KR0157074B1 - Cephalosporin derivatives and processes for the preparation thereof - Google Patents

Abstract

The present invention relates to novel cephalosporin derivatives or pharmaceutically acceptable non-toxic salts thereof useful as antibiotics and methods for their preparation.

The structure of the novel cephalosporin derivative of the present invention is as follows.

Wherein R ¹ is C _1-3 alkyl, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ is hydrogen, C _1-3 alkyl, halogen, C _1-3 hydroxyalkyl, or C _{1- 3} hydroxyalkylthio and Q is N or CCl.

Description

Cephalosporin derivatives and preparation methods thereof

The present invention relates to cephalosporin derivatives and methods for their preparation, and more particularly to novel cephalosporin derivatives or pharmaceutically acceptable non-toxic salts thereof useful as antibiotics and methods for their preparation.

Cephalosporin antibiotics have been widely used as antibiotics in mammals including humans, and various studies have been extensively conducted to increase the effectiveness and stability thereof, and various cephalosporin antibiotics have been published in many publications. Particularly, representative examples of these known cephalosporin antibiotics are Cytoxime, which is disclosed in German Patent No. 2,702,501 and the like, and in addition, a quaternary ammoniomethyl group or 2- (2-aminothiazol-4-yl in 3-position. Various cephalosporin-based derivatives having a) -2-hydroxy (or substituted hydroxy) iminoacetamido group have been synthesized and patented. For example, ceftazidime is disclosed in German Patent No. 2,921,316 and the like.

Among these conventional cephalosporin antibiotics, ceftazidime shows excellent antimicrobial activity against Gram-negative bacteria containing Pseudomonas aeruginosa, but is relatively resistant to Gram-positive bacteria containing Staphylococcus. Inferior antimicrobial activity. On the other hand, Cytoxim has superior antibacterial activity to Gram-positive bacteria Staphylococcus than ceftazidime, but inferior to Gram-negative bacteria Pseudomonas aeruginosa.

Accordingly, the present inventors have intensively studied to develop cephalosporin-based antibiotics having more improved properties. As a result, a pyrrolo [1,2-a] pyraziniomethyl group optionally substituted at the 3-position of the cephalosporin-based compound has been studied. And cephalosporin derivatives having several acyl amido groups in the 7-position at the same time for Pseudomonas aeruginosa and Staphylococcus, as well as most pathogens belonging to the genus Escherichia coli, Serratia, Enterobacta and Proteus. The present invention has been completed by discovering a strong antimicrobial action.

In particular, most of the compounds having a nitrogen-containing aromatic heterocycle in the 3-position quaternary ammoniomethyl group in the conventional cephalosporin-based antibiotics have a compound having a monocycline pyridinium group with or without a substituent in its ring. The compound of the present invention containing a pyrrolo [1,2-a] pyrazinium group forming a condensed ring at the 3,4-position is not described in any patent application, nor is its synthesis described.

In other words, an object of the present invention is to provide a novel cephalosporin derivative or a pharmaceutically acceptable non-toxic salt thereof exhibiting strong antibacterial activity against a wide range of pathogens, and an object of the present invention is to provide a method for preparing such a compound, Providing a pharmaceutical composition containing as a component.

The present invention is described in detail as follows.

The present invention includes providing a cephalosporin derivative represented by the following general formula (I) or a pharmaceutically acceptable non-toxic salt thereof.

Wherein R ¹ is C _1-3 alkyl, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ is hydrogen, C _1-3 alkyl, halogen, C _1-3 hydroxy alkyl, or C _{1- 3} hydroxyalkylthio and Q is N or CCl.

Examples of preferred compounds having particularly high antimicrobial activity among the compounds of the present invention include the compounds exemplified below and non-toxic salts thereof, as shown in Table 1 below.

The compound of the present invention represented by general formula (I) contains an oxyimino group. Therefore, the compounds of the present invention represented by general formula (I) are the geometric isomers, the syn- and anti-isomers containing at least 90% of the syn- or syn-isomers. It contains a mixture of.

In addition, the compound of the present invention represented by general formula (I) contains a 5-amino-1,2,4-thiadiazol-3-yl group or a 2-amino-5-chlorothiazol-4-yl group, These moieties can form a tautomer with a 5-imino-1,2,4-thiadiazolin-3-yl group or a 2-amino-5-chlorothiazolin-4-yl group as follows. Representative structures may be interchanged with each other and thus considered to be identical to each other.

Partial structures in the specification and claims of the present invention are shown as one of the following tautomers having the following partial structure for convenience, and the present invention is not limited thereto.

In addition, the compound of the present invention represented by general formula (I) includes a pyrrolo [1,2-a] pyrazinium-2-yl group optionally substituted at the 3-position. Therefore, the positive charge is put into the nitrogen atom at the 1-position of pyrazine for convenience, but the quaternary nitrogen of the pyrrolo [1,2-a] pyrazinium-2-yl group is the nitrogen atom at the 4-position of pyrazine. The monovalent positive charge may be delocalized to the pyrazine ring or even to the total condensed ring. Therefore, the following structures can be regarded as the same as each other.

Pharmaceutically acceptable non-toxic salts of the compounds of the present invention represented by general formula (I) may include inorganic acid salts, organic acid salts, and the like.

: Inorganic acid salts such as hydrochloric acid, bromic acid, phosphoric acid, sulfuric acid or acetic acid, trifluoroacetic acid, citric acid, formic acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, maldenic acid, ascorbic acid, methanesulfonic acid, benzene Organic carboxylic acids or sulfonic acid salts such as sulfonic acid, p-toluenesulfonic acid

In addition, it includes acid addition salts commonly used in the art of penicillin and cephalosporin-based antibiotics. These acid addition salts can be prepared by conventional techniques.

In addition, the compound of the present invention represented by the general formula (I) can also form a non-toxic salt with a base according to the R ¹ group, in which bases that can be used include alkali metal hydroxides (for example, caustic soda, caustic, etc.). And inorganic bases such as alkaline earth metal hydroxides (eg, calcium hydroxide), sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, or calcium carbonate, and organic bases such as amino acids.

The compounds of the present invention represented by general formula (I) may form a pharmaceutical composition together with known pharmaceutical carriers or excipients, which may be formulated by known methods. The compounds of the invention may also be formulated in the form of solutions, suspensions or emulsifiers in oils or aqueous media and may contain conventional dispersing agents, suspending agents or stabilizers. In addition, the compounds of the present invention may be in the form of dry powder which is reconstituted before use with sterile, pyrogen-free water, or may be formulated into suppositories using conventional suppository bases such as cocoa butter or other glycerides. . If desired, the compounds of the present invention may be administered in combination with penicillin or other antibacterial agents such as cephalosporin antibiotics other than the compounds of the present invention.

The compound of the present invention may be administered 1-50 mg / day, more preferably 1-20 mg / day, per 1 kg of body weight of humans and animals infected with various Gram-positive and Gram-negative bacteria, in unit dosage form or in multi-dose containers. It may be heard.

The present invention includes providing a method for producing a compound represented by the general formula (I). The compound of the present invention represented by general formula (I) can be prepared by the production method described below.

In the above process, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as defined above, X is iodine, bromine or chlorine and Z ¹ is hydrogen or protecting group for amino group . Examples of protecting groups for amino groups include acyl, substituted or unsubstituted aromatic (lower) alkyl (e.g., benzyl, diphenylmethyl, triphenylmethyl, 4-methoxybenzyl, etc.), halo (lower) alkyl (trichloromethyl , Trichloroethyl and the like), tetra hydropyranyl, substituted phenylthio, substituted alkylidene, substituted aralkylidene, substituted cycloidene and the like and conventional aminoprotecting groups.

When the double acyl is used as an amino protecting group, it may be an aliphatic acyl group or an acyl group having an aromatic or heterocycle. Examples of such acyl groups include C _1-6 lower alkanoyls (eg formyl, acetyl, etc.), C _2-6 alkoxycarbonyls (eg methoxycarbonyl, ethoxy carbonyl, etc.), lower alkanesul Ponyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), arenesulfonyl (e.g. benzenesulfonyl, p-toluenesulfonyl, etc.), ar (lower) alkanoyl (e.g., phenylacetyl, etc.) or ar (lower) Alkoxycarbonyl (for example, benzyloxycarbonyl, etc.) etc. are mentioned, The acyl group mentioned above may have 1-3 suitable substituents, such as halogen, hydroxy, cyano, nitro. In addition to the above, the reaction product of the silane, boron, phosphorus compound and amino group may also be an amino protecting group.

The amino protecting group as described above can be easily removed under mild reaction conditions such as hydrolysis or reduction to form a free amino group, and can be appropriately selected and used according to the chemical properties of the compound of formula (I).

The method for preparing a compound represented by the general formula (I) of the present invention includes a condensation reaction and a removal of a protecting group as described in the reaction scheme, and each of these reactions is described in detail as follows.

Condensation reaction

The condensation reaction between the compound of formula (II) and the compound of formula (III) is inert in the presence of N, O-bis (trimethylsilyl) acetamide, triethylamine, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate and the like. The compound of formula (IV) can be obtained by reacting a reactive derivative of the compound of formula (III) in a solvent (eg, ethyl acetate, acetonitrile, dichloromethane, etc.). The reaction can be carried out at about -50 to about 50 ° C.

The reactive derivative of the compound of formula (III) used in this condensation reaction is treated with a compound of formula (III) with phosphorus pentachloride, thionyl chloride, oxalyl chloride, or the compound of formula (III) N It can be prepared by treating with N-dimethylformamide, Vilsmeirreagent prepared from phosphorus oxychloride or oxalyl chloride. In addition, one of the reactive derivatives of the compound of the general formula (III) is a common condensation reagent for the compound of the general formula (III) under an organic solvent (N, N, -dimethylformamide, dichloromethane, tetrahydrofuran, acetonitrile) It can be used to make an activator produced by reacting with N-hydroxybenzotriazole or benzthiazyl disulfide and the like.

Removal reaction of protection group

The reaction to remove the protecting group from general formula (IV) can be carried out with an inorganic acid (e.g. hydrochloric acid), an organic acid (e.g. formic acid or trifluoroacetic acid) or mixtures thereof, or a scavenger ( For example, in the presence of anisole or thioanisole), the desired compound of formula (1) can be obtained. The reaction can be carried out at about 0 ° C to about 50 ° C, preferably at 15 ° C to 30 ° C for 30 minutes to 2 hours.

The compounds of the present invention represented by general formula (I) show high antimicrobial activity against various Gram-positive and Gram-negative bacteria, and can be used for the purpose of prevention and treatment of bacterial infection in animals including humans. In particular, the compound of the present invention represented by the general formula (I) has a broad antibacterial spectrum, as can be seen in the following test example, against various Gram-negative bacteria and Gram-positive bacteria including Pseudomonas aeruginosa Excellent antimicrobial activity.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples. However, the present invention is not limited thereto.

Reference Example 1

Preparation of 7-amino-3- (pyrrolo [1,2-a] pyrazinium-2-yl) methyl-3-cepem-4-carboxylate HI

Step 1: Preparation of 2-pyrrolealdehydeaminoacetal

Toluene (100 ml) was added to 2-pyrrolecarboxaldehyde (24 g) and amino acetaldehyde dimethylacetal (40.5 ml). The reaction solution was refluxed for 2 hours using a Dean-Stark apparatus, the solvent was concentrated under reduced pressure, and then vacuum distilled to obtain the title compound (45 g) as a pale yellow liquid.

Step 2: Preparation of Pyrrolo [1,2-a] pyrazine

2-pyrrolealdehydeaminoacetal (20 g) prepared in step 1 was dissolved in cyclohexane (20 ml) and added to polyphosphoric acid (150 g) in which phosphorus oxychloride was dissolved. The reaction solution was stirred at 120 ° C. for 20 minutes, then poured into 1,500 ml of ice water and washed with benzene. The aqueous layer was adjusted to pH = 7.5 to 8.0 and then extracted with benzene (500 ml x 3). The organic layer was washed with water and saturated brine and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (5.3 g) in light yellow color.

Step 3. Preparation of 7-Amino-3- (pyrrolo [1,2-a] pyrazinium-2-yl) methyl-3-cepem-4-carboxylate.HI

7-amino-3-iodinemethyl-3-cepem-4-carboxylate (2.5 g) was suspended in acetonitrile (30 ml), followed by dissolution by addition of bistrimethylsilylacetamide (2 ml). Pyrrolo [1,2-a] pyrazine (2 g) prepared in step 1 was added to the reaction solution. The reaction solution was reacted at 10 ° C. for 1 hour and then cooled to 0 ° C. After adding 0.6 ml of water, the resulting solid was filtered and washed with cold acetonitrile (30 ml) to give a pale yellow title compound (2.4 g).

Reference Example 2

Preparation of 7-amino-3- [6- (hydroxymethyl) pyrrolo [1,2-a] pyrazinium-2-yl] methyl-3-cepem-4-carboxylate.HI

Step 1: Preparation of 6- (hydroxymethyl) pyrrolo [1,2-a] pyrazine

Pyrrolo [1,2-a] pyrazine (2.5 g) prepared in step 2 of Reference Example 1 was suspended in 20 ml of water and 5 ml of concentrated hydrochloric acid was added at room temperature. 7 ml of formalin (36%) was added dropwise to the reaction solution at 80 ° C. for 2 hours. The reaction solution was cooled to room temperature, neutralized with 10% caustic soda solution, and extracted with ethyl acetate (20 ml x 3). The organic layer was separated, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.5 g of the title compound and 1.0 g of 6- (hydroxymethyl) pyrrolo [1,2-a] pyrazine. Yield: 15.8%

Step 2: Preparation of 7-amino-3- [6- (hydroxymethyl) pyrrolo [1,2-a] pyrazinium-2-yl] methyl-3-cepem-4-carboxylate.HI

The title compound was prepared in the same manner as in Step 3 of Reference Example 1, using 6- (hydroxymethyl) pyrrolo [1,2-a] pyrazine prepared in Step 1.

Reference Example 3

Preparation of 7-amino-3- [8- (1-hydroxyethyl) pyrrolo [1,2-a] pyrazinium-2-yl] methyl-3-cepem-4-carboxylate.HI

Step 1: Preparation of 8-acetylpyrrolo [1,2-a] pyrazine

20 g of pyrrolo [1,2-a] pyrazine prepared in Step 2 of Reference Example 1 was dissolved in 200 ml of 1,2-dichloroethane and 4 g of aluminum trichloride was added. 24 ml of acetyl chloride was added dropwise to the reaction solution, followed by stirring at 40 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was poured into 100 ml of water and neutralized with 10% caustic soda solution. After extracting with ethyl acetate (50ml x 3), the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 5 g of 8-acetylpyrrolo [1,2-a] pyrazine.

Step 2: Preparation of 8- (1-hydroxyethyl) pyrrolo [1,2-a] pyrazine

To 2.2 g of 8-acetylpyrrolo [1,2-a] pyrazine obtained in step 1, 40 ml of water and 2 g of sodium borohydride were added. After reacting at 50 ° C. for 2 hours, the reaction solution was cooled to room temperature and neutralized with 10% hydrochloric acid solution. After extraction with ethyl acetate (30ml x 3), the organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1 g of the title compound.

Step 3: 7-Amino-3- [8- (1-hydroxyethyl) pyrrolo [1,2-a] pyrazinium-2-yl] methyl-3-cepem-4-carboxylate. Produce

The title compound was prepared in the same manner as in Step 3 of Reference Example 1, using 8- (hydroxyethyl) pyrrolo [1,2-a] pyrazine prepared in Step 2.

Reference Example 4

Preparation of 7-amino-3- [6- (2-hydroxyethylthio) pyrrolo [1,2-a] pyrazinium-2-yl] methyl-3-cepem-4-carboxylate HI

Step 1: Preparation of 6-bromopyrrolo [1,2-a] pyrazine

Pyrrolo [1,2-a] pyrazine (2.6 g) obtained in Step 2 of Reference Example 1 was dissolved in ethyl acetate and cooled to 0 ° C. N-bromosuccinimide (3.9 g) was added to the reaction solution and stirred for 30 minutes. The reaction was poured into water, extracted with ethyl acetate, dehydrated and concentrated to obtain 2.0 g of the title compound.

Step 2: Preparation of 6- (2-hydroxyethylthio) pyrrolo [1.2-a] pyrazine

6-bromopyrrolo [1,2-a] pyrazine (2.5 g) obtained in step 1 was dissolved in acetonitrile (30 ml) and 2-mercaptoethanol (1 ml) was added. The reaction solution was refluxed for 12 hours, cooled to room temperature, poured into ice water, and extracted with ethyl acetate. The organic layer was dehydrated and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1 g).

Step 3: of 7-amino-3- [6- (2-hydroxyethylthio) pyrrolo [1,2-a] pyrazinium-2-yl] methyl-3-cepem-4-carboxylate HI Produce

The title compound was prepared in the same manner as in Step 3 of Reference Example 1, using 6- (2-hydroxyethylthio) pyrrolopyrazine prepared in Step 2.

Reference Example 5

Preparation of 7-amino-3- [8- (hydroxymethyl) pyrrolo [1,2-a] pyrazinium-2-yl] methyl-3-cepem-4-carboxylate.HI

The title compound was prepared in the same manner as in Step 3 of Reference Example 1, using 8- (hydroxymethyl) pyrrolo [1,2-a] pyrazine obtained in Step 1 of Reference Example 2.

Reference Example 6

Preparation of 7-amino-3- (1-methylpyrrolo [1,2-a] pyrazinium-2-yl) methyl-3-cepem-4-carboxylate.HI

Step 1: Preparation of 1-methylpyrrolo [1,2-a] pyrazine

The title compound was prepared in the same manner using 2-acetylpyrrole instead of 2-pyrrolecarboxaldehyde in the reaction of Steps 1 and 2 of Reference Example 1.

Step 2: Preparation of 7-amino-3- (1-methylpyrrolo [1,2-a] pyrazinium-2-yl) methyl-3-cepem-4-carboxylate.HI

The title compound was prepared in the same manner as in Step 3 of Reference Example 1, using 1-methylpyrrolo [1,2-a] pyrazine prepared in Step 1.

Reference Example 7

Preparation of 7-amino-3- (6-hydroxy-1-methylpyrrolo [1,2-a] pyrazinium-2-yl) methyl-3-cepem-4-carboxylate.HI

Step 1: Preparation of 6-hydroxy-1-methylpyrrolo [1,2-a] pyrazine

1-methylpyrrolo [1,2-a] pyrazine (3 g, 22.7 mmol) was dissolved in 15 ml of water and 35 ml of c-HCl under ice water cooling.

The temperature of this solution was heated to 70 ° C. and formalin (60 ml) was added dropwise for 40 minutes. The reaction solution was further stirred at 75 ° C. for 30 minutes, cooled, neutralized with NaOH solution, NaHCO ₃ , and solution to pH 8.0. Extracted with ethyl acetate (100 ml x 3), dehydrated with anhydrous MgSO ₄ and concentrated. The residue was purified by silica gel column chromatography to obtain 1.8 g of the title compound (yield: 48.9%).

Step 2: Preparation of 7-amino-3- (6-hydroxy-1-methylpyrrolo [1,2-a] pyrazinium-2-yl) methyl-3-cepem-4-carboxylate.HI

3-Udomethylcefem (2.0 g, 5.89 mmol) was suspended in 25 ml of acetonitrile and dissolved in 2.2 ml of N, O-bistrimethylsilylacetamide. While the solution was cooled to 0 ° C., a solution of 6-hydroxy-1-methylpyrrolo [1,2-a] pyrazine (1.0 g, 6.16 mmol) in 10 ml of acetonitrile and 0.5 ml of BSA was mixed for 20 minutes. I dropped it. The reaction solution was stirred at the same temperature for 30 minutes, 2 ml of methanol was added, and the resultant precipitate was collected by filtration for 20 minutes. The precipitate was collected by filtration and washed with acetone to obtain the title compound (2.1 g, 71%).

Reference Example 8

Preparation of 7-amino-3- (6-bromo-1-methylpyrrolo [1,2-a] pyrazinium-2-yl) methyl-3-cepem-4-carboxylate.HI

Step 1: Preparation of 6-bromo-1-methylpyrrolo [1,2-a] pyrazine

1-methylpyrrolo [1,2-a] pyrazine (3.5 g) prepared in step 1 of Reference Example 3 was dissolved in dimethyl sulfoxide (20 ml) and ethyl acetate (20 ml), and N-bromosuccinimide (4.8). g) was added. The reaction solution was stirred at 0 ° C. for 1 hour. The reaction solution was poured into water, extracted with ethyl acetate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (1.3 g).

Step 2: Preparation of 7-amino-3- (6-bromo-1-methylpyrrolo [1,2-a] pyrazinium-2-yl) methyl-3-cepem-4-carboxylate.HI

The title compound was obtained in the same manner as the Reference Example 2 using 6-bromo-1-methylpyrrolo [1,2-a] pyrazine obtained in Step 1.

Example 1

7β-[(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (methoxyimino) acetamido] -3- (pyrrolo [1,2-a] pyra Preparation of Genium-2-yl) methyl-3-cepem-4-carboxylate

0.5 g of 7-amino-3- (pyrrolo [1,2-a] pyrazinium-2-yl) methyl-3-cepem-4-carboxylate prepared in Step 3 of Reference Example 1 was dissolved in 3% bicarbonate. It was dissolved in aqueous sodium solution (20 ml) and acetonitrile (20 ml). 0.5 g of 2- (2-amino-5-chlorothiazol-4-yl) -2- (Z) -methoxyiminoacetic acid-N-hydroxybenzotriazole activator was added to the reaction solution, followed by 35 ° C. It stirred at the temperature for 3 hours. After cooling the reaction solution to room temperature, silica gel chromatography (eluate: acetonitrile / water: 4) was carried out, and the acetonitrile was concentrated under reduced pressure. The concentrated aqueous solution was lyophilized to obtain 0.1 g of the title compound.

Example 2

7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3-{(pyrrolo [1, 2-a] Pyrazinium-2-yl) methyl} -3-cepem-4-carboxylate

0.5 g of 7-amino-3-{(pyrrolo [1,2-a] pyrazinium-2-yl) methyl} -3-cepem-4-carboxylate prepared in step 3 of Reference Example 1 It was dissolved in% aqueous sodium bicarbonate solution (20 ml) and acetonitrile (20 ml). 0.45 g of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (Z) -methoxyiminoacetic acid-N-hydroxybenzotriazole activator was added to this reaction solution. It stirred at 35 degreeC temperature for 8 hours. After cooling the reaction solution to room temperature, silica gel chromatography (eluate: acetonitrile / water = 4) was carried out, and the acetonitrile was concentrated under reduced pressure. The concentrated aqueous solution was lyophilized to obtain 0.1 g of the title compound.

Example 3

7β-[(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2- (methoxyiminoacetamido] -3- (6-hydroxymethylpyrrolo [1, 2-a] Pyrazinium-2-yl) methyl} -methyl-3-cepem-4-carboxylate

The title compound was prepared in the same manner as in Example 1, using the Sepem intermediate prepared in Step 2 of Reference Example 2.

Example 4

7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyiminoacetamido] -3- (6-hydroxymethylpy Preparation of Lolo [1,2-a] pyrazinium-2-yl) methyl-3-cepem-4-carboxylate

The title compound was prepared in the same manner as in Example 2 using the cefem compound prepared in Step 2 of Reference Example 2.

Example 5

7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3-{[6- (1- Preparation of Hydroxyethyl) Pyrrolo [1,2-a] pyrazinium-2-yl] methyl} -3-cepem-4-carboxylate

The title compound was prepared in the same manner as in Example 2 using the cefem compound prepared in Step 2 of Reference Example 3.

Example 6

7β-[(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-methoxyiminoacetamido] 3- {6- (2-hydroxyethylthio) pyrrolo Preparation of [1,2-a] pyrazinium-2-yl] methyl} -3-cepem-4-carboxylate

The title compound was prepared in the same manner as in Example 1 using the cefem compound prepared in Step 2 of Reference Example 7.

Example 7

7β-[(Z) -2- (2-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] 3- (6- (2-hydroxyethyl Preparation of Thio) pyrrolo [l, 2-a] pyrazinium-2-yl] methyl) -3-cepem-4-carboxylate

The title compound was prepared in the same manner as in Example 2 using the cefe compound prepared in Step 2 of Reference Example 7.

Example 8

7β-[(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-methoxyiminoacetamido] 3- (8-hydroxymethylpyrrolo [1,2- a] Preparation of pyrazinium-2-yl) methyl-3-cepem-4-carboxylate

The title compound was prepared in the same manner as in Example 1 using the cefem compound prepared in Reference Example 5.

Example 9

7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] -3-{[8- (hydroxy Preparation of Methyl) pyrrolo [1,2-a] pyrazinium-2-yl] methyl} -3-cepem-4-carboxylate

The title compound was prepared in the same manner as in Example 2 using the cefem compound prepared in Reference Example 5.

Example 10

7β-[(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-methoxyiminoacetamido] 3- (1-methylpyrrolo [1,2-a] Preparation of Pyrazinium-2-yl) methyl-3-cepem-4-carboxylate

The title compound was prepared in the same manner as in Example 1, using the cefem compound prepared in Step 2 of Reference Example 6.

Example 11

7β-[(Z) -2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (methoxyimino) acetamido] 3-{(1-methylpyrrolo ( 1,2-a] pyrazinium-2-yl) methyl} -3-cepem-4-carboxylate

By using 7-amino-3-{(1-methylpyrrolo [1,2-a] pyrazinium-2-yl) methyl} -3-cepem-4-carboxylate prepared in Reference Example 3. The title compound was obtained in the same manner as in Example 1.

Example 12

7β-[(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-methoxyiminoacetamido] 3- (6-hydroxy-1-methylpyrrolo [1 Preparation of, 2-a] pyrazinium-2-yl) methyl-3-cepem-4-carboxylate

The title compound was prepared in the same manner as in Example 1, using the cefe compound prepared in Step 2 of Reference Example 7.

Example 13

7β-[(Z) -2- (2-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] 3- (6-bromo1-methylpy Preparation of Lolo [1,2-a] pyrazinium-2-ylmethyl-3-cepem-4-carboxylate

The title compound was prepared in the same manner as in Example 2 using the cefem compound prepared in Step 2 of Reference Example 8.

[Test Example (MIC Measurement Test)]

The results of obtaining the minimum growth inhibitory concentration (MIC) in vitro for ceftazidime and cell taksim as the compound prepared in Example and the comparative compound are shown in Table 2. Minimum growth inhibitory concentration (MIC) was measured by agar dilution using Mueller Hinton Agar medium (Difco, USA). The test bacteria were inoculated at 10 ⁶ CFU / ml and inoculated on the surface of the agar using a microplanter (Microplanter, Toyo, Japan), followed by cultivation at 35-37 ° C for 17 ± 1 hours and visually observed the growth of the bacteria. The minimum concentration at which growth was inhibited was defined as the minimum growth inhibition concentration (MIC). Ceftazidime (CAZ) and cytotaxime (CTX) structures used as comparative compounds are as follows.

Comparative Compound

As can be seen in Table 2, the compounds of the present invention show excellent antimicrobial activity compared to cephatasporidin-based cephalosporin-based compounds and cephataxime, which are widely known as broad-spectrum antibiotics. In addition, Gram-negative bacteria have excellent antibacterial activity of 2-4 times.

In addition, Pseudomonas aeruginosa, which causes serious problems in the human body, shows the same or superior antibacterial activity as ceftazidime, and thus it can be confirmed that it is a broad antibiotic having an excellent antibacterial activity of 2-4 times or more as a whole.

Acute Toxicity Test

1. Test Method

The test substance (compound of Example 1) was administered once intravenously to Crjy: CD-1 (ICR) male mice at a dose of 0, 2000 mg / kg to evaluate the safety of the test substance.

Clinical symptoms were observed daily for 7 days after the administration of the test substance and confirmed death twice a day during the observation period.

Body weights were measured immediately prior to administration of the test substance, 1 day, 3 days, 7 days from the test substance administration and just before necropsy.

The autopsy examined the surviving test system after the observation period, and observed in vitro and all body cavity, cranial cavity, brain and spinal cord surface, nasal and paranasal cavity, thoracic / abdominal / pelvic cavity and included organ and cervical organ.

LD was calculated using the Richfield-Wilcoxon method from the cumulative mortality rate during the observation period of the test system.

2. Test result

(1) Mortality and clinical symptoms

There were no deaths in either group. Clinical symptoms were found to be symptom of ataxia, lethargy, dyspnea and convulsions in all subjects of the 2000 mg / kg group.

(2) weight change

Compared with the control group who lost weight until 1 day after the administration and then recovered, the 2000 mg / kg administration group showed significant weight loss on the 3rd day after administration but recovered after the administration.

(3) autopsy findings

As a result of autopsy of the surviving subjects, hepatic pale was observed in one case of the 2000 mg / kg administration group, but it was a common change in the control group at the time of necropsy.

(4) LD

Considering that all individuals in the 2000 mg / kg administration group survived, it is determined that the heaviest lethal dose (LD) is 2000 mg / kg or more.

Claims (9)

A cephalosporin derivative represented by the following general formula (l) or a pharmaceutically acceptable non-toxic salt thereof. Wherein R ¹ is C _1-3 alkyl, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ is hydrogen, C _1-3 alkyl, halogen, C _1-3 hydroxy alkyl, or C _{1- 3} hydroxyalkylthio and Q is N or CCl. The compound of claim 1, wherein in the compound represented by formula (I), R ¹ is methyl, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ are hydrogen, and Q is N or CCl. A cephalosporin derivative or a pharmaceutically acceptable non-toxic salt thereof. The compound represented by the formula (I) according to claim 1, wherein R ¹ is methyl, R ² , R ³ , R ⁴ , R ⁶ , R ⁷ is hydrogen, and R ⁵ is C _1-3 hydroxyalkyl And Q is N or CCl, or a cephalosporin derivative or a pharmaceutically acceptable non-toxic salt thereof. The compound represented by the formula (I) according to claim 1, wherein R ¹ is methyl, R ₂ , R ₃ , R ₄ , R ₆ , R ₇ is hydrogen, and R ⁵ is C _1-3 hydroxyalkyl A cephalosporin derivative or a pharmaceutically acceptable non-toxic salt thereof, wherein the compound is thio and Q is N or CCl. The compound represented by the formula (I) according to claim 1, wherein R ¹ is methyl, R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ is hydrogen, and R ³ is C _1-3 hydroxyalkyl And Q is N or CCl, or a cephalosporin derivative or a pharmaceutically acceptable non-toxic salt thereof. The compound of claim 1, wherein in the compound represented by formula (I), R ¹ , R ² are methyl, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ are hydrogen, and Q is N or CCl. A cephalosporin derivative or a pharmaceutically acceptable non-toxic salt thereof. The compound of formula (I) according to claim 1, wherein in the compound represented by formula (I), R ¹ , R ² are methyl, R ³ , R ⁴ , R ⁶ , R ⁷ are hydrogen, and R ⁵ is C _1-3 hydroxyalkyl Or a pharmaceutically acceptable non-toxic salt thereof, wherein the cephalosporin derivative is or is halogen and Q is N or CCl. A method for producing a compound represented by the following general formula (I), comprising reacting a compound represented by the following general formula (II) with a compound represented by the following general formula (III). Wherein R ¹ is C _1-3 alkyl, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ is hydrogen, C _1-3 alkyl, halogen, C _1-3 hydroxyalkyl, or C _{1- 3} hydroxyalkylthio, Q is N, or CCl, and Z ¹ is hydrogen or a protecting group for an amino group. An antimicrobial composition comprising the cephalosporin derivative represented by the following general formula (I) or a pharmaceutically acceptable non-toxic salt thereof and a pharmaceutically acceptable carrier. Wherein R ¹ is C _1-3 alkyl, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ is hydrogen, C _1-3 alkyl, halogen, C _1-3 hydroxyalkyl, or C _{1- 3} hydroxyalkylthio and Q is N or CCl.