by Formula 1 of the present invention, having a quaternized hetero compound, exhibits strong antimicrobial activity against both Gram-positive bacteria and Gram-negative bacteria, and is excellent against Pseudomonas aeruginosa and Staphylococcus aureus. In addition to showing activity, as a result of acute toxicity test, it is a very stable compound and can be usefully used as an antibacterial agent.

Claims (6)

Sepharoseporin derivative represented by the following formula (1) and pharmaceutically acceptable salts thereof. Formula 1 Where X is C or N, R is Or an alkyl group. The compound of claim 1, wherein X is C and R is Separosporin derivative represented by the formula (1), and a pharmaceutically acceptable salt thereof, characterized in that The cephalosporin derivative represented by the formula (1) according to claim 1, wherein X is N and R is an alkyl group, and a pharmaceutically acceptable salt thereof. The compound of claim 1 wherein 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [3- (4-methylisoxazol-2-yl) -1-pyridino] Methyl-3-cefe-4-carboxylate, 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [3- (3,4-cyclohexylisoxazol-2-yl) -1- Pyridino] methyl-3-cepem-4-carboxylate, 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [3- (3,4-cyclopentylisoxazol-2-yl) -1- Pyridino] methyl-3-cepem-4-carboxylate, 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [4- (4-methylisoxazol-2-yl) -1-pyridino] Methyl-3-cefe-4-carboxylate, 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [4- (3,4-cyclohexylisoxazol-2-yl) -1- Pyridino] methyl-3-cepem-4-carboxylate, 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [4- (3,4-cyclopentylisoxazol-2-yl) -1- Pyridino] methyl-3-cepem-4-carboxylate, or 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [3-methyl-2-pyridazino] methyl-3-cepem-4-car Sepharoseporin derivative represented by the formula (1) characterized in that it is a carboxylate and pharmaceutically acceptable salts thereof. A method for producing the cephalosporin derivative according to claim 1, prepared by reacting cephataxime with pyridin or pyridazine substituted with R in the presence of a nucleophile. Scheme 1 (R and X are as defined above.) A pharmaceutical composition for an antimicrobial agent, comprising the cephalosporin derivative of claim 1 or a pharmaceutically acceptable salt thereof.